Displaying One Session

Poster Fri, Sep 11, 2020
Session Type
Poster
Date
Fri, Sep 11, 2020
Biostatistical Methods Poster Presentation

P0001 - A new software and analysis suite for experimental autoimmune encephalomyelitis (ID 831)

Speakers
Presentation Number
P0001
Presentation Topic
Biostatistical Methods

Abstract

Background

Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used multiple sclerosis animal model. In this model, animals develop an autoimmune inflammatory immune response to myelin protein leading to the development of ascending paralysis. The degree of motor dysfunction is scored daily and used as a metric of disease progression referred to as EAE disease score. Despite the common use of EAE animal models, there is still a large degree of heterogeneity in the field on EAE disease score data presentation and statistical assessment, making it challenging to compare results across studies.

Objectives

In an effort to standardize EAE disease score assessment, our objective was to develop an easy to use web-based application and associated package that provides researchers with a user interface for graphing and conducting statistical analysis of their data.

Methods

Using the programming language R, a shiny based application was developed to provide users with an interface to process their EAE data. For statistical testing, the application was flexibly designed to allow for parametric and non-parametric testing paradigms in addition to a number of different p-value correction methods.

Results

Our application uses a multifaceted analysis including EAE score curves (graphing EAE disease scores by group over time), area under the curve, Poisson modeling of frequency of days over a score threshold, and hierarchical clustering with a unique option of aligning animals by the day of disease onset. With this tool, researchers can quickly analyze their EAE data without code from the user while still maintaining a wide degree of flexibility in graphic and models parameters.

Conclusions

We have developed an application and an accompanying package that can be used quickly and easily to generate results for EAE disease score analysis. In the application, a user-friendly interface designed specifically for EAE models helps researchers assess their data by auto-generating graphs and statistical tests in a fast reproducible manner. We hope that this application and its analyses will assist researchers while initiating discussion and moving towards a field standard of EAE data presentation and analysis.

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Machine Learning/Network Science Poster Presentation

P0002 - Applying machine learning to multimodal neuroimaging data to predict visual episodic memory performance in multiple sclerosis  (ID 1530)

Speakers
Presentation Number
P0002
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Episodic memory (EM) impairment is common in MS. The thalamus, hippocampus, fornix and cingulum are important hubs in the Papez circuit involved in EM processing. The extent to which MS-related early structural and functional changes in these regions relate to visual EM is not known.

Objectives

To build a brain model which represents multimodal MRI measures mostly associated with visual EM processing in early MS using a machine learning approach (Elastic Net-EN).

Methods

A computerized nonverbal test of visual episodic memory (CANTAB Paired Associate Learning-PAL) was administered to 180 MS patients (RADIEMS cohort: 162 relapsing remitting, 18 clinically isolated syndrome, 123 female, mean age = 34.4 ± 7.5, mean years since diagnosis = 2.1 ± 1.4, mean premorbid intelligence = 108.3 ± 8.8). Raw scores of first trial memory were selected for statistical assessment. Neuroimaging data were acquired via a 3T MRI scanner. Lesion load over 12 regions across the brain, volume of bilateral 12 hippocampal subfields, 25 thalamic nuclei, functional and structural connectivity (assessed by fractional anisotropy and mean diffusivity) between bilateral subiculum of hippocampus and anterior thalamic nuclei and structural connectivity of fornix and cingulum were used to build a model predicting EM. Age, sex, IQ and EDSS scores were also included in the model. Five-fold cross-validation was used to train and test the model with 50 repetitions. Pearson’s correlation (r) was used to assess the univariate relationships between the continuous variables and model’s prediction accuracy.

Results

PAL test score was positively correlated with IQ (r = 0.24, p < 0.05), and negatively correlated with age and EDSS score (r = -0.25 and r = -0.23, p < 0.05). The correlation between the model’s predicted memory and actual memory scores was 0.26 ± 0.14, indicating moderate performance similar to pevious literature predicting cognitive scores from imaging variables. The most important MRI predictors of better memory were right hippocampus molecular layer and right thalamus parataenial nucleus volume, functional connectivity between left thalamus anteroventral nuclei and left hippocampus subiculum, left thalamus medial pulvinar and right hippocampus CA4 volume and lesion load in medulla and limbic lobe.

Conclusions

Atrophy and lesions in select regions of Papez Circuit are important imaging predictors of memory in early MS. A next essential step to understanding disease-specificity of these findings is comparison to matched health controls.

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Machine Learning/Network Science Poster Presentation

P0003 - Combinatorial Genetic Interaction Analysis of Multiple Sclerosis Risk Variants (ID 1040)

Speakers
Authors
Presentation Number
P0003
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Common genetic variation within the major histocompatibility complex (MHC), primarily HLA-DRB1*15:01 and HLA-A*02:01, and 200 non-MHC variants contribute to MS risk. It is unknown if specific combinations of these risk variants disproportionately confer elevated risk, as interactions between risk variants have not been extensively studied.

Objectives

To identify if there are specific combinations of risk variants that disproportionately confer increased MS risk using a novel machine learning approach.

Methods

We applied association rule mining (ARM), a combinatorial rule-based machine learning algorithm, to data from non-Hispanic white MS cases (N=207) and controls (N=179). The genetic data consisted of HLA-DRB1*15:01, HLA-A*02:01, and 200 non-MHC risk variants assuming a dominant model. We identified patterns (rules) of 2 to 5 risk variants that were enriched in MS cases compared to controls. Probabilistic measures (confidence and support) evaluated the strength of rules. Odds ratios (ORs), 95% bias corrected confidence intervals (CIs), and permutation p-values obtained from bootstrapped logistic regression models adjusted for genetic ancestry. A Bonferroni approach adjusted for multiple testing. Hahsler and Karpienko’s grouped matrix method identified rules with similar characteristics.

Results

122 rules met minimum requirements of 80% confidence and 5% support. 3 rules met the Bonferroni threshold for significance, and all consisted of 3 variants. The top 3 rules were: 1. HLA-DRB1*15:01, SLC30A7-rs56678847 and rs6880909– carriers of these variants had 20.2-fold increased odds of MS (95% CI: (8.5, 37.5); p=4x10-9); 2. HLA-DRB1*15:01, ADCY3-rs11125803, and rs13327021 (OR: 6.8, 95% CI: (3.1, 20.9); p=0.0001); and 3. HLA-DRB1*15:01, rs13327021, and LOC105375752-rs735542 (OR: 4.9, 95% CI: (2.4, 12.0); p=0.0002). Interestingly, several variants were shared across several of the 122 rules. In particular, INTS8-rs78727559 was present in 34% of top rules and TNIP3-rs17051321 was present in 32% of top rules. HLA-DRB1*15:01, rs35486093, and SLC30A7-rs56678847 were present in 21% of top rules.

Conclusions

In summary, we identified strong evidence suggesting specific combinations of MS risk variants confer elevated risk by applying a robust and novel analytical framework to a modestly sized study population. Replication analyses are underway. These results have the potential to significantly inform efforts aimed at developing risk prediction models for MS.

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Machine Learning/Network Science Poster Presentation

P0004 - Convolutional neural network framework for predicting progression in early MS (ID 1679)

Speakers
Presentation Number
P0004
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Brain tissue damage is closely linked to disability in multiple sclerosis (MS). The localization of white matter (WM) lesions influences the course of the disease.

Objectives

However, the interrelation between lesions topography and cortical atrophy distribution for predicting the clinical disability remains unclear. Use a deep learning neural network framework with the purpose to identify critical co-varying patterns for individualized disease prediction.

Methods

Clinical disability was measured using the Expanded Disability Status Score at baseline and at a one-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Co-varying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel ICA and used as features for constructing a deep learning convolutional neural network. The prediction was conducted for each identified lesion pattern separately using 50% as training cohort and 50% as testing cohort.

Results

In the study cohort, we identified three distinct distribution types of WM lesions (“cerebellar”, “bihemispheric” and “left-lateralized”). The “cerebellar” and “left-lateralized” patterns were reproducibly detected in the second cohort. Each of the patterns predicted to different extents, short-term disability progression, while the “cerebellar” pattern predicting individual disability progression with an 10-fold cross-validation accuracy of above 90% for the Study cohort (95% CI: 88%-94%) and above 85% for the replication cohort (95% CI: 81%-88%) respectively.

Conclusions

These findings highlight that role of distinct spatial distribution of cortical atrophy and WM lesions predicting disability. The cerebellar involvement is shown as a key feature in the CNN framework for prediction of rapid clinical deterioration.

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Machine Learning/Network Science Poster Presentation

P0005 - Decoding the EDSS Scores of Multiple Sclerosis Patients from MRI Biomarkers (ID 1620)

Speakers
Presentation Number
P0005
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Treatment response in multiple sclerosis (MS) is frequently suboptimal and, in many cases, different disease-modifying therapies need to be tested. The expanded disability status scale (EDSS) score and other markers of disease activity (such as relapses, new lesions, brain atrophy, etc.) are crucial for treatment decision making. However, EDSS suffers from poor reliability, repeatability, and high inter-rater variability. Therefore, automatic and objective disability scoring using MRI information could help to monitor disease progression reliably and optimize treatment.

Objectives

Develop a machine-learning model that learns relations between MRI-based brain volumes and clinical disability measured by EDSS.

Methods

Multi-center FLAIR and T1 MRI data from 325 MS patients were used. Individuals were rated in each center using EDSS within 0-89 days before or after the MRI scan. Automated image analysis was performed using icobrain, providing volumetric quantification of gray matter, white matter, whole brain, lateral ventricles, T1 hypointense and FLAIR hyperintense lesions. Moreover, other features, such as age, sex, and center, were available. A machine-learning model based on random forest regression was built for estimating EDSS automatically from these features. The model’s performance was assessed by means of mean squared error (MSE) and mean absolute error (MAE) evaluated overall, and on two EDSS subgroups, <=4 and >4,in a 100 repetition 10-fold-cross-validation fashion. Subsequently, the percentage of cases for which the automatic EDSS was within 1.5, 1 or 0.5 points, respectively, from the clinically reported EDSS was computed.

Results

The proposed automatic EDSS estimation model obtained MSE=2.36±0.03, MAE=1.24±0.89 for the overall interval, with MSE=1.83±0.04, MAE=1.11±0.76 for EDSS<=4 (N=200) and MSE=3.26±0.06, MAE=1.46±1.05 for EDSS>4 (N=118). The percentage of cases with absolute error strictly below 1.5, 1 and 0.5 EDSS points was 67%, 46% and 24%, respectively.

Conclusions

A good match between the automatic EDSS and the measured EDSS is only possible up to a certain extent, suggesting that the MRI-based EDSS score might also capture complementary information on disease activity compared to the clinically measured EDSS. Understanding such differences is a prerequisite for predicting future disability progression in MS.

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Machine Learning/Network Science Poster Presentation

P0006 - Detecting treatment response on T1 gadolinium enhancing lesion burden in clinical trials of multiple sclerosis with deep learning (ID 998)

Speakers
Presentation Number
P0006
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS). It suppresses the development of new areas of inflammation as shown by the reduction in the number of T1 gadolinium (Gd) enhancing lesions. Deep learning (DL) based segmentation of lesions has the potential to automate these manual reads; enabling faster and more reproducible quantification.

Objectives

To evaluate a DL model’s ability to detect OCR treatment response on the number of T1 Gd enhancing lesions in clinical trials of relapsing remitting MS (RRMS).

Methods

We used images from Opera I trials (NCT01247324, n=898), to train a Unet model to segment both unenhancing and Gd-enhancing T1 lesions. T1 Gd- enhancing lesions in ground truth (GT) masks were present in ~44% of patients at baseline and ~15% across all time points. We created a dataset with an equal number of imaging volumes with and without enhancing lesions and used 70%-30% data splits for training and validation. The model was tested on images from Opera II trials (NCT01412333, n=905). To detect significant differences between treatment and control arms, we performed a negative binomial regression on the number of T1 Gd-enhancing lesions with baseline imaging and clinical covariates.

Results

The DL model achieved a mean dice coefficient (DC) of 0.72, lesion true positive rate of 0.92 (LTPR), lesion false positive rate (LFPR) of 0.06 and a volume correlation coefficient (CC) of 0.97 for Gd-enhancing lesion segmentation. For unenhancing lesion segmentation, the mean DC was 0.68, LTPR 0.78, LFPR 0.18 and volume CC of 0.97. The model had the highest false positives for lesions smaller than 10 voxels (voxel size: 1x1x3 mm3). For Gd-enhancing lesion segmentation a significant OCR treatment effect (p<0.001) in reducing the mean number of Gd-enhancing lesions at 24, 48 and 96 weeks (92%, 96%, 97% reduction from GT manual reads vs 67%, 71%, 78% from model predictions) was detected.

Conclusions

Our DL model performed Gd-enhancing lesion segmentation comparably to similar DL models in the literature and showed a high correlation to GT manual reads. Our model also had sufficiently high sensitivity to detect an OCR treatment response consistent with neuro-radiologist assessments. To our knowledge, this is the first study to report that a DL model has the sensitivity to detect treatment response on Gd-enhancing lesions.

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Machine Learning/Network Science Poster Presentation

P0007 - Detecting treatment response on T2 lesion burden in multiple sclerosis clinical trials with deep learning (ID 1171)

Speakers
Presentation Number
P0007
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Deep Learning (DL) methods are promising to automate or assist the radiologist in many of the measurements currently made manually during clinical trial drug development; thereby reducing inter/intra rater variability and reading time. T2 lesion burden is a routine imaging endpoint in Multiple Sclerosis (MS) clinical trials. Ocrelizumab (OCR) is a humanized anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of MS. It has been shown to strongly suppress the number of new and enlarging T2 lesions (compared to control treatment) in the relapsing remitting MS (RRMS) based on manual neuro-radiologist assessments.

Objectives

Evaluate DL models to quantify T2 lesion burden and detect the therapeutic response identified by manual neuro-radiologist assessments.

Methods

We evaluated three DL models using multimodal brain MRI (T2w, FLAIR and T1w; voxel size of 1x1x3 mm3): a stack model with three consecutive slices as input; a patch model with 3D sub volumes as input; and a novel model architecture. Models were trained on Opera I (NCT01247324, n=898) datasets (baseline) and tested on Opera II (NCT01412333, n=905) datasets (baseline, 24, 48 and 96 weeks). Number of new and enlarging T2 lesions were estimated heuristically from serial lesion masks predicted by the model.

Results

Lesion size distributions were heavily skewed toward small lesions (~40% < 10 voxels, ~80% < 50 voxels with a minimum lesion size threshold of 3 voxels). All models achieved similar mean dice coefficient (0.7), mean lesion true positive rate (LTPR) of 0.87, 0.85, 0.82 and mean lesion false positive rate (LFPR) of 0.23, 0.24, 0.18. Generally, the models overestimated the number of new and enlarging T2 lesions when compared to the ground truth (GT) masks. This was driven by a high number of false positives (FP) for small lesions. All three models were able to detect a significant treatment response in favor of OCR at weeks 48 (p<0.01) and 96 (p<0.001). Only the novel model showed a significant treatment effect at week 24 (p<0.01).

Conclusions

The cross-sectional performance metrics of all 3 models were comparable to those reported in literature. All models successfully reproduced the treatment response from GT manual reads at 48 and 96 weeks, but only the novel model detected the early response at 24 weeks seen in the GT assessments. To further improve the model’s reliability, future work will be aimed to reduce the number of FPs for small size lesions.

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Machine Learning/Network Science Poster Presentation

P0008 - Divergent patterns of ventral attention network centrality relate to cognitive conversion in MS (ID 473)

Speakers
Presentation Number
P0008
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Cognitive impairment (CI) is common in multiple sclerosis (MS), but due to a lack of longitudinal data it remains unclear which mechanisms relate to conversion to mild or even severe CI. Previous cross-sectional work has suggested the importance of cognition-related resting-state networks, such as the default-mode and attention networks.

Objectives

To characterize the functional network changes related to conversion to CI in a large sample of MS patients over a period of 5 years.

Methods

A total of 233 MS patients and 59 healthy controls (HC), all part of the Amsterdam MS cohort, underwent extensive neuropsychological testing and resting-state fMRI at baseline and follow-up (mean time-interval 4.9±0.9 years). At baseline, MS patients were categorized as being cognitively impaired (scoring ≤-2 SD on ≥2 domains, N=74), mildly impaired (MCI, being impaired on 1 domain or scoring between -1.5 and -2SD on ≥2 domains, N=33) or preserved (CP, not fulfilling the CI or MCI criteria, N=126). In addition, these groups were categorized according to the group to which they converted at follow-up (e.g. CP to CI). Network function was quantified using eigenvector centrality, a measure of network importance, which was averaged over established resting-state networks at both time-points. Correlations with brain volumes were calculated.

Results

Over time, 26.2% of CP patients deteriorated and developed MCI (66.7%) or CI (33.3%) and 73.8% remained CP. 23.5% of MCI patients, progressed to CI. Centrality analysis showed that patients who were CI at baseline demonstrated a higher cross-sectional DMN centrality compared to controls (P=.05). Longitudinally, patients who remained CP and CP-to-MCI converters showed increasing ventral attention network (VAN) centrality over time time (P=.017 and .008, respectively), , whereas in the MCI and CI converter groups this increase was absent. Patients with less severe deep gray matter atrophy at baseline showed stronger increases in VAN centrality over time.

Conclusions

We showed that conversion from intact cognition to impairment in MS is related to an increase in centrality of the VAN, which is absent when overt impairment has manifested, then shifting towards DMN dysfunction. As the ventral attention network is known to normally relay information to the DMN, our results suggest that developing cognitive impairment is related to a progressive loss of control over the DMN by means of VAN dysfunction.

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Biostatistical Methods Poster Presentation

P0009 - ENTIMOS: a discrete event simulation model for maximizing efficiency of infusion suites in centres treating multiple sclerosis patients (ID 1630)

Speakers
Presentation Number
P0009
Presentation Topic
Biostatistical Methods

Abstract

Background

Multiple sclerosis patients are treated with intravenous (IV) disease modifying treatments (DMTs). Infusion suite resources are thus vital components of MS patient care. Infusion suites may be dedicated to MS patients, or shared with patients with other neurological conditions, or other patients requiring infusion. Here, we describe a resource utilization model for the infusion suites of Charing Cross (UK), which serves patients with different neurological conditions.

Objectives

To maximize the clinical efficiency of the infusion suite based on three resource constraints: percentage of patients IV MS DMTs, number of infusion chairs, and number of nurses. Efficiency gains in the infusion suite may benefit both patients and the healthcare system.

Methods

ENTIMOS, a discrete event simulation (DES) model, was created using SIMUL8 based on qualitative information from infusion centers and populated with data specific to the Charing Cross hospital neurology infusion suite. Posology, administration information, and rates of immune related-reactions (IRRs) were applied from published data sources from both MS and non-MS DMTs of interest.

The infusion suite model assumes 75 MS and 21 non-MS patients weekly, including up to seven MS patients initiating IV treatment; is equipped with 12 infusion chairs and six beds; and is staffed with a total of six nurses. We simulated the effects of changing the three resource constraints described on the number of patients waiting for an appointment (queue size), the time for patients to get an appointment for their first or subsequent IV treatments (waiting times), and general resource utilization.

Results

Changing the number of chairs, moving a subset of patients from IV to any non-IV alternative treatments, moving patients between MS IV treatments, or changing the allocation of nurse resources may all have an impact on the queue size and waiting times. Once the changes are implemented in the model, existing resources optimised and the queue size reduced, the effective centre throughput can be increased.

Conclusions

ENTIMOS allows users to optimize their use of constrained resources in an infusion suite to improve patient experience and infusion suite efficiency.

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Machine Learning/Network Science Poster Presentation

P0010 - Integration of the Extreme Gradient Boosting model with clinical data to enable the early diagnosis of multiple sclerosis (ID 715)

Speakers
Presentation Number
P0010
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Delayed multiple sclerosis (MS) diagnoses are not uncommon, especially in Asia, where MS is relatively rare. Therefore, an early MS diagnostic tool is urgently warranted.

Objectives

We aimed to develop an effective tool through machine learning techniques for the early diagnosis of MS in Chinese people.

Methods

Two case sets were established. The first MS cohort had 239 cases and 1142 controls (the training set), and the second MS cohort had 23 cases and 92 controls (the test set). The Extreme Gradient Boosting (XGBoost), Random Forest (RF), Naive Bayes, K-nearest-neighbor (KNN), Support Vector Machine (SVM) algorithms were fitted using Bayesian optimization, and the best parameter sets were assessed using the F1 scores of 5-fold cross-validations. The utility of machine learning algorithms in MS early diagnosis was evaluated by precision, recall, specificity, accuracy and F1 score through 5-fold cross validation.

Results

The XGBoost algorithm performed better than the other algorithms in 5-fold cross-validation. Thirty-four variables were set for the XGBoost algorithm, and their relative importance with MS were ranked. The training set recall was 0.632, with a specificity of 0.903, and the test set recall was 0.609, with a specificity of 0.902. Our study found that 61%, 51%, and 49% of the patients could be diagnosed with MS, 1, 2, and 3 years earlier than their real diagnostic time point, respectively.

Conclusions

A diagnostic tool for early MS recognition based on the XGBoost model and medical record data were developed to help reduce diagnostic delays in MS patients.

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Machine Learning/Network Science Poster Presentation

P0011 - Lesion disconnectomics using atlas-based tractography (ID 1293)

Speakers
Presentation Number
P0011
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Recent studies have described Multiple Sclerosis (MS) as a disconnection syndrome (Rocca et al. 2015). Modelling disconnectomes using brain networks enables to quantify connectivity loss using graph analysis. To build structural connectomes, high-quality diffusion Magnetic Resonance Imaging (dMRI) and robust tractography algorithms are typically required. However, high-quality dMRI is rarely acquired in clinical workups due to time constraints.

Objectives

We propose to use a tractography atlas to extract brain connectivity loss in response to lesions without requiring dMRI, and to model structural disconnectomes with brain graphs. Topological graph features are proposed as new radiological biomarkers and their relation with Total Lesion Volume (TLV) and Expanded Disability Status Scale (EDSS) are studied.

Methods

589 MS patients (159 males, age 28±8yo, EDSS 2.40±1.22, TLV 13.0±14.6mL) underwent MRI at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). Acquisition protocols included T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR).

Lesions were segmented using LeMan-PV, a prototype lesion segmentation algorithm (Fartaria et al. 2016). The lesion masks were registered to standard MNI space and overlapped with the HCP842 tractography atlas (Yeh et al. 2018). Streamlines passing through lesions were isolated to define the affected connectivity.

The disconnectome graph was built using brain regions from the Brainnetome atlas (Fan et al. 2016) as nodes, whilst edges were weighted by the percent of unaffected streamlines connecting two nodes relative to the atlas connectivity. Topological features were extracted from the disconnectome graph and their Spearman’s correlations with TLV and EDSS were computed.

Results

Transitivity (T) and global efficiency (GE) decreased for larger TLV (R=-0.42 and R=-0.78), whereas the average shortest path length (PL) increased (R=0.78). When looking at correlations with EDSS, T (R=-0.17), GE (R=-0.24) and PL (R=0.23) showed stronger associations than lesion count (R=0.14) but were comparable to TLV (R=0.23). All correlations were significant (p<0.001).

Conclusions

We proposed an atlas-based disconnectome model which allowed to study connectivity loss in MS patients without requiring dMRI. Overall, patients showed a lower small-worldness and efficiency for larger TLV and worse disability. These observations were consistent with previous studies on diffusion-based connectomes and open new avenues of research for routine clinical data.

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Machine Learning/Network Science Poster Presentation

P0012 - Machine-learning optimized Combinatorial MRI scale (COMRISv2) correlates highly with MS disability (ID 1438)

Speakers
Presentation Number
P0012
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Volumetric biomarkers derived from brain MRI correlate only mildly to moderately with disability scales in multiple sclerosis (MS) patients. We previously addressed this issue by employing machine learning (ML) to select semi-quantitative MRI (semi-qMRI) features and their weights in the Combinatorial MRI Scale (COMRISv1). COMRISv1 correlated strongly with physical and cognitive disability in an independent validation cohort.

Objectives

Building on this work, we aimed to test the hypothesis that more powerful ML algorithm (i.e., Random Forests; RF) to both fully quantitative (qMRI) and semi-qMRI biomarkers in COMRISv2 will outperform COMRISv1 in the ability to predict physical and cognitive disability in an independent cohort of MS patients.

Methods

The prospectively acquired MS patients (n=283, divided 2:1 into training and validation cohorts) underwent brain MRI imaging within days of clinical evaluation. Neurological examination was transcribed to NeurEx app that automatically computes disability scales. Semi-qMRI features were determined weekly by consensus of MS-trained neurologists, while qMRI features were computed by lesion-TOADS algorithm implemented to QMENTA platform. All measurements were acquired as part of an IRB-approved clinical protocol, and support was provided by the National Institute of Allergy and Infectious Disease Division of Intramural Research.

Results

All RF-based COMRISv2 models validated (p<0.0001 for all) in the independent cohort. The predictions were stronger for models of physical disability, from which the model based on granular CombiWISE scale achieved the highest correlation (Spearman Rho = 0.855; Linh’s concordance coefficient that reflects 1:1 concordance between predicted and measured outcome; CCC = 0.824). COMRISv2 model of cognitive disability predicted measured symbol digit modalities tests (SDMT) with Rho = 0.493. Unexpectedly, formal comparison of the models consisting only from qMRI or semi-qMRI features demonstrated stronger predictive power of the latter.

Conclusions

COMRISv2 predicts clinical outcomes with strong accuracy but models of physical disability favor qMRI biomarkers reflecting disease burden in the infratentorial compartment, which is currently not measurable as qMRI biomarkers with sufficient accuracy. Addition of qMRI biomarkers of telencephalon damage only strengthened the performance of cognitive disability COMRISv2 model.

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Biostatistical Methods Poster Presentation

P0013 - Modeling a long-term virtual placebo arm for SPMS population in the EXPAND study: Comparing different statistical methods (ID 1774)

Speakers
Presentation Number
P0013
Presentation Topic
Biostatistical Methods

Abstract

Background

Siponimod significantly reduced the risk of 3-/6-month confirmed disability progression (3m/6mCDP) versus placebo by 21% and 26%, respectively in patients with secondary progressive multiple sclerosis (SPMS), during the core part of the EXPAND study. At the end of EXPAND-Core, patients were offered a switch to open-label siponimod in the ongoing EXPAND-Extension allowing follow-up for up to an additional 7 years; therefore, a long-term comparison between siponimod and placebo was not possible and a modeling for the placebo long-term trajectory was proposed using different statistical methodology.

Objectives

To estimate the long-term effect of siponimod versus placebo by modeling placebo treatment corrected for switch at the end of EXPAND-Core.

Methods

In the EXPAND-Extension part, 6mCDP was analyzed to assess disability. Time to 6mCDP to account for the switch to siponimod in placebo-treated patients was modeled by 3 methods: 1) Rank Preserving Structural Failure Time (RPSFT) model that uses the actual time to 6mCDP for switchers to compute a hypothetical time to 6mCDP as if they had never switched; 2) simulating the hypothetical time from the switch to 6mCDP based on core part data as if patients had never switched (Two-stage method); and 3) a parametrical model (Weibull distribution) to extrapolate a placebo survival curve.

Results

As of 6 April 2019, 878 patients (siponimod, n=593; placebo-siponimod switch, n=285) were still ongoing in the EXPAND-Extension. All 3 methods confirmed the long-term effect of siponimod versus placebo in the EXPAND population. The RPSFT model seems to provide the more accurate estimate for time to 6mCDP (hazard ratio [95% confidence interval]: 0.69 [0.53; 0.90]) vs the Two-stage (0.76 [0.64; 0.92]) and Weibull modeling methods (0.58 [0.49; 0.67]). The RPSFT results were indicative of a persistent treatment effect over 5 years with a ~50–60% increase in the time to 6mCDP in siponimod versus placebo-corrected switch (median time to 6mCDP: 42.5 months for placebo-corrected switch as opposed to 51.7 months for uncorrected placebo; median not reached with siponimod). Accuracy of RPSFT is supported by simulations conducted under conditions similar to the EXPAND study, which included waning and increasing treatment effects, that found very low difference between the true hazard ratio and the hazard ratio obtained with RPSFT.

Conclusions

The results support the reliability of RPSFT to model a virtual placebo arm in the long-term in a SPMS population. RPSFT results confirmed a long-term benefit of siponimod over placebo with a preserved hazard ratio on 6mCDP and ~50‒60% prolongation of time to 6mCDP.

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Biostatistical Methods Poster Presentation

P0014 - Personalized and dynamic prognostic model from the Barcelona CIS cohot (ID 1607)

Abstract

Background

In the constantly evolving field of MS, personalized medicine is still one of the most important unmet need that requires further attention

Objectives

We aimed to develop a dynamic risk calculator to predict the long-term prognosis of MS in the context of a large MS Centre in Catalonia

Methods

This is an observational study based on data prospectively acquired from a deeply phenotyped CIS cohort from Barcelona. We first built a natural history baseline risk score (BRS) for predicting moderate disability, integrating baseline prognostic factors: Sex, age at CIS, CIS topography, number of T2 lesions, contrast-enhancing lesions (CEL) and oligoclonal bands. This BRS was designed as follows: For untreated patients, we built a Weibull model to estimate the median time to confirmed EDSS 3.0 and with these estimates we identified risk groups based on the median of the cut-offs of 2000 survival trees. Then we obtained the BRS of the full cohort. In patients with more than ten years of follow-up, we performed an inverse probability weighting to balance patients during their follow up for the propensity of being treated or lost to follow-up. The weights were estimated via a proportional hazards (PH) Cox model considering both baseline information (CIS year, BRS) and time-dependent (diagnosis status, new T2 lesions, CEL and cumulative number of relapses). Finally, a weighted PH Cox model was built to estimate the time to confirmed EDSS 3.0 considering the BRS and time-dependent events (new T2 lesions, cumulative number of relapses and first or second-line treatment use). Sensitivity analyses using other disability outcomes and different follow-ups were conducted.

Results

Of 956 patients, 577 (60.4%) were untreated before confirmed EDSS 3.0. Two BRS were obtained: low and high-BRS. Of 400 patients followed for more than ten years, 226 (56.5%) were low-BRS and 174 (43.5%) were high-BRS. High-BRS showed a HR=2.16 95%CI (1.16,4.02). Each new T2 lesion presented HR=1.04 95%CI (1.00,1.08) and each new relapse HR=1.46 95%CI (1.23,1.74). Being on second-line treatment showed a protective effect (HR=0.23 95%CI (0.06,0.94)) but no association was found for first-line treatments (HR=1.32 95%CI (0.67,2.60). Sensitivity analyses confirmed the association between BRS, new T2 lesions and the accumulation of relapses with the prognosis. However, treatment results were inconclusive.

Conclusions

Presenting a high-BRS doubles the risk of reaching moderate disability. Each new lesion and new relapse increses the risk by 4% and 46%, respectively; and second-line treatments seem to be protective. If validated, this risk calculator could be a crucial step to personalized medicine.

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Machine Learning/Network Science Poster Presentation

P0015 - Predicted brain age as a cognitive biomarker in Multiple Sclerosis (ID 1388)

Speakers
Presentation Number
P0015
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Brain-predicted age difference (BPAD) is the difference between chronological and brain age, the latter being decoded from brain MR images by a machine learning model. BPAD has been established as a biomarker for physical deterioration in multiple sclerosis (MS).

Objectives

The objective was to examine the value of brain-predicted age difference as a biomarker for cognitive deterioration in MS.

Methods

In the first phase we used supervised machine learning (ridge regression, 7-fold cross-validation) to predict chronological age from brain volumes. This was achieved on a sample of 1743 healthy controls (HC) with T1-weighted MR images from a range of public collections, using the icobrain software to compute normalized brain volumes (whole brain, white matter, (cortical) grey matter and lateral ventricles). The age range of this sample was 8 to 94 years. In the second phase we applied this algorithm to decode brain age in 231 T1-weighted MR images from MS patients from two clinical centers. The age range of this sample was 14 to 77 years. BPAD computed for HC (BPADHC) and MS (BPADMS) were compared with an independent student t-test. Cognitive functioning was assessed through the symbol digit modalities test (SDMT), available for all 231 included MS patients, the brief visuospatial memory test revised (BVMT-R) and California verbal learning test II (CVLT-II), the latter two being available for a subset of 97 patients from one center. Pearson correlation was computed between the BPAD values and scores on each cognitive test. P-values were corrected for multiple comparisons by the Benjamini/Hochberg method.

Results

After training, the mean (SD) BPADHC in the best-performing of seven folds was -0.5 (9.2) years, opposed to 9.7 (12.0) years for BPADMS. This difference was statistically significant (p < 0.001). Correlations between BPADMS and SDMT, BVMT-R and CVLT-II were -0.19 (p = 0.005), -0.14 (p = 0.157) and -0.30 (p = 0.005) respectively.

Conclusions

Our results showed a significant association between BPADMS and two cognitive measures in MS, information processing speed and verbal memory. These findings support a potential role for BPADMS as a cognitive biomarker in MS.

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Machine Learning/Network Science Poster Presentation

P0016 - Progressive multifocal leukoencephalopathy lesion and brain parenchymal segmentation from MRI using serial deep convolutional neural networks (ID 1531)

Speakers
Presentation Number
P0016
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus associated with significant morbidity and mortality, which can occur in the context of certain MS disease modifying therapies. There are currently no validated automatic methods for quantification of PML lesion burden or brain atrophy on MRI.

Objectives

We assessed whether deep learning techniques can be employed for automated brain parenchymal and lesion segmentation in PML using an approach dubbed “JCnet,” named after the causative viral agent.

Methods

We performed a retrospective analysis of PML patients who were evaluated at the NIH Neuroimmunology Clinic. MRI scans were acquired on either a Siemens Skyra or a Philips 3T MRI scanners. For PML brain and lesion segmentation, we implement a 3D patch-based approach with two consecutive fully convolutional neural networks (CNNs) with a feature pyramid architecture. The first network performs brain extraction as foreground, with meninges and cerebrospinal fluid spaces as background , while the second segments the underlying PML lesion(s). We measured the segmentation accuracy using Dice similarity coefficient (DSC) and absolute volume differences (AVD). We evaluated JCnet against methods designed for normal-appearing brain segmentation, FSL/FMRIB's Automated Segmentation Tool (FAST) and FreeSurfer, as well as MS lesion segmentation, Lesion Segmentation Toolbox (LST) and Lesion-TOpology-preserving Anatomical Segmentation (LTOADS). Comparisons were performed using Wilcoxon matched-pairs signed-ranks test.

Results

A total of 41 PML patients (mean age 55 years, SD 13; 44% female) were included in the analysis. The cohort was empirically divided into 31 training and 10 testing cases sampled at random. The mean time between PML onset and MRI acquisition was 4.5 months (range 0.6 – 44.5 months). JCnet resulted in a 4% and 64cm3 absolute improvement in DSC and AVD compared to FAST (p=0.005 and 0.01), and a 6% and 41cm3 absolute improvement compared to FreeSurfer respectively (p=0.005 and p=0.02). This was driven in part by improved segmentation of brain tissue within T1-hypointense PML lesions. For PML lesion segmentation, there was an absolute improvement of 42% and 14cm3 in DSC and AVD respectively compared to LST, and 53% and 19cm3 absolute improvements compared to LTOADS respectively (p=0.005 for all lesion comparisons). This was driven by improved sensitivity of supra- and infratentorial PML lesion identification and segmentation.

Conclusions

We employ an end-to-end deep learning-based method for automated segmentation of lesion and brain parenchymal volume in PML. By tracking quantitative measurements of PML-related MRI changes, this approach provides a window for clinicians and scientists to accurately monitor PML radiographically and its response to experimental therapies.

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Machine Learning/Network Science Poster Presentation

P0017 - Translating MPRAGE to MP2RAGE improves the automatic tissue and lesion segmentation in Multiple Sclerosis patients (ID 766)

Speakers
Presentation Number
P0017
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Compared to the conventional magnetization-prepared rapid gradient-echo imaging (MPRAGE) MRI, magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) (Marques, J. P., 2010) shows a higher brain tissue and lesion contrast in multiple sclerosis (MS) patients. This specialized sequence is, however, mainly limited to research settings and not widely acquired in clinical routine.

Objectives

To synthesize realistic-looking MP2RAGE images from MPRAGE acquisitions via generative adversarial network (GAN) and verify if these improve the performance of automatic MS lesion and brain tissue segmentation tools.

Methods

We propose a GAN inspired by the pix2pix framework (Isola, P., 2018) which takes as input 2D slices of 3D MPRAGE images and generates a synthetic MP2RAGE (synMP2RAGE). Differently from pix2pix, the generator of the GAN combines three loss functions: a pixel-wise L1 loss, an adversarial loss, and a perceptual loss. Our framework is trained on 12 healthy controls and 8 MS patients and tested on 36 MS patients, for which an expert manually delineated cortical and white matter lesions. Imaging was performed with a 3T MRI scanner (Siemens Healthcare, Erlangen, Germany) with a 1x1x1.2 mm resolution. Evaluation is performed with reference-based metrics and through automatic segmentation of MS lesions (La Rosa, F., 2020) and brain tissue (Avants, B.B., 2011).

Results

Considering as reference the acquired MP2RAGE, synMP2RAGE achieves a peak signal-to-noise ratio of 31.39, normalized root mean square error of 0.13, and structural similarity index of 0.98, overperforming the MPRAGE (29.49, 0.17, 0.97, respectively) for all metrics. Compared to the initial MPRAGE it also significantly improves the lesion and tissue segmentation masks in terms of the Dice coefficient and volume difference (p-values < 0.001). On the contrary, no significant differences between the real and synMP2RAGE are found in the patient-wise comparison of the lesions’ segmentation (p-values > 0.05), whereas they are significant between MPRAGE and MP2RAGE (p-value < 0.001).

Conclusions

Our proposed framework successfully translates MPRAGE to MP2RAGE, synthesizing realistic-looking images which improve the performance of automatic segmentation tools tested on MS patients. In accordance with previous claims (Finck, T., 2020), these results confirm that GANs can be helpful in the automatic analysis of MRI images.

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Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Biosensors Poster Presentation

P0019 - A Comparison of Digital Gait Technologies in a Population of People with MS –When the Same Isn’t Always Exactly the Same (ID 1944)

Speakers
Presentation Number
P0019
Presentation Topic
Biosensors

Abstract

Background

Multiple Sclerosis (MS), a disease characterized both by relapses and progression, commonly impacts ambulation. Impaired ambulation results in loss of independence. Current approaches to document disease impact/progression on ambulation including EDSS/T25FW are insufficiently sensitive to quantify subtle but critical change. Patient Reported Outcomes (PRO) for gait relate to several critical elements of the gait cycle beyond velocity. Earlier recognition of critical change might improve disease modifying therapy choice and timing of change. Objective multi-dimensional analytics have included digital devices of varying types utilizing different technologies (e.g. foot pressure, accelerometer, 3D video capture). Comparing different technologies in people with MS (PwMS) along a spectrum of disability would be important to optimal technology choice. Simultaneous comparisons of similar outcome measures of gait components would enhance technology choice.

Objectives

To compare and contrast quantified outcome measures of the gait cycle as measured by the use of three different validated and digital ambulatory devices.

Methods

PwMS performed one pass (20 feet) while ambulating at a preferred walking speed along the Zeno™ walkway (ZW, ProtoKinetics), while wearing Opal sensors (OS, APDM), and captured using VSTBalance (VB, VirtuSense) simultaneously. Relevant gait parameters (GP) captured: velocity, stride length, total double support, and cadence. Univariate regression modeling and T-tests were used for statistical analysis for each GP.

Results

9 PwMS (69% female, average age =53.1±11.8 years). Regression modeling showed the following relationships: velocity: ZWvsVB (r2 =0.93, p=1.2E-25), ZWvsOS (r2 =0.99, p=6.9E-40), VBvsOS (r2 =0.96, p=1.8E-25) Stride Length: ZWvsVB (r2 =0.32, p=7.8E-25), ZWvsOS (r2 =0.9, p=1.02E-16), VBvsOS (r2 =0.30, p=1.3E-4). Total double support %: ZWvsVB (r2 =0.22, p=1.6E-3), ZWvsOS (r2 =0.87, p=3.2E-20), VBvsOS (r2 =0.27, p=3.9E-4). Cadence: ZWvsVB (r2 =0.18, p=5.3E-3), ZWvsOS (r2 =0.92, p=1.2E-23), VBvsOS (r2 =0.19, p=4.2E-3). T-tests showed the following relationships: velocity: ZWvsVB (p=0.47), ZWvsOS (p=0.21), VBvsOS (p=0.63). Stride Length: ZWvsVB (p=7.25E-6), ZWvsOS (p=0.08), VBvsOS (p=0.001). Total Double Support %: ZWvsVB (p=0.91), ZWvsOS (p=0.01), VBvsOS (p=0.02). Cadence: ZWvsVB (p=5.6E-5), ZWvsOS (p=0.92), VBvsOS (p=6.3E-5).

Conclusions

Gait velocity had the strongest concordant relationship between all three technologies. Despite this concordance, there was still ~10% variability of this important measure. Other elements of the gait cycle had sub-optimal cross-device relationships. There was considerable discordance with stride length and cadence (ZWvsVB and OSvsVB), and double support (ZWvsOS and VBvsOS). Inconsistent relationships demonstrate the need to carefully select digital gait outcome measurement devices for PwMS.

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Biomarkers and Bioinformatics Poster Presentation

P0020 - A down-regulation of the type I interferon signaling pathway is associated with the response to teriflunomide in multiple sclerosis. (ID 1584)

Abstract

Background

Teriflunomide is an oral first-line treatment of patients with relapsing-remitting multiple sclerosis (RRMS) that has been shown to decrease clinical relapses, reduce brain magnetic resonance imaging (MRI) activity, and slow progression of disability. However, the drug exhibits only limited effectiveness and does not produce clinical benefits in a proportion of MS patients.

Objectives

We aimed to identify differentially expressed genes and cellular pathways associated with the responder and non-responder status in RRMS patients treated with teriflunomide by means of RNA sequencing (RNA-seq).

Methods

RRMS patients treated with teriflunomide were classified into those with No evidence of disease activity (NEDA 3) and those with EDA after 12 months of treatment. Eleven responders [8 females; mean age (standard deviation): 45.8 years (4.5)] and 10 non-responders [8 females; 41.8 years (10.3)] were included in the study. RNA-seq was performed in RNA samples isolated from peripheral blood mononuclear cells before and after 12 months of teriflunomide treatment. 100 bp, paired-end RNA sequencing was performed by using DNAseqTM Technology. Comparative analysis of differentially expressed genes between responders and non-responders was performed at baseline and after 12 months of treatment. Pathway analysis was based on KEGG database using statistically significant genes.

Results

Pathway analysis revealed the type I interferon (IFN) signaling pathway as the most significantly associated with the responder phenotype after 12 months of teriflunomide treatment (p<0.0001). In this context, expression levels for genes known to be predominantly or selectively induced by type I IFNs such as SP100, ZBP1, IFI27, ISG20, IFITM1, IFITM2, MX1, STAT1, PARP9, IFI35, RGS1, RSAD2, IFI44L, IRF1, DDX58, IFI6, IFIT1 and IFIT5 were significantly reduced by the effect of teriflunomide after 12 months of treatment in responders compared to non-responders. At baseline, expression levels for type I IFN genes were similar between responders and non-responders.

Conclusions

Type I IFNs are known to activate dendritic cells, enhance humoral immunity, and favor Th1 immune responses. A down-regulation of type I IFN genes after 12 months of treatment may explain the beneficial effect of teriflunomide in responders. Mechanistic studies are currently underway to investigate the functional implication of the type I interferon signaling pathway in the response to teriflunomide.

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Clinical Outcome Measures Poster Presentation

P0021 - A propensity-matched comparison of long-term disability progression in MS patients treated with dimethyl fumarate or fingolimod (ID 709)

Speakers
Presentation Number
P0021
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Previous comparative effectiveness studies in multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY) on measures of inflammatory disease activity but most studies did not assess long-term disability.

Objectives

To compare long-term disability progression over 5 years (yrs), as assessed by Patient-Determined Disease Steps (PDDS), in NARCOMS registry participants (pts) treated with DMF or FTY.

Methods

The NARCOMS registry is a voluntary self-report registry of people with MS. Pts provide health-related information at enrollment and every 6 months thereafter. We identified pts with RRMS; living in the US; and initiating index DMT (DMF or FTY) from Spring 2011 through Spring 2018. Pts were included if they had ≥1 yr follow-up on index DMT. DMF pts treated with prior FTY, and FTY pts treated with prior DMF, were excluded. We used 1:1 propensity-score matching (PSM) to match FTY to DMF pts. Baseline factors (at time of index DMT initiation) used for PSM were age, disease duration, sex, number of prior DMTs, education, PDDS, cognition score, depression score, relapses in last 6 months, and cardiovascular comorbidities. Time to 6-month confirmed disability progression (≥1-point increase on PDDS sustained for ≥6 months) was estimated using the Kaplan-Meier method and compared using a Cox proportional hazards regression model with robust sandwich estimators. Pts were censored at last follow-up or at the time of DMT discontinuation.

Results

Overall, 689 DMF and 565 FTY pts were included. After PSM, 468 DMF pts were matched with 468 FTY pts. The survey compliance was high in both groups, with >93% of pts in both groups completing ≥50% of surveys while on treatment. Baseline characteristics were well-balanced after PSM, with standardized differences <0.1 for each covariate. Median treatment duration was 3.0 yrs for DMF and 4.0 yrs for FTY. At 5 yrs, 68.3% (95% CI: 62.4-73.5) of DMF pts and 63.3% (95% CI: 59.6-70.1) of FTY pts were free from 6-month confirmed PDDS progression (hazard ratio: 1.01 [95% CI: 0.79-1.28]; p=0.95).

Conclusions

In this propensity-matched analysis of MS pts from the NARCOMS registry, there was no significant difference between DMF and FTY on confirmed disability (PDDS) progression over 5 yrs. These results are consistent with previous studies that have shown similar effectiveness between DMF and FTY on relapse and MRI outcomes.

Supported by: Biogen; NARCOMS is a project of the CMSC

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Clinical Outcome Measures Poster Presentation

P0022 - A systematic literature review and meta-analysis of the efficacy and effectiveness of PR-fampridine in patients with multiple sclerosis (ID 1316)

Speakers
Presentation Number
P0022
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Prolonged release (PR) fampridine is indicated for the improvement of walking in adult multiple sclerosis (MS) patients. Several studies have supported that PR-fampridine improves walking ability in this population; however, reported effects have varied widely across studies and study design.

Objectives

To conduct a systematic literature review (SLR) and meta-analysis (MA) to summarize the evidence on the efficacy and effectiveness of PR-fampridine in MS patients.

Methods

Following PRISMA guidelines, a systematic search of PubMed, EMBASE, YORK and Cochrane Library was conducted from January 1, 2006-April 1, 2019 to identify publications comparing the efficacy and effectiveness of PR-fampridine from Randomized Controlled Trials (RCTs) and observational studies (OBS). For RCTs, outcome measures include Timed 25-Foot Walk (T25FW) and 12-item Multiple Sclerosis Walking Scale (MSWS-12) responders and MSWS-12 scores; for OBS, T25FW walking time and MSWS-12 scores. In the MA, pooled estimates were derived using odds ratios (OR) and standardized mean differences (SMD) of both endpoints. Results from RCTs and OBS were reported separately using a random effects model.

Results

Of a total of 897 unique citations, 27 studies met all criteria for inclusion in the MA, 9 RCTs and 18 single-arm OBS. A pooled estimate based on T25FW responder data from 4 RCTs showed statistically significant improvements in walking ability in the PR-fampridine vs. placebo group; OR (95% CI): 4.8 (2.9-7.9), p<0.0005. Also, findings based on MSWS-12 responder data from 2 RCTs showed significant improvements in walking ability in the PR-fampridine group vs. placebo; OR (95% CI): 1.7 (1.1-2.5); p=0.011. A pooled estimate of mean MSWS-12 scores from 4 RCTs also showed significant improvements in the PR-fampridine vs. placebo group; OR (95% CI): 1.5 (1.2-1.9); p<0.0005. Summary estimates from OBS suggest a significant improvement vs. baseline on T25FW time derived from 9 studies showing that walking time was significantly improved vs. baseline; with SMD (95% CI): –0.31 (-0.479 to -0.146); p<0.0005. Also, the pooled estimate from MSWS-12 endpoint in 6 studies showed that walking ability was statistically improved vs. baseline; SMD (95% CI): -0.98 (-0.892 to -1.058); p<0.0005.

Conclusions

Across randomized and observational data, the use of PR-fampridine is consistently associated with significantly improved walking ability in MS patients measured by MSWS-12 or T25FW endpoints.

This study is funded by Biogen. Biogen funded the analyses for this abstract.

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Clinical Outcome Measures Poster Presentation

P0023 - Alemtuzumab Real World Evidence in a Private Practice Setting (ID 1858)

Speakers
Presentation Number
P0023
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Alemtuzumab significantly improved clinical, MRI, and disability outcomes compared to sub-cutaneous interferon β-1a in MS patients in two phase 3 clinical trials and provided efficacy and safety rationale for treating relapsing multiple sclerosis (RMS) patients in a clinical trial setting. The need for additional data illustrating the efficacy and safety of alemtuzumab use in MS patients outside the clinical trial setting and in the real world exists.

Objectives

To describe patient characteristics and clinical outcomes in RMS patients who have received alemtuzumab in a single neurology center in the United States.

Methods

This retrospective, observational study included patients treated with alemtuzumab and had at least 24 months of follow-up. Patient characteristics and clinical outcomes [annualized relapse rate; disability progression, magnetic resonance imaging (MRI)] were analyzed. Patient data for at least 1 year prior and for up to 2 years after initiation of alemtuzumab was collected via chart reviews for all patients.

Results

A total of 250 patients were included in the study. Mean (standard deviation) age at baseline was 49.7 (10.5). 85% of patients switched from natalizumab during the pre-index period primarily due to JCV positive status (57%). Annualized relapse rate was reduced from 0.088 (2-year pre-) to 0.004 (2-year post) index date (p<0.0001) and 0.164 (1-year pre-) to 0.004 (1-year post) index date (p<0.0003). At 2 years, more patients were stable on brain MRI (98.3% vs. 85.0%) and less patients demonstrated brain MRI worsening (1.27% vs. 14.2%) compared to index date (p <0.0001). Mean (95% Confidence Interval) observed EDSS was 3.58 (3.37, 3.79) at baseline and decreased to 3.03 (2.78, 3.28) and 2.82 (2.53, 3.11) at year 1 and year 2, respectively. The average follow-up time for EDSS was 3.72 years (range: 0 - 4.58 years). At 2 years, 84% of patients did not require ambulatory aid.

Conclusions

This study further supports clinical and radiological efficacy of alemtuzumab in RMS patients. After treatment with alemtuzumab, there was a significant reduction in annualized relapse rate, a significant increase in the proportion of patients with stable brain MRI, improvement in disability, and reduced usage of ambulatory aid. Long term follow-up of this cohort will help assess clinical efficacy in a real-world setting.

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Clinical Outcome Measures Poster Presentation

P0024 - Alemtuzumab slowed brain atrophy over 6 years in patients without relapse and MRI disease activity: post hoc analysis of the pooled CARE-MS studies (ID 784)

Abstract

Background

Over 2 years in the CARE-MS trials (NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline (BL): 5 days; 12 months later: 3 days) significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Alemtuzumab efficacy was maintained through a 4-year extension study (NCT00930553), wherein patients could receive additional 3-day courses (≥12 months apart, as needed for disease activity) or receive other disease-modifying therapy per investigator’s discretion.

Objectives

To evaluate post hoc the effects of alemtuzumab on brain atrophy over 6 years in CARE-MS patients without relapses and MRI disease activity.

Methods

Analysis included pooled CARE-MS patients with or without disease activity between BL and Year 1 or BL and Year 2. Absence of disease activity was defined as no BL gadolinium (Gd)-enhancing T1 lesions and no clinical relapses or MRI disease activity (new Gd-enhancing or new/enlarging T2 lesions) from Years 0-1 or Years 0-2 (Definition 1). A second definition had the additional criterion of no relapse within 60 days before BL (Definition 2). Brain atrophy was measured by brain parenchymal fraction (BPF); differences in the median annualized percent change in BPF were assessed using ranked ANCOVA adjusted for region and BL BPF.

Results

Compared with SC IFNB-1a, alemtuzumab reduced median annualized percent change in BPF in patients free of disease activity during Years 0-1 (Definition 1: -0.37% vs -0.61%, P=0.006; Definition 2: -0.36% vs -0.54%, P=0.024) or Years 0-2 (Definition 1: -0.27% vs -0.44%, P=0.014; Definition 2: -0.28% vs -0.41%, P=0.045). Median annualized percent change in BPF was reduced with alemtuzumab versus SC IFNB-1a in patients with disease activity in Years 0-1 (-0.61% vs -0.79%, P=0.005) or Years 0-2 (-0.40% vs -0.56%, P<0.0001). Over 6 years, brain volume loss (BVL) was slower in patients without disease activity who initiated alemtuzumab at core study BL (-1.66%) than in those who received SC IFNB-1a in the core studies and initiated alemtuzumab in the extension (-2.05%).

Conclusions

Brain atrophy was reduced with alemtuzumab compared with SC IFNB-1a in patients without disease activity over 2 years. A slower rate of BVL was maintained through Year 6 in patients without disease activity who received alemtuzumab in the core study compared with SC IFNB-1a, suggesting alemtuzumab may slow neurodegeneration associated with BVL.

STUDY SUPPORT: Sanofi.

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Clinical Outcome Measures Poster Presentation

P0025 - Analysis fo the results of the establishment of a SARS-CoV-2 safety protocol for Multiple Sclerosis patients  (ID 1512)

Speakers
Presentation Number
P0025
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The SARS-CoV-2 infection has spread worlwide becoming a pandemic never before seen. Immunosuppressive (IS) treatments used in Multiple Sclerosis (MS) patients could activate the infection in asymptomatic carriers or reactivate COVID-19 in apparently recovered cases. Our similar experience in some MS patients during the pandemic lead us to design a safety protocol at our MS Unit. It was based on epidemiological data and testing for PCR in nasopharyngeal swabs and serology before administration of monoclonal antibodies, doses of pulsed disease modifying therapies (DMTs), new starts of oral DMTs and methylprednisolone pulses.

Objectives

To describe our experience in the establishment of a SARS-CoV-2 safety protocol in MS patients. We analyze its utility to prevent COVID-19 complications

Methods

Observational, prospective and clinical practice study in the establishment of a multidisciplinary safety protocol (MS Unit – Neurology/Microbiology/Preventive Medicine). Sequential protocol over time adapted to the different pandemic phases and levels of available resources.

Results

152 PCR and 140 serology tests were performed in 90 patients over 3 months. They were performed preceding the treatment with Natalizumab (96 tests), Ocrelizumab (36 tests), Rituximab (3 tests), Methylprednisolone (7 tests), Cladribine (4 tests) and Dimethyl Fumarate (3 tests). 7 asymptomatic carriers were diagnosed (7,8%), 5 of them with positive IgM+IgG serology (5,6%). 5 patients with positive IgM+IgG serology post-infection were confirmed. No COVID-19 reactivation was detected after the establishment of the protocol.

Conclusions

The combined analysis of PCR and serology increased the sensitivity of the SARS-CoV-2 infection diagnosis during the pandemic peak of cases phase. However, this does not happen at pandemic phases with less daily cases, when testing PCR alone detected the same number of cases than testing combined PCR and serology. The safety protocol reaches its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers.

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Clinical Outcome Measures Poster Presentation

P0026 - Analysis of association between expanded disability status scale and patient determined disease steps (ID 421)

Speakers
Presentation Number
P0026
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The Expanded Disability Status Scale (EDSS) is a commonly used measure of disability based on a clinician administered neurological exam in patients with Multiple Sclerosis (pwMS). Ordinal scores range from 0 (no disability) to 10 (death) in 0.5-point increments. The Patient Determined Disease Steps (PDDS) is a patient-reported measure of disability in pwMS, with ordinal scores ranging from 0 (no disability) to 8 (bedridden) in 1-point increments. Few studies have characterized the association between EDSS and PDDS. Those that have are limited by small sample sizes (n=96 to 103) and inconsistent and sometimes unrealistic correlations for patients with mild disability. For example, one of the studies reported a PDDS of 0 corresponds to an EDDS of 2.9.

Objectives

To characterize the association between EDSS and PDDS in a large sample of pwMS, which can help in the better application of PDDS in practice.

Methods

A total of 406 subjects participating in a US-based prospective cohort study were used for the analyses. All subjects had EDSS and PDDS assessments at baseline and approximately 12-months post-baseline, providing a total of 812 assessments. Mixed effect regression models using cubic splines, growth curve models and quadratic polynomials were employed to characterize the association between EDSS and PDDS and compared with models available in literature.

Results

The mean (standard deviation) age was 48.6 (10.35) years and 72.9% were female. Based on the Akaike’s Information Criterion, the quadratic polynomial regression was found to be the best fitting model. The equation predicting EDSS had the following form: EDSS = 1.4359 + 0.0830 * PDDS + 0.0999 * PDDS2, which was modestly convex in shape. Patients with a PDDS of zero were predicted to have an EDSS of 1.4 and patients with a PDDS of 8 were predicted to have an EDSS of 8.4.

Conclusions

The fitted relationship between EDSS and PDDS in this large sample of pwMS showed generally similar scores across the ranges of the scales. The equation predicting EDSS as a function of PDDS revealed a more realistic fit when compared against other published equations. This study successfully developed a user-friendly crosswalk between EDSS and PDDS scores, using repeat measurements over a large sample. This crosswalk can aid in the better application and interpretation of PDDS.

Sponsored by: Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0027 - Are we ready for precision medicine in Multiple Sclerosis? A web-based survey across Europe   (ID 1411)

Presentation Number
P0027
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

We designed a web-based survey to assess the willingness and interest of European neurologists working with MS to implement precision medicine in their routine clinical practice. This study is a part of the EU-funded MULTIPLEMS grant.

Objectives

1) To assess how neurologists across European countries view the role of body-fluid biomarkers in clinical practice; 2) To survey clinical practices of diagnostic work up, therapy selection and monitoring, and frequency of data collection and clinical and paraclinical measurements.

Methods

The survey had three parts: a) demographics of respondents; b) opinion of the role of predictive, diagnostic, disease-activity biomarkers and treatment-response body-fluid biomarkers in clinical practice; c) survey of clinical practice and management of MS cases (including therapy choice and use of biomarkers) by evaluating 5 clinical cases with different characteristics (therapeutic management in drug naive patients and in patients displaying different forms of remaining disease activity, as well as stopping threapy in stable diasease since long).

Results

194 neurologists across 11 European countries responded to the survey, with a mean response rate of 45%. 57.7% were male and the mean age was 49.8 years. The importance of biomarkers in clinical practice was rated from 1 (low) to 7 (high), and it was generally high: 4.1 for predictive and disease-activity biomarkers, 5.2 for treatment-response and 5.7 for diagnostic biomarkers, with neurologists in Belgium, Denmark, Spain, Sweden and UK being the most positive. Determination of cerebrospinal fluid (CSF) oligoclonal bands was considered the most established biomarker for diagnosis (98.5% of neurologists), prediction (56.7%) and disease activity (36.5%), trailed by anti-aquaporin 4 (90.7%) and anti-myelin oligodendrocyte antibodies (85.1%) for diagnosis. Anti-JC (93.8%) and varicella virus (61.9%) and anti-drug (natalizumab (74.7%) and interferon-beta (68.6%)) were considered useful in context of therapy selection and monitoring by most neurologists, while neurofilament levels in CSF and serum and vitamin D levels were less established. Therapeutic management in the five case examples varied widely, likely as a result of differences in local and national guidelines.

Conclusions

European MS neurologists express a positive opinion on the role of body-fluid biomarkers to manage MS in clinical practice, however, these seem still to have had a limited impact on therapeutic management and selection, which also varied markedly across countries. This underscores the need for further research in this area.

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Biomarkers and Bioinformatics Poster Presentation

P0028 - Assessing the temporal relationship of serum neurofilament light and subclinical disease activity: Findings from APLIOS trial (ID 1641)

Speakers
Presentation Number
P0028
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Several studies showed prognostic value of serum neurofilament light chain (sNfL) in relapsing multiple sclerosis (RMS). For the first time, we explored the association of sNfL and subclinical disease activity using data from the APLIOS trial.

Objectives

To evaluate the potential of sNfL as a patient-level biomarker for monitoring subclinical disease activity in RMS patients.

Methods

In the APLIOS open-label study of ofatumumab 20 mg s.c in RMS (n=284), frequent (14 time points over 12 weeks) sNfL measurements were performed (Siemens sNfL RUO assay on ADVIA Centaur®). MRI scans were done every 4 weeks. The potential monitoring value of sNfL was examined in 3 ways: 1) Age-adjusted geometric mean sNfL over time was estimated in 3 subgroups: patients who had on-study clinical relapses (r+), patients with presence of gadolinium-enhancing T1 (GdT1) lesions at or post-baseline but no clinical relapses (GdT1+r) and patients with neither lesions nor clinical relapses (GdT1r); 2) As high-frequency sampling permitted an estimation of daily sNfL levels, every report of GdT1 lesion was linked to the estimated sNfL level at the time of the scan (using a recurrent-events analysis); and 3) Patient-level predictions of GdT1 lesion were done using the last sNfL value before the corresponding scan and compared with MRI-based predictions (in terms of across-scan average area under the receiver operating characteristics curve [AUC]).

Results

Over the study course, the age-adjusted geometric mean sNfL levels in the GdT1rgroup (n=153) were low compared to other two subgroups, with 95% CIs below those of the r+ (n=15) and GdT1+r(n=116) groups. After adjusting for baseline age and MRI covariates, a between-patient difference of 50% higher sNfL at the time of GdT1 scan was associated with a 29% higher risk of persistent GdT1 lesion (p<0.0001). At the individual patient level, the predictive power of the last sNfL value (AUC=0.76) before scan for presence of GdT1 lesion was similar to that of baseline GdT1-count (AUC=0.77).

Conclusions

This study suggests sNfL may have utility for monitoring of subclinical disease activity in RMS patients as shown by its predictive value of GdT1 lesion activity. Assessments of sNfL could complement regular MRIs, and may provide an alternative in cases where standard MRI monitoring is infeasible.

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Clinical Outcome Measures Poster Presentation

P0029 - Assessment of Multiple Sclerosis Severity Score and Age-Related Multiple Sclerosis Severity Score as health indicators in a population-based cohort (ID 447)

Speakers
Presentation Number
P0029
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Persons with multiple sclerosis (MS) present varying degrees of disability throughout the course of the disease. The Multiple Sclerosis Severity Score (MSSS) and the Age-Related Multiple Sclerosis Severity Score (ARMSSS) adjust the score obtained in the Expanded Disability Status Scale (EDSS) according to disease duration and age, respectively. These measures could be useful as health outcome indicators.

Objectives

The aim of this study was to describe the severity of MS in our health district and assess MSSS and ARMSSS consistency over time.

Methods

Patients diagnosed with MS according to 2010 McDonald criteria, with at least one year of disease duration and followed up in our MS unit within the previous 18 months were selected. Sex, age at onset, disease duration, clinical course, age and irreversible EDSS at last follow-up visit were collected. MSSS and ARMSSS were calculated. Our cohort was studied twice, in 2017 and 2020 to assess the consistency of both instruments.

Results

One hundred and seventy-seven patients were included in 2017, and 208 in 2020. Prevalence of MS in our health district was 90 and 105 per 100,000 inhabitants, respectively, in line with the expected prevalence. Median MSSS and ARMSSS were similar in both study years. In 2017, median MSSS was 1.77 (IQR 0.76-4.28) and ARMSSS was 2.9 (IQR 1.47-5.72). In 2020, median MSSS was 2.03 (IQR 0.82-4.36) and ARMSSS was 2.93 (IQR 1.51-5.56).

Conclusions

According to MSSS and ARMSSS, our cohort presented mild disease, and the results were consistent at both time points. MSSS and ARMSSS may be reliable health outcome measures.

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Biomarkers and Bioinformatics Poster Presentation

P0030 - Association of average blood cell telomere length with the clinical course of MS over a 10-year period (ID 352)

Speakers
Presentation Number
P0030
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS.

Objectives

The aim of this study was to evaluate the length of telomeric DNA sequences in peripheral blood in relation to clinical MS phenotypes and disease progression.

Methods

We measured the average leukocyte telomere length (LTL) in biobanked samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS) and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistics and regression models adjusted for age and sex.

Results

The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up period.

Conclusions

Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between age- and disease-related immune system alterations and blood cell telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained by exploring the distribution of telomere lengths in specific cell populations.

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Clinical Outcome Measures Poster Presentation

P0031 - Asymptomatic anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes (ID 1838)

Speakers
Presentation Number
P0031
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Optical coherence tomography is gaining increasing relevance in the assessment of people with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS.

Objectives

The present study aims at exploring the usefulness of optical coherence tomography as a marker of inflammation and disease burden in the earliest phases of the disease.

Methods

a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder. For the present study, patients also received a visual pathway assessment - including OCT, VEP, visual acuity testing –, measurement of CSF inflammatory markers – a set of 17 cytokines-chemokines and, count of extracellular vesicles of myeloid origin –, and dosage of serum neurofilaments.

Results

19.2% of clinically isolated syndromes had abnormal visual evoked potentials in eyes without optic neuritis. Similarly, optical coherence tomography identified neuro-retinal thinning in 17.8% of patients without prior visual symptoms. The presence of asymptomatic involvement of the anterior optic pathway tested with either techniques was associated with a greater disease burden.

A thinner ganglion cell layer in eyes without prior optic neuritis or instrumental evidences of it was correlated with higher EDSS, lower low contrast visual acuity, longer disease duration, higher brain lesion load, presence of gadolinium enhancing lesions, more severe abnormalities along motor and somatosensory evoked potentials, and higher frequency of CSF-specific oligoclonal bands.

We also found that inner nuclear layer thickens in a post-acute (1.1 – 3.7 months) phase after a relapse, particularly in those who did not receive steroid treatment. Likewise, a longitudinal analysis on 65 patients, showed that this swelling is transient and returns to normal values after one year of follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study were strictly associated with one-another but none of them was associated with inner nuclear layer volume.

Conclusions

The present findings suggest that instrumental evidence of asymptomatic optic nerve involvement is associated with a greater disease burden in early MS and clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

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Biomarkers and Bioinformatics Poster Presentation

P0032 - Baseline serum Neurofilament light chain levels predict conversion to McDonald 2005 MS within 2 yrs of a first clinical demyelinating event in REFLEX (ID 1096)

Speakers
Presentation Number
P0032
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum Neurofilament light chain (sNfL) is a biomarker of neuronal damage, reflecting disease activity, drug response, and is predictive of future disability in established multiple sclerosis (MS).

Objectives

Post hoc analysis to assess whether baseline (Month [M] 0) sNfL concentration can predict conversion to McDonald (McD) 2005 MS in patients (pts) with a first clinical demyelinating event (FCDE) receiving subcutaneous interferon β-1a (scIFNβ-1a) once (qw) or three (tiw) times weekly, or placebo (PBO) in the phase 3 trial REFLEX.

Methods

Pts randomized to scIFNβ-1a tiw (n=171) or qw (n=175), or PBO (n=171) were followed-up over 2 yrs; converters to 'clinically definite MS' switched to open label scIFNβ-1a tiw. High and low M0 sNfL subgroups were defined by median sNfL concentration (26.1 pg/ml at M0). Median (95% confidence intervals [CI]) time to McD MS (days) by treatment group and M0 sNfL subgroup was calculated by Kaplan Meier. Hazard ratios (HR; 95% CI) to determine factors influencing risk of conversion to McD MS were calculated using a univariate Cox’s proportional hazard model. A stepwise multivariate Cox’s proportional hazard model was performed using factors selected from the univariate model (threshold P<0.15). For both models, variable selection was based on a two-sided Wald test.

Results

High sNfL levels at baseline correlated with the likelihood for conversion to McD MS (low vs high M0 sNfL, HR [95% CI]: 0.58 [0.47; 0.72], P<0.001). Other baseline factors that reduced the risk of conversion to McD MS (univariate model) included: classification of FCDE (mono- vs multifocal: 0.68 [0.55; 0.83], P<0.001) and low numbers of MRI lesions (number of T2 lesions: 1.02 [1.02; 1.03], P<0.001; number of T1 gadolinium-enhancing [Gd+] lesions: 1.14 [1.11; 1.17], P<0.001; number of T1 hypointense lesions: 1.04 [1.02; 1.05]; P<0.001). Furthermore, treatment with scIFNβ-1a tiw (vs PBO: 0.53 [0.41; 0.69], P<0.001) or qw (0.71 [0.56; 0.91], P=0.006) reduced the risk of conversion to McD MS. These findings were confirmed by multivariate models for baseline sNfL subgroup (P=0.024), classification of FCDE (P<0.001), most baseline imaging findings (number of T2 lesions, number of T1 Gd+ lesions; (P≤0.001), and on-study treatment (both P<0.001).

Conclusions

Among other factors, baseline sNfL concentration was identified as a predictor of conversion to McD MS in patients with a FCDE.

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Biomarkers and Bioinformatics Poster Presentation

P0033 - Baseline serum neurofilament light levels have prognostic value for on-study MRI activity: Results from ASCLEPIOS trials (ID 1669)

Speakers
Presentation Number
P0033
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In the ASCLEPIOS I/II trials, ofatumumab significantly lowered serum neurofilament light (sNfL) levels, a marker of disease activity and treatment response, in the first assessment at month 3 and at all subsequent visits versus teriflunomide.

Objectives

To investigate the prognostic value of baseline sNfL for on-study disease activity and worsening in patients with relapsing MS, particularly in newly diagnosed, treatment-naïve patients.

Methods

Patients (pooled N=1882) were randomized to ofatumumab or teriflunomide, receiving treatment for up to 30 months. Patients were stratified by median baseline sNfL levels. We assessed annual on-study T2 lesion formation and brain volume loss (BVL, Jacobian integration) by sNfL category in all patients and in the subgroup of newly diagnosed within 3 year of screening without prior disease-modifying treatment (representing natural course of sNfL and disease at baseline) at month 24 or end of study. The annualized rate of new or enlarging T2 (neT2) lesions in year-2 versus year-1 was assessed in all patients by sNfL category (negative binomial model with time [in year] as offset).

Results

Patients with high sNfL (>median) levels at baseline developed more neT2 lesions per year on study than patients with low (≤median) sNfL levels (adjusted mean rate: ofatumumab: 0.95 vs 0.39, relative increase 143%, p<0.001; teriflunomide 5.28 vs 3.02, relative increase 74.5%, p<0.001). The prognostic value of baseline sNfL persists for year-2 (high vs low, ofatumumab: 0.09 vs 0.06, 64.5%, p=0.124; teriflunomide 4.53 vs 3.12, 45.6%, p=0.003. A single sNfL assessment at baseline had no prognostic value for on-study relapses and disability worsening. Patients with high baseline sNfL had higher annualized rate of BVL than patients with low sNfL (ofatumumab: 0.32% vs 0.23%, relative difference 37.3%, p=0.045; teriflunomide: 0.43% vs 0.29%, relative difference 49.4%, p<0.001). The results were consistent in the subgroup of newly diagnosed, treatment-naïve patients. The relative treatment effect of ofatumumab versus teriflunomide was similar across all measures in both the high and low sNfL groups.

Conclusions

Baseline sNfL levels were prognostic for on-study lesion formation and BVL for at least 2 years, in all patients and in the subgroup of newly diagnosed, treatment-naïve patients. sNfL levels can supplement clinical assessments and help identify patients at high risk for future disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0034 - Can Digital Biomarkers Acquired on a Smarphone Distinguish Healthy Controls from Radiologically Isolated Syndrome Subjects? (ID 238)

Speakers
Presentation Number
P0034
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Radiologically isolated syndrome (RIS) is defined by the incidental finding of MRI lesions suggestive of multiple sclerosis in subjects with a normal neurological examination. Some studies suggested that the use of wearables could unveil infra-clinical differences between RIS subjects and healthy controls (HC).

Objectives

To demonstrate that digital biomarkers collected by a smartphone application can distinguish healthy controls (HC) from subjects with radiologically isolated syndrome (RIS).

Methods

We created a mobile app called MS Screen Test (MSST) that contains:

- Finger tapping speed test: during this task, we measure the mean tapping speed for the dominant hand and the non dominant hand

- Level test: the subject is asked to tilt the phone to move a ball inside a target, then maintain it inside the target for 10 seconds. We measure the required time to bring the ball to the target, then the proportion of time during which the ball is maintained inside the target

- Low contrast vision (LCV) test: letters with varying contrast randomly appearing on the screen. The subject has to tap on the screen each time a letter is seen. The number of good answers is collected

- Cognition test: letters or digits randomly appear on the screen. The subject has to tap on the screen only if a letter is seen. The mean tap latency in milliseconds is collected as well as bad answers

A cohort of HC and RIS subjects were evaluated to compare performances on MSST.

Results

60 HC and 16 RIS subjects were prospectively included (F/M 3.15, mean age 41.6 yrs)

Compared to HC, RIS subjects had a lower tapping speed on both dominant (5.6 Hz vs 6.5 Hz, p=0.001) and non dominant hand (5.1 Hz vs 5.6 Hz, p=0.04), fewer detected letters on the LCV test (10 vs 13, p=0.001) and a higher latency of response on the cognitive test (731 ms vs 599 ms, p<0.0001).

On the level test, the time during which the ball was maintained is the target was shorter for RIS subjects (3 sec vs 4.9 sec, p=0.05).

Conclusions

Our study confirms that digital biomarkers collected by a smartphone can unveil differences between HC and subjects at a presymptomatic stage of MS.

It would be relevant to evaluate whether those biomarkers could predict the risk of conversion to multiple sclerosis, as well as to evaluate their potential predictive value in early diagnosed MS patients

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Biomarkers and Bioinformatics Poster Presentation

P0035 - Can gait modelling predict disease progression in MS? A study using small body worn sensors in a clincial setting.  (ID 1377)

Speakers
Presentation Number
P0035
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Accurate assessment of mobility is critical for the clinical management of people with MS (pwMS), and as a biomarker in clinical trials. Small, body worn sensors hold the possibility to provide greater reliability and accuracy than existing clinical tools. Since these sensors can provide a variety of metrics, they have the potential to provide a richer and more holistic assessment of gait impairment than existing clinical tools. Paradoxically however, the sheer number and partial overlap between the metrics provided by these sensors has led to confusion and impeded their clinical translation and acceptability.

Objectives

This study in the first to establish a data driven conceptual model of factors contributing to gait disturbance in pwMS using data obtained from body worn sensors. We then tested the model for its ability to quantify gait differences across different levels of disability and clinical courses of MS.

Methods

We studied 114 pwMS, divided in three groups according to their Expanded Disability Status Scale (EDSS) score. (mild, EDSS ≤ 3.5, moderate, 4.0 ≤ EDSS ≤ 5.5, and severe EDSS ≥ 6), as well as the clinical course of their illness (relapsing remitting or progressive), and 24 healthy controls. Gait was assessed with inertial sensors (OPAL, APDM), located on the lower shanks and on the lower back while they walked for 6 minutes at their self-selected speed along a 10-m path in a hospital corridor.

Results

Thirty-six metrics were initially computed from the sensor data. Twenty of these met quality criteria for exploratory factor analysis, which revealed a gait model consisting of five factors: rhythm/variability, pace, asymmetry, and forward and lateral dynamic balance. After confirming overall goodness with a confirmatory factor analysis, the model was used to investigate differences in gait features across pwMS with different levels of disability. We found significant alterations in rhythm/variability, asymmetry, and pace domains in the mild disability group, which further progressed in the moderate and severe disability group. Dynamic balance, conversely, appeared to be conserved in mild and moderate disability groups, only deteriorating in the severe disability group.

Conclusions

This model of gait in pwMS highlights clinically relevant and differential gait impairment across different clinical disease course and disability levels. The data can be obtained from small body worn sensors in a clinical setting. This approach has potential as an accurate and responsive clinical biomarker in clinical trials and more widely in clinical practise.

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Biomarkers and Bioinformatics Poster Presentation

P0036 - Cerebral hypometabolism is a marker of disease severity in multiple sclerosis: a non-invasive imaging study using T2-Relaxation-Under-Spin-Tagging MRI (ID 1856)

Speakers
Presentation Number
P0036
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO2; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO2 trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO2: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO2 was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO2 was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

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Biomarkers and Bioinformatics Poster Presentation

P0037 - Change in serum neurofilament light chain levels: ENSEMBLE 1-year interim results (ID 945)

Speakers
Presentation Number
P0037
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Early treatment of multiple sclerosis (MS) provides significant long-term benefits. The aim of the Phase IIIb ENSEMBLE study (NCT03085810) is to evaluate the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Neurofilament light chain (NfL) is a marker of neuroaxonal injury. OCR reduced elevated NfL levels in patients with relapsing MS and primary progressive MS to those of healthy donors in the OPERA and ORATORIO studies over 96 weeks. NfL levels are assessed yearly in ENSEMBLE.

Objectives

To report 1-year NfL analyses from ENSEMBLE.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; Expanded Disability Status Scale [EDSS] score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients will receive OCR 600 mg every 24 weeks (first dose, 2×300 mg separated by 14 days) for the 192-week treatment period (maximum 8 doses). Serum NfL levels are measured via the Simoa Quanterix Advantage kit.

Results

A total of 582 patients were included in the NfL evaluation (female, 64.3%; mean [SD]: age, 32.4 [9.2] years; baseline EDSS, 1.70 [0.96]; time since MS symptom onset, 1.08 [0.84] years) with characteristics comparable with the overall population (N=678). The median serum NfL level at baseline was 13.20 pg/mL; 81.8% of patients had levels greater than healthy donors (HDs; 7.1 pg/mL). Median NfL levels at baseline in patients stratified by age, gender and EDSS score were consistent with those of the overall population. The highest median NfL levels at baseline were observed in patients with T1-weighted contrast-enhancing lesions (CELs) at screening (18.71 pg/mL; n=260) and relapses within 3 months of enrollment (14.91 pg/mL; n=217). At Week 48 the median serum NfL level was reduced to 6.35 pg/mL; 60.8% of patients had levels comparable to or lower than the HD level. Decreases in median serum NfL levels were observed, independent of the baseline demographics and disease characteristics of age, gender, EDSS score, CELs, relapses and reason for enrollment.

Conclusions

NfL levels at baseline and patterns of change over 48 weeks were in line with previous evaluations and decreased considerably after 1 year of treatment with ocrelizumab.

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Biomarkers and Bioinformatics Poster Presentation

P0038 - CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity (ID 783)

Speakers
Presentation Number
P0038
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evidence for a role of innate immune cells such as the CNS-resident macrophages or microglia in MS pathogenesis is growing, and the heterogeneity of microglial subsets is increasingly recognized. Several biomarkers directly reflect the neurodegenerative and inflammatory processes in MS. Macrophage and microglia-related biomarkers in CSF have been reported in other neurological diseases.

Objectives

We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity
(relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

Methods

In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3–like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia-related markers in publicly available RNA expression data from postmortem brain tissue.

Results

CHIT1 levels at diagnostic LP correlated with 2 aspects of long-term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E-04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E-04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.

Conclusions

CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0039 - Circulating microRNAs as potential inflammatory biomarkers of acute exacerbation in relapsing-remitting multiple sclerosis (ID 938)

Abstract

Background

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory-degenerative disease of the central nervous system. MicroRNAs (miRNAs) are short sequences of 19-25 non-coding single-stranded RNA nucleotides that regulate transcriptional gene expression by inhibiting the translation of specific messenger RNA targets and protein expression respectively. miRNAs are involved in various physiological and pathological processes, in particular contribute to the activation of the Th1 and Th17 pathways that regulate the immune response. Many studies show that the miRNAs are involved in MS epigenetic mechanisms affecting both the expression of inflammatory cells and myelination factors.

Objectives

This study aimed to compare the serum miRNAs in relapsing MS patients compared to remitting ones and to healthy controls for better understanding of MS pathogenesis.

Methods

We evaluated 3 groups of subjects: 16 relapsing-remitting (RR)MS patients in relapse (Group I); 12 RRMS patients in remission (Group II) and 12 sex- and age-matched healthy controls (Group III). Total extraction of RNA from sera was performed with a column-based method that includes small RNAs and minimizes the carryover of enzyme inhibitors typically contained in biofluids (miRNEeasy serum/plasma kit, QIAGEN). Total RNA was labeled and hybridized with Human miRNA Microarray Release 21 (Agilent) containing probes for 2549 human microRNAs from the Sanger database. Arrays were verified for quality control and extracted by Agilent Feature Extraction 10.7.3.1 software and entirely processed by MATLAB (The MathWorks Inc.) in house-built routines. Deregulated miRNAs were established by permutation test and a false discovery procedure used for multiple comparisons. Unsupervised hierarchical clustering was performed to individuate specific pattern of expression among samples and clusters of miRNAs. The results obtained were validated by Real-Time PCR.

Results

We analyzed 2549 miRNA that were expressed in at least 50% of the samples. After eliminating 10 samples that expressed only a few of these miRNAs, we found 66 expressed miRNAs in the half of remained samples. Microarray analysis identified a signature of 8 deregulated miRNAs in relapsing MS patients compared to controls and remitting MS patients. In particular, among these eight miRNAs, two were up-regulated (miR-2861 and miR-6821-5p) while six were down-regulated (miR-4281, miR-5196-5p, miR-6076, miR-642a -3p, miR-671-5p, miR-6879-5p).

Conclusions

We have found several upregulated or downregulated miRNA to be correlated with disease exacerbation in RRMS patients. Previous studies have reported five of these miRNAs to be involved in other inflammatory disorders. We hypothesize that the miRNA could be useful biomarkers not only to improve diagnosis and disease control, but also to predict the phase of acute exacerbation in MS.

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Clinical Outcome Measures Poster Presentation

P0040 - Cladribine tablets versus other DMT in achieving disability improvement in relapsing remitting multiple sclerosis patients – network meta-analysis (ID 573)

Presentation Number
P0040
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis is a chronic disease of the central nervous system, most often with relapsing-remitting (RRMS) course.

Cladribine tablets was tested against placebo in randomized controlled trials (RCT) in RRMS.

As there is lack of head-to-head trials directly comparing CT to other highly active DMTs, an indirect comparison via network meta-analysis (NMA) was performed with placebo as a common comparator.

Objectives

To compare probabilities of sustained disability improvement (SDI) on the EDSS, in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FIN), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR).

Methods

In compliance with the Polish HTA guidelines, a systematic review was conducted in Pubmed, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied, using the WinBUGS© software.

Results

Finally, 6 trials presenting SDI results and applicable for NMA were included: 5 non-RCTs, with control groups selected by propensity score matching (Kalincik 2018, Kalincik 2015, Kalincik 2017, Barnocini 2016, Guger 2018) and 1 RCT (CARE MS II), allowing for comparison of CT vs FIN, NAT, ALE. Due to the lack of proper data, comparison with OCR was not possible. Additionally, there were only 37 patients treated with CT with SDI data available (Kalincik 2018). NMA results revealed that Hazard Ratios (95% CrI) for achieving 6-month SDI with CT was statistically significantly higher in comparison with all other high efficacy disease modifying treatments studied in this analysis: CT vs FIN – 5,17 (1,81; 15,01), CT vs NAT – 3,06 (1,06; 8,62), CT vs ALE – 9,45 (2,79; 31,94).

Conclusions

Cladribine tablets treatment was associated with higher probability of sustained recovery from disability compared to fingolimod, natalizumab and alemtuzumab in RRMS patients with highly active disease. The conclusion is based on limited quality of identified clinical data.

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Clinical Outcome Measures Poster Presentation

P0041 - Clinical characteristics and outcome of late onset Multiple Sclerosis (ID 1467)

Speakers
Presentation Number
P0041
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Clinical characteristics and disability progression in late onset MS (LOMS) (> 50 years at symptom onset) compared to adult onset MS (AOMS) (> 18- 50 years at symptom onset) is less well studied.

Objectives

To describe clinical characteristics and risk for disability progression in LOMS and AOMS within the Swedish MS population.

Methods

Data were collected from the nationwide Swedish MS registry (SMSreg). Patients with a diagnosis of MS, symptom onset > 18 years and ≥ 2 expanded disability status scale (EDSS) scores recorded were included. Clinical and demographic factors in LOMS and AOMS were compared. The risk for disease progression was assessed by analyzing time to reach sustained EDSS of 4,0 and 6,0 after disease onset, using Cox proportional hazard regression models adjusted for age, sex, disease course at onset.

Results

A total of 13,040 eligible AOMS were included of which 1,120 (8,6%) had LOMS. Median age (inter quartile range, IQR) at symptom onset was 54.0 (51.0-57.0) years in LOMS and 31.0 (26.0-39.0) yeas in EOMS. Diagnostic delay (time from symptom onset to diagnosis; median (IQR)) in LOMS; 1,21 years (0.41-3.35) and EOMS; 1,38 years (0.36-5.0) and sex distribution (female; 68,0 % vs 70,1%) were comparable in both groups. Close to one third of LOMS patients (29,2%) presented with primary progressive MS (PPMS) compared to 5,9% of AOMS. A relapsing onset was observed in 40.0% of LOMS and 65.4% of AOMS. Exposure to first line treatment was documented in 34.9% of LOMS and 59.6% had been exposed to a second line treatment (defined as fingolimod, natalizumab, rituximab or alemtuzumab). The risks to reach EDSS 4.0 (HR 1.96; 95% CI 1.72-2.24) and 6.0 (HR 2.42; 95% CI 2.13-2.75) were increased in LOMS compared to AOMS.

Conclusions

LOMS is characterized by a significantly higher incidence of PPMS as initial disease course and increased risk of disability progression compared to AOMS even after adjustment for age, sex and course, and even though more than half of the LOMS patients had been treated with a second line DMT.

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Clinical Outcome Measures Poster Presentation

P0042 - Clinical evolution of spasticity in adults with multiple sclerosis: systematic review (ID 1615)

Speakers
Presentation Number
P0042
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Spasticity is a common symptom for people with multiple sclerosis (MS), occurring in >80% of MS patients and increasing in prevalence and severity throughout the disease course. Worsening spasticity is associated with pain, sleep disorders, further impaired mobility, bladder dysfunction and other symptoms, impacting negatively on quality of life and increasing health resource utilization and costs. Data showing evolution of spasticity over time appear limited and, when reported, often use non-validated categorical scales.

Objectives

To conduct a systematic review of published evidence on the prevalence and clinical evolution of MS-related spasticity.

Methods

Searches were conducted in bibliographic databases. Two reviewers selected articles according to pre-defined inclusion criteria. Data were extracted to describe the frequency of spasticity, and progression of spasticity severity.

Results

Four studies were eligible for inclusion including a total of 29,196 patients. Study design was either retrospective (n=3), or longitudinal (n=1). Study duration ranged from approximately three to 30 years. Study population, timeframe for evaluation and method of assessment of spasticity within the included studies were heterogeneous which precluded meta-analysis. Two studies reported symptom prevalence and severity (measured using categorical mild/moderate/severe scales) over time. Results demonstrated an increased proportion of patients with severe symptoms, despite treatment. A continuous decrease in the proportion of participants with milder severity was also reported. The remaining two studies reported the clinical evolution of spasticity over time. Both studies used the 0–10 numeric rating scale (NRS) (0 no spasticity to 10 worst possible spasticity) to measure change in spasticity: one compared symptoms pre- vs post-MS diagnosis split by relapse- and progressive-onset disease, and the other in patients with treatment-resistant (≤1 prior therapy) MS-related spasticity, indicated a deterioration in spasticity over time (1 to 3 years [mean 2.1 years], mean NRS 5.7 [1.9] to 5.9 [2.1]).

Conclusions

Few studies consider the evolution of MS spasticity over the longer term. While there was a high degree of variation between the included studies, all indicated a deterioration in MS spasticity symptoms over time despite available treatments. Tracking MS spasticity seems necessary in MS to inform clinical management.

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Clinical Outcome Measures Poster Presentation

P0043 - Clinical practice experience with Cladribine in Multiple Sclerosis (ID 1499)

Speakers
Presentation Number
P0043
Presentation Topic
Clinical Outcome Measures

Abstract

Background

There are different disease-modifying therapies (DMTs) for treating patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Oral Cladribine was commercialized in 2018.

Objectives

To analyze the first year of treatment with Cladribine in RRMS patients: tolerability, security and initial approach to its effectiveness.

Methods

Retrospective, longitudinal and unicenter study in RRMS patients treated with Cladribine. We analyzed its security measuring overall lymphocyte count by Friedman Test and time to appearance of lymphopenia by Kaplan-Meier. We studied its effectiveness by comparing the following variables with the Wilcoxon Test: relapses, Expanded Disability Status Scale (EDSS) score and gadolinium enhancing lesions before and one year after starting Cladribine (statistically significant p<0’05).

Results

53 patients were studied. 88,7% were women with a mean age of 44,8 years old (DS10,25). 56,6% of the patients had a RRMS evolution of less than 10 years, 32,1% between 10 and 20 years, and 9,4% between 20 and 30 years. 64,1% had been previously treated with one or two DMTs. Patients were exposed to Cladribine for 8 months as a median (percentiles P15=2 months, P85=15 months): 36,4% patients for 6 months, 34,1% between 6-12 months and 29,5% for more than 12 months. The overall lymphocyte count reduction regarding the basal level after starting the drug was statistically significant (p<0’05). The lymphocyte count reduction rate was 52,89% during the first year of treatment and 58,99% during the second one. Tolerability was good in 93,02% of the patients. We observed significant reduction of the relapses rate after one year of treatment.

Conclusions

Cladribine seems to be a secure treatment. The most common adverse effect was lymphopenia (81,8%) but it was severe only in 9,09% of the patients and not associated with severe infections. Its tolerability was very good. Effectiveness results are positive, but, to date, they are preliminary.

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Clinical Outcome Measures Poster Presentation

P0044 - CogEval in the Real World: Feasibility, Implementation, and Real World Implications (ID 1295)

Speakers
Authors
Presentation Number
P0044
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction in multiple sclerosis (MS) patients is common, and routine/efficient screening for cognitive dysfunction is commonly not feasible in a real-world setting for a variety of reasons.

Objectives

To determine patient satisfaction with the CogEval app using the Processing Speed Test (PST), a validated analog of the Symbol Digit Modalities Test (SDMT) as well as time it takes to complete the PST, and clinical decision making as a result of PST testing.

Methods

30 established or new MS patients in our clinic were followed over a period of 64 weeks, and at each visit, PST was administered. Upon consent, patients were administered a single seven-question satisfaction survey using a 5-point Likert scale (1-strongly disagree, 2-disagree, 3-neutral, 4-agree, 5-strongly agree) during one of these visits. Time to complete practice test and PST was captured. Retrospective chart review was performed to determine clinical decision making as a result of performing the PST.

Results

The average time to complete PST was 4 minutes 23 seconds. Likert scale scores were as follows: I liked using the app (4.6/5), The directions on the app were easy to understand (4.8/5), I was familiar with the risk of cognitive dysfunction in MS before using the app (4.5/5), I like the fact that my provider is testing my cognitive status (4.9/5), Because of this app, I’ll be more motivated to learn about the potential effects of MS on my cognition (4.6/5), The app did not take too long to complete (4.8/5), I am willing to repeat cognitive testing at future visits (4.7/5).

Retrospective chart review regarding medical decision making as a result of performing PST are as follows: Discussion about cognitive dysfunction in MS-30 patients, MRI brain-11 patients, labs to rule out other potential causes of cognitive dysfunction-9 patients, initiate high efficacy therapy-9 patients, switch to high efficacy therapy-4 patients.

Conclusions

Based on Likert Scale scores, patient satisfaction with PST testing was high, instructions were easy for patients to understand, patients appreciated the fact that routine cognitive screening was performed at their clinic visits, and the time to complete PST testing was not burdensome. The average time for PST practice test/test completion was 4 minutes 23 seconds. The PST is an efficient, rapid, and repeatable tool to assess for cognitive dysfunction in MS patients longitudinally.

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Clinical Outcome Measures Poster Presentation

P0045 - Comorbidities present before the MS diagnosis are not predictors for progression (ID 1539)

Speakers
Presentation Number
P0045
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Comorbidities are common in multiple sclerosis (MS) population and have been associated with the course of the disease, delays and greater disability in diagnosis, the progression of disability, higher risk of hospitalization, and shorter life expectancy. Predicting functional status and identifying potentially modifiable risk factors early in the course of the disease can help to guide the patient’s treatment.

Objectives

This study evaluated the association between the presence of comorbidities before MS diagnosis and the progression of the disease.

Methods

A retrospective cohort was performed in a reference center for MS care located in Porto Alegre – RS, Brazil. The patients were included between January 1, 2016, and December 30, 2019. A review was conducted on medical records accessing clinical and demographic data regarding age, gender, initial EDSS (EDSSi), current EDSS (EDSSc), and comorbidities before MS onset. The correlation between EDSSi, EDSSc, and the Charlston Comorbidity Index (CCI) and the Elixhauser Comorbidity Measure (ECM) was assessed.

Results

The study included 213 relapsing-remitting MS patients, 77% were females. At the time of diagnosis, 99 patients (46%) presented at least one comorbidity. Throughout the follow-up 128 patients (60%) had progression of EDSS, from whom 59 (46%) had some comorbidity prior to diagnosis, and 69 (54%) were healthy. There was no significant difference between patients with and without comorbidities in the distributions by gender (χ2 = .52; p = .46), but patients with comorbidities were significantly older (Mann-Whitney test z-score = - 3.09, p = .002). There was no significant difference between the groups in EDSSi (z-score = - 1.44, p = .14), EDSSc (z-score = - 0.02, p = .98), and in the progression of EDSS during follow-up (z-score = 0.37, p = .71). The correlation of CCI with EDSSi and EDSSc were not significant (rs = -0.02, p = 0.79 and rs= - 0.149, p = 0.14), as well as that of ECM (rs = 0.07, p = 0.45, and rs = 0.16, p = 0.10).

Conclusions

The presence of comorbidities before the MS diagnosis did not influence the disease's progression in the studied sample. The scores of the tools for measuring comorbidities have no significant association with the disability at the time of diagnosis of MS and also do not impact the worsening of EDSS. Other factors, possibly genetic and environmental, must be evaluated as causal for the progression of MS in the local population.

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Clinical Outcome Measures Poster Presentation

P0046 - Comparative Effectiveness of Ozanimod Versus Dimethyl Fumarate: Results of a Matching-Adjusted Indirect Comparison (ID 492)

Speakers
Presentation Number
P0046
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Ozanimod is a selective S1P1-5 modulator recently approved in the US for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head studies, a matching-adjusted indirect comparison (MAIC) can be used to compare ozanimod with other oral disease-modifying therapies in patients with MS.

Objectives

The objective of this study was to conduct a MAIC of the relative efficacy and safety of ozanimod 1.0 mg with dimethyl fumarate (DMF) 240 mg.

Methods

A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod vs DMF. Individual patient data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate level data for DMF were obtained from CONFIRM and DEFINE. A MAIC was conducted while adjusting for imbalances between studies by reweighting IPD from ozanimod trials to match the mean baseline characteristics reported in the DMF trials. In the absence of a common comparator between ozanimod and DMF, an unanchored comparison was used. Thus, potential treatment effect modifiers and prognostic factors were included in matching.

Results

After matching, baseline patient characteristics were balanced between ozanimod and DMF patients. Compared with DMF, ozanimod demonstrated improved annualized relapse rate (ARR; rate ratio [RR]: 0.80; 95% CI: 0.67–0.97), proportion of patients relapsed (odds ratio [OR]: 0.66; 95% CI: 0.52–0.83), overall adverse events (AEs; OR: 0.11; 95% CI: 0.08–0.16), serious AEs (OR: 0.27; 95% CI: 0.19–0.39), and discontinuations (OR: 0.11; 95% CI: 0.07–0.17) as well as nonsignificant differences for confirmed disability progression (CDP) at weeks 12 (RR: 0.79; 95% CI: 0.58–1.07) and 24 (RR: 0.89; 95% CI: 0.62–1.26).

Conclusions

After adjustment of baseline patient characteristics, ozanimod demonstrated improved relapse outcomes, lower risks of adverse outcomes, and low discontinuations compared with DMF. There were no significant differences in CDP.

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Clinical Outcome Measures Poster Presentation

P0047 - Comparative Efficacy and Safety of Ozanimod Versus Teriflunomide for Relapsing-Remitting Multiple Sclerosis: a Matching-Adjusted Indirect Comparison (ID 569)

Speakers
Presentation Number
P0047
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Ozanimod is a selective S1P1-5 modulator recently approved in the US for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head studies, a matching-adjusted indirect comparison (MAIC) can be used to compare ozanimod with other oral disease-modifying therapies in patients with MS.

Objectives

The objective of this study was to compare the relative efficacy and safety of ozanimod 1.0 mg and teriflunomide (TEF) 14 mg.

Methods

A systematic literature review was performed to identify clinical trials that evaluated the efficacy and safety of ozanimod and TEF. Individual patient data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate level data for TEF were obtained from 6 clinical trials. Heterogeneity was observed between the ozanimod and TEF trials with respect to Expanded Disability Status Scale score, gadolinium-enhanced lesions, disease duration from symptom onset, prior relapse and DMT use, age, sex, region, and weight. An unanchored (no common comparator) MAIC was conducted while adjusting for imbalances between studies by weighting IPD from the ozanimod trials to match the mean baseline characteristics reported in the TEF trials. The following outcomes of interest were assessed: annualized relapse rate (ARR), proportion of patients relapsed, confirmed disability progression (CDP) sustained for 12 and 24 weeks, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs.

Results

After matching, baseline patient characteristics were balanced between ozanimod and TEF. Compared with TEF, ozanimod demonstrated improvements in ARR (rate ratio [RR]: 0.73; 95% CI: 0.62–0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44–0.70), overall AEs (OR: 0.35; 95% CI: 0.29–0.43), SAEs (OR: 0.53; 95% CI: 0.37–0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09–0.21) and similar CDP at 12 (RR: 0.80; 95% CI: 0.61–1.05) and 24 (RR: 0.80; 95% CI: 0.59–1.08) weeks.

Conclusions

Ozanimod was associated with improved relapse outcomes and lower risks of AEs over 1–2 years of follow-up compared with TEF, with no differences in CDP.

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Clinical Outcome Measures Poster Presentation

P0048 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Longitudinal Model-Based Meta-Analysis for Confirmed Disability Accumulation (ID 1257)

Speakers
Presentation Number
P0048
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis (MS) is an inflammatory autoimmune disorder and causes progressive neurological disability in young adults. Ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator, is under development for treatment of relapsing multiple sclerosis (RMS).

Objectives

To assess the effect of ponesimod on confirmed disability accumulation (CDA) relative to placebo and other disease-modifying therapies (DMTs) in treating RMS.

Methods

A literature review was performed and a database of 154 unique trials with 58 MS treatments was developed. The database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Results for CDA were reported with Kaplan-Meier plots; thus, extensive data were available to develop a longitudinal model for probability of a 12-week CDA event. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time. Arm-level variables explored as effect modifiers included: percent of patients with remitting RMS, trial start year, mean duration of disease, percent of patients who received DMT within past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.

Results

This model utilized longitudinal data from 26 RCTs in RMS (18 unique treatments [including placebo], 69 treatment arms, and 417 timepoints in 31,160 patients). HRs were estimated for 12-week CDA for 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (6 treatments). Relative treatment effect was found to be significantly smaller in trials with higher pDMT. Results favored ponesimod in comparison to placebo (HR: 0.61; 95% CI: 0.44–0.83), glatiramer acetate (0.65; 0.44–0.94), and interferon β-1b (0.51; 0.33–0.77) in delaying 12-week CDA. Ponesimod was estimated to have numerical improvement to S1P receptor modulators fingolimod, ozanimod, laquinimod, as well as teriflunomide, interferon β-1a (intramuscular and subcutaneous), peginterferon β-1a, cladribine, daclizumab, and dimethyl fumarate (HR range: 0.77–0.94).

Conclusions

Ponesimod was statistically superior compared to placebo and a range of other DMTs suggesting robust efficacy in the treatment of MS.

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Clinical Outcome Measures Poster Presentation

P0049 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Model-Based Meta-Analysis for Annual Relapse Rate (ID 1256)

Speakers
Presentation Number
P0049
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis (MS), an inflammatory autoimmune disorder, is responsible for progressive neurological disability among young adults. Ponesimod is a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator under development for relapsing multiple sclerosis (RMS).

Objectives

To assess the effect of ponesimod on the annual relapse rate (ARR) relative to other disease-modifying therapies (DMTs) for treatment of RMS.

Methods

A literature review was performed and a database with 154 unique clinical trials with 58 MS treatments was created. This database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Mean ARR for each treatment arm was modeled and rate ratios (RRs) between treatments were assumed constant from 48 to 156 weeks. Multiple arm-level variables were explored as modifiers of relative treatment effect: percent of patients with remitting RMS, trial start year, mean disease duration, percent of patients with history of DMT use in past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.

Results

The model utilized mean ARR data from 41 RCTs in RMS (18 unique treatments [including placebo], 106 treatment arms, 33,904 patients). Rate ratios were estimated for all 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (8 treatments). Relative treatment effect was smaller in trials with higher pDMT. In addition to superiority of ponesimod vs. teriflunomide, results suggested that ponesimod reduced ARR significantly compared to placebo (RR: 0.47; 95% CI: 0.32–0.68), interferon β-1a (intramuscular, 0.57; 0.39–0.85), laquinimod (0.58; 0.38–0.88), and interferon β-1b (0.65; 0.44–0.97). Results suggested that ponesimod had numerically superior ARR benefits compared to interferon β-1a (subcutaneous), peginterferon β-1a, glatiramer acetate, and dimethyl fumarate (RR range: 0.68–0.94). Ponesimod had similar ARR benefits to S1P receptor modulators ozanimod, fingolimod, cladribine, and daclizumab (RR range: 1.00–1.04).

Conclusions

Ponesimod reduced ARR in patients with RMS, and was statistically superior as compared with placebo and a range of other DMTs.

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Biomarkers and Bioinformatics Poster Presentation

P0050 - Comparative transcriptomics of multiple sclerosis vs. viral infections, including SARS-CoV-2 (ID 1045)

Speakers
Presentation Number
P0050
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There are accumulating evidence in the literature that viral infections provide an environmental trigger for the onset of multiple sclerosis (MS) in genetically susceptible individuals. Furthermore, viral infections may contribute to the progression of disability in MS, triggering relapses and promoting neurodgeneration. There are multiple studies assessing the effect of viral infections both in vitro and ex vivo. No study to date has performed a head to head comparison of transcriptomic modulations between MS and viral infections. Furthermore, no study to date has performed these comparisons with the novel coronavirus, SARS-CoV-2, whose neurotropism potential is still under scrutiny.

Objectives

The purpose of this study is to discover common pathways between multiple sclerosis and viral infections, including SARS-CoV-2, on a transcriptomic and functional level.

Methods

The Gene Expression Omnibus (GEO) database was inquired using a query containing the keywords “Virus”, “Multiple Sclerosis”, “Infection”. Included studies involved ex vivo samples of peripheral blood mononuclear cells (PBMCs) following a case – control design. For SARS-CoV-2, a gene signature extracted from a recent infection translatomics experiment (Bojkova et al, 2020) was used in over-representation analyses, and subsequently comapred with the signatures extracted from the MS datasets.

Results

The initial search retrieved 35 studies. Applying the predetermined inclusion criteria, 2 MS vs Healthy Controls (HC) studies and 3 studies of viral infection vs. HC (Dengue, SARS Coronavirus and Rotavirus infections). Multiple common, differentially expressed genes (DEGs) and associated significantly enriched pathways emerged between the MS vs viral infection subgroups. The “Epstein Barr infection” pathway was salient among MS-related viral infection pathways (False Discovery Rate (FDR) <0.05). Furthermore, comparative transcriptomics revealed 4 common gene signatures of 80 to 150 genes, associated with nuclear transport, neuroactive peptide binding and the spliceosome (FDR<0.0001). Comparisons between the MS datasets and the SARS-CoV-2 - host interactome revealed overlapping perturbations in pathways associated with neurodegeneration and mRNA surveillance pathways (FDR<0.05). Notably, a confirmatory analysis of the SARS-CoV-2 interactome with Enrichr, comapring said interactome with disease-control experiments in the Gene Expression Omnibus (GEO) databases revealed relapsing remitting MS among diseases with overlapping gene signatures (FDR<0.05).

Conclusions

Ours is the first study to directly compare viral infection mechanisms with the molecular pathophysiology of MS in a transcriptomic level. Our results indicate a “response to infection” phenotype in MS PBMCs, associated with alternative splicing and disruptions of transcriptional surveillance.

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Biomarkers and Bioinformatics Poster Presentation

P0051 - Comparison of serum and CSF fluid biomarkers for predicting long term disease progression in MS
  (ID 1448)

Speakers
Presentation Number
P0051
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.

Objectives

Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.

Methods

In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.

Results

67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).

Conclusions

This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.

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Clinical Outcome Measures Poster Presentation

P0052 - Completion rates by clinicians in global MS studies for the electronic EDSS compared to paper (ID 1904)

Speakers
Authors
Presentation Number
P0052
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The Expanded Disability Status Scale (EDSS) is a widely used assessment in multiple sclerosis (MS) clinical trials and often used as primary or secondary endpoints, contributing to labeling claims. However, inter- and intra-rater variability is high, which can lead to decreased power to detect treatment effects. Electronic implementations of the EDSS have been shown to reduce inconsistencies and improved inter-rater reliability. Yet, clinician acceptance of electronic implementations of the EDSS has rarely been examined.

Objectives

The aim of this study is to determine clinicians’ acceptance of the electronic EDSS by comparing the completion rates of the electronic version of the EDSS versus the pencil-and-paper version.

Methods

Data was collected as part of two phase 3, multicenter global MS trials during a 2-year period. All clinicians were provided ERT’s electronic EDSS, which uses the Neurostatus system of scoring algorithms and feedback including real-time, on-device detection of inconsistencies and post-submission guidance and queries on inconsistencies by expert reviewers. Clinicians had the option to complete the EDSS electronically in real-time or complete the assessment using the pencil-and-paper version prior to entering the scores on the electronic device.

Results

A total of 9142 assessments were completed with 2160 patients, from 357 sites, in 39 countries. 69.1% of the assessments were completed electronically in real-time and 30.8% were completed on paper first and transcribed onto the electronic device. 0.1% of the assessments were completed using neither the electronic nor paper version, but scores were entered electronically from clinicians’ recollection of the assessment. A majority of the sites used the electronic EDSS for more than 50% of their assessments. Sites in Thailand, Taiwan, Norway and Italy used the electronic EDSS for 100% of their assessments. Assessments using the electronic EDSS took an average of 82.1 minutes to complete. It took an average of 43.4 days for assessments completed on paper to be entered on the electronic device.

Conclusions

Overall, the use of the electronic EDSS was widely accepted by clinicians across the majority of the countries. This finding supports the use of an electronic EDSS to reduce inconsistencies, improve inter-rater reliability, and expedite the collection of data.

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Biomarkers and Bioinformatics Poster Presentation

P0053 - Correlation Between Spinal Fluid and Blood Levels of Neurofilament Light, GFAP, Tau, and UCHL1: Do We Need a Correction Factor? (ID 1942)

Speakers
Presentation Number
P0053
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Plasma neurofilament light(pNFL) levels account for 30-60% of the variance in CSF neurofilament light(cNFL) levels depending on the study. Age, disability, relapses, and the presence of contrast enhancing MRI lesions can increase both pNFL and cNFL. Additional nervous system biomarkers can now be studied in plasma. Understanding the factors that increase their variability in blood may be helpful in normalizing levels to better understand what levels are concerning for ongoing disease activity.

Objectives

To evaluate factors contributing to blood and cerebrospinal fluid(CSF) discordance and determine if a correction of blood levels can better estimate what is happening in the CSF compartment.

Methods

Matched plasma and CSF samples were identified in the Rocky Mountain Multiple Sclerosis Center Biorepository at the University of Colorado. Neurofilament Light(NFL), Glial Fibrillary Acidic Protein(GFAP), tau, and Ubiquitin carboxy-terminal hydrolase L1(UCHL1) levels were assessed using Single Molecule Array(SIMOA) in a Quanterix SR-X machine. Analyses were done on log transformed NFL concentrations.

Results

Fifty-seven patients had matched plasma and cerebrospinal fluid samples evaluated for neurofilament light which included 24 patients with multiple sclerosis(MS), 7 with neuromyelitis optica spectrum disorder(NMOSD), and 18 patients with headache whose opening pressures were <20cmH2O. These patients had a mean age of 46.5(+/-11.2) years, 75% female, mean albumin index of 6.3(+/-5.5), and BMI of 27.4(+/-5.8). The CSF and plasma concentrations in pg/ml were for NFL 1059.3(+/-3052.4) and 12.2(+/-32.4), GFAP 7621.5(+/-9713.4) and 52.9(+/-39.7), tau 41.5(+/-41.3) and 1.3(+/-0.8), UCHL1 1356.0(+/-1677.1) and 23.6(+/-32.8). Respectively the CSF vs plasma Spearman correlations (95% confidence intervals, p values) were: 0.79(0.67-0.87,<0.0001), 0.67(0.50-0.79,<0.0001), 0.75(0.61-0.85,<0.0001), and 0.70(0.54-0.81,<0.0001). Adjusting individually for age, BMI, or albumin index did not affect the correlation for NFL.

Conclusions

Blood and CSF levels of NFL, GFAP, tau, and UCHL1 correlated well. Models will be created that explore the relationship between Blood and CSF levels of these biomarkers.

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Clinical Outcome Measures Poster Presentation

P0054 - Cost of a relapse-free patient in relapsing-remitting multiple sclerosis, a reliable result-based health indicator. (ID 461)

Speakers
Presentation Number
P0054
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Nowadays we know the efficacy and safety of disease-modifying therapies (DMTs) in multiple sclerosis (MS) but we lack result-based health indicators to evaluate its cost-effectiveness.

Objectives

The objective of the study is to analyze if the cost per year of a relapse-free patient is a reliable health indicator comparing the cost between 2016 and 2019 of DMTs in a cohort of relapsing-remitting MS (RRMS) treated with DMTs in a representative population cohort.

Methods

Patients followed in our MS unit during 2019, diagnosed with MS and belonging to our sanitary district were evaluated, our center has the only MS unit in the district. From them, patients diagnosed with RRMS were retrospectively selected for this study. Clinical data were collected prospectively on a 6-monthly basis and at the time of any relapse. All patients were visited by a qualified neurologist who performed a neurological examination assessing the disease severity by the Expanded Disease Status Scale (EDSS). Data from magnetic resonance imaging (MRI) were retrospectively retrieved. The proportion of patients with no evidence of disease activity (NEDA) was analysed. The mean cost of DMTs during 2019 had been analyzed as well as the cost of a relapse-free patient. The cost of a relapse-free patient was a ratio between the total cost of DMTs and the number of relapse-free patients. The results of 2019 were compared with the results already obtained in 2016.

Results

A total of 214 patients belonging to our sanitary district diagnosed with MS and followed in our MS unit in 2019, were selected. They indicated an MS prevalence of 105 per 100000 inhabitants, representative of the expected prevalence of MS in epidemiological population-based studies performed in our area. From them, 183 patients were RRMS and were included in our study. They were 67.8% women, their mean age was 48.3 (SD 12.9) years, their mean age at onset was 31.8 (SD 10.8) years, their disease duration was 16.32 (SD 11.7) years and their median irreversible EDSS was 2.0 (range 0-7.5). From those 183, 126 patients (68.9% of the cohort) were treated with DMTs during 2019, 151 patients (82.5% of the cohort) remained free of relapses during 2019, 171 patients did not increase their EDSS (93.4% of the cohort) and 126 of the 144 with Magnetic Resonance Imaging (MRI) in 2019 had neither new T2 lesions nor gadolinium-enhancing lesions (87.5%). The proportion of NEDA (no evidence of disease activity) in those 144 patients was 69.4%. The mean cost of DMTs per patient in 2019 was 6985.4 euros (95% CI: 5986.9-7983.9) when all patients were considered, relapse-free and relapsing patients as well as treated and not treated, in 2016 it was 7414.3 euros (95% CI: 6325.2-8503.4). The cost per year of DMTs of a relapse-free patient was 8465.8 euros in 2019 and 9762.2 euros in 2016.

Conclusions

The cost per year of a relapse-free patient may be a reliable result-based health indicator given its stability in successive measurements in the same population.

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Biomarkers and Bioinformatics Poster Presentation

P0055 - Cross-sectional and longitudinal estimation of radiographic and clinical endpoints to quantify MS disease trajectory with blood serum protein levels. (ID 836)

Speakers
Presentation Number
P0055
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Quantification of the activity and progression of multiple sclerosis (MS) is an important tool for research on MS as well as its clinical treatment. Currently, disease activity and progression assessments rely on qualitative clinical evaluations or the acquisition of radiographic data such as magnetic resonance imaging (MRI).

Objectives

Quantifying MS disease activity (DA) and progression (DP) instead through the use of blood biomarkers would provide a significant reduction in barriers to such testing (e.g. monetary cost, time and specialized personnel requirements, invasiveness, operational difficulty, etc.). The use of an ensemble of proteins representing various biological pathways involved in MS pathophysiology would also provide useful insights into this complex and heterogeneous disease.

Methods

We investigated proteomic biomarkers associated with different levels of MS DA and DP using 205 blood serum samples from 88 patients (University Hospital Basel), extracting protein levels using Proximity Extension Assays (PEA) from OlinkTM. We then conducted a focused statistical analysis on 21 proteins that were selected for a custom MS assay panel development project based on their association with endpoints in previous studies. We corrected these protein levels using clinical data, including: age, sex, disease duration, age of the bio-banked sample, and medication status. We then compared protein levels to five different radiographic and clinical endpoints.

– Primary Endpoint: Gadolinium (Gd) enhanced lesion count

– Secondary Endpoints: T2 lesion volume, Expanded Disability Status Scale (EDSS) score, Clinically Defined Relapse Status, and Annualized Relapse Rate (ARR)

Results

In this report, we examine the univariate performance of selected proteins on the prediction of all five endpoints, comparing it to that of several multivariate machine learning techniques. We draw distinctions between the highest performing models for each endpoint and draw connections to the underlying biology governing MS activity and progression.

Conclusions

We found significant improvements in predictive power from the use of multivariate models in comparison to even the highest performing univariate techniques. The samples analyzed in this study will be re-assayed for validation purposes alongside additional cohorts in the forthcoming 21-plex custom MS proteomic assay panel.

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Biomarkers and Bioinformatics Poster Presentation

P0056 - CSF inflammatory profile of primary progressive multiple sclerosis (ID 1657)

Speakers
Presentation Number
P0056
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: So far, no specific biomarkers that help to stratify primary progressive multiple sclerosis (PPMS) from relapsing remitting multiple sclerosis (RRMS) patients are still unknown. In the diagnosis of PPMS, among with clinical and imaging assessment, the analysis of cerebrospinal fluid with regard to evidence of oligoclonal bands and/or elevated IgG index is helpful.

Objectives

Objectives: To evaluate the levels of 69 pro and anti-inflammatory cytokines and chemochines as well as Nf-L in the CSF of PPMS at the diagnosis.

Methods

Methods: Levels of 69 inflammatory mediators and of NF-L has been evaluated in the CSF obtained at the diagnosis from 16 patients with PPMS, 80 patients with RRMS and 12 patients with central nervous system non-inflammatory neurological disorders by mean of immune-assay multiplex techniques based on the Luminex technology and Human NF-light enzyme-linked immunosorbentassays. Clinical assessment including EDSS and white and grey matter (WM and GM) lesion volume and numbers were collected by using 3-T MRI analysis.

Results

Results: No significant differences were noticed in IgG index, CSF lymphocyte count, NF-L levels, WM and GM lesion volume and number were not significantly different between PPMS and RRMS. PPMS patients had higher EDSS when compared to RRMS group (median[IQR] 3 [3-4] vs 2[1-2.375]) and older age (mean54.5±9.6y vs 36.8 ± 11.9, p<0.001). Among selected molecules that appeared increased in both PPMS and RRMS groups respect to controls, a multivariate logistic regression analysis showed that at diagnosis altered levels of some B-cell related cytokines such as IL-10 (OR=0.28, CI95%[0.09-0.96]) and CXCL12 (OR=3.97, CI95%[1.34-11.7]) and the monocyte-related osteopontin (OR=2.24, CI95%[1.01-4.99]) were predictive for a primary progressive course of the disease instead of a relapsing one. Kegg pathway analysis confirmed that most of molecules characterizing PPMS CSF profile are involved in chronic immune inflammatory diseases.

Conclusions

Conclusions: At the diagnosis, CSF of PPMS patients appeared characterized by high levels of inflammatory mediators. A detailed CSF profiling obtained at the diagnosis could help to differentiate progressive forms of MS, providing new insights into its pathogenesis and useful tools in clinical practice.

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Biomarkers and Bioinformatics Poster Presentation

P0057 - Decline in serum neurofilament is associated with decreased clinical and radiological disease activity over two years of dimethyl fumarate treatment (ID 1294)

Speakers
Presentation Number
P0057
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Dimethyl fumarate (DMF) treatment is associated with a decrease in serum neurofilament light chain (sNfL) in patients with relapsing-remitting multiple sclerosis (RRMS). sNfL is an exploratory biomarker of MS disease activity. Additional data describing the association between sNfL and disease activity are needed to further investigate this biomarker as a potential predictor of treatment response, which could enable a more holistic disease monitoring approach to treatment.

Objectives

To describe variation in sNfL levels with respect to clinical and radiological disease activity in DMF-treated patients.

Methods

DMF-treated patients with RRMS and complete 2Y follow-up data were analyzed. Serum samples were collected, and routine clinical and radiological assessments were conducted at baseline (BL) and at regular intervals. sNfL concentrations were measured by Single Molecule Array (SiMoA). Normative sNfL data from a cohort of 135 healthy adult controls (age range 21-82 years) were used as a comparator. Age-normative sNfL cutoffs were defined based on the 95th percentile of sNfL levels.

Results

Forty-one patients with 2Y follow-up data were included. Mean (SD) age and disease duration were 37.5 (10.1) and 6.0 (6.5) years, respectively, with mean (SD) time on DMF treatment 43.8 (9.15) months. Twenty-nine (70.7%) patients were treated with a previous MS therapy. Nineteen (46.3%) and 22 (53.7%) patients were below and above age-normative sNfL level at BL, respectively. Over 2Y, mean (95% CI) sNfL level decreased from 8.5 (7.1, 10.2) to 3.4 (2.0, 4.0) pg/ml, representing a 36.6% annual decrease, and 60% decrease over 2Y. Patients experienced a 71.1% (95% CI: 38.8%, 86.3%) reduction in ARR from 1Y prior to BL (0.463, 95% CI [0.279, 0.724]) to 2Y (0.134 [0.067, 0.24]), and 75.6% (59.4%, 87.1%) patients were free of new T2 lesions at 2Y. sNfL was below age-normative level in 53.7% (37.6%, 69%) of patients at BL vs 97.6% (85.6%, 99.9%) at 2Y. Patients with sNfL below age-normative level at BL generally remained below this threshold. At 2Y, patients both above and below age-normative sNfL level at BL experienced low cumulative ARR (95% CI) of 0.132 (0.043, 0.307) and 0.136 (0.05, 0.297), respectively, representing reductions of 75% and 66.7%.

Conclusions

DMF-treated patients reached NfL levels approaching that of healthy controls over 2Y with a reduction in disease activity, regardless of sNfL level at BL in this real-world setting. These data support a correlation between reductions in sNfL levels and decreased disease activity over 2Y of treatment, and potential of sNfL as a biomarker of treatment response that could be assessed during treatment in addition to standard of care monitoring.

Supported by: Biogen.

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Biomarkers and Bioinformatics Poster Presentation

P0058 - Decrease of peripheral CD19+ IgG+ B-cells with age and immunotherapy in patients with relapsing remitting Multiple sclerosis. (ID 1459)

Speakers
Presentation Number
P0058
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Little is known about the impact of aging, long term immunotherapy and the combination of both on the immune system in MS.

Objectives

Identification of age and treatment dependent peripheral immune cell changes in MS patients that are distinct from people with other neurological conditions or healthy controls.

Methods

We performed flow cytometric immunophenotyping on whole blood samples of 133 patients with relapsing-remitting MS (range: 17-66 years; median: 39). A cohort of 95 patients with other neurological diseases as well as 13 healthy people served as controls (range: 17-85 years; median: 45). The focus was on characterizing subsets of CD3+ T cells and CD19+ B cells. We used 22 different fluorochromes, split into two panels, labelling well-established surface markers. We observed 20 identifiable subsets in the T cell panel and 15 subsets in the B cell panel. Relative abundance of each identified subset in a sample was plotted against patient age. Linear regression was performed to determine age-related trends. Trend lines of MS and control group were then compared and an F-test used to determine whether slopes significantly differed from one another. As this was an exploratory study, we decided to also compare overall mean values for each parameter between MS and control group, irrespective of age, with a T-test.

Results

We observed a significant age-related decrease in eight subsets and increases in two subsets of the MS-patients. Controls showed a significant decrease in nine subsets and an increase in three. When comparing slopes, all but one were not different between MS patients and controls (p < 0.05). Only the relative abundance of CD19+ IgG+ cells decreased significantly with increasing age in MS patients (p = 0.0007), whereas there was no obvious trend in the control group (p = 0.5887), suggesting the change was specific to the MS group. Comparing slopes of these trend lines with an F-test, significant difference was achieved (p = 0.0261). Omitting age as a factor in the comparison of MS and control patients, we found differences in mean abundance of CD19+ CD27- IgD+ cells (p = 0.0014), CD19+ IgG+ cells (p = 0.0455), CD19+ CD27+ cells (p = 0.0152) and central memory CD3+ CD4+ cells (p = 0.0003). A subgroup analysis comparing CD19+ IgG+ cells in therapy naive (n = 22) and treated (n = 103) patients showed lower mean values in the latter (p = 0.0062), although the treated group did not contain patients that were on B-cell depleting therapy.

Conclusions

Our results show an age-dependent decrease of CD19+ IgG+ B lymphocytes in MS patients which is likely explained by previous immunotherapies. The identified CD19+ IgG+ subgroup represents terminally differentiated populations of B cells. Further studies will focus on their relation to clinical phenotypes, disease trajectories and the impact of different immunotherapies on this subset.

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Clinical Outcome Measures Poster Presentation

P0059 - Defining predictors of disease activity and worsening in multiple sclerosis: an analysis of the CombiRx trial (ID 828)

Speakers
Presentation Number
P0059
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes.

Objectives

The aim of the study is to identify and assess clinical characteristics in MS that predict disease activity and progression.

Methods

The study population consisted of a prospective cohort of 1,008 patients with relapsing-remitting (RR) onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics (age <38 vs. ≥38, sex, race), clinical history (number of relapses in prior year <3 vs. ≥3, disease duration, Expanded Disability Status Scale (EDSS)), and MRI metrics (presence or absence of gadolinium (Gd) and number of T2 lesions), and treatment (glatiramer acetate (GA), interferon-beta 1a (IFN), or combination therapy); with outcomes of time to first new disease activity over 7-years of follow-up including relapse, MRI activity defined by new combined unique active lesion, and disease worsening as defined by confirmed 6-month increase in EDSS.

Results

1,008 participants were randomized, with 959 eligible for assessment of disease worsening and activity on follow-up MRI. Participants were median 38 (range 18, 61) years of age at baseline, 72.7% female, 88.3% Caucasian, 7.1% black/African American, mean 1.2 years since diagnosis, with median 2 relapses in the prior 12 months and median EDSS 2 (IQR 1, 2.5). Risk of relapse was higher in patients younger than 38 at BL vs. older (HR 1.36, 95% CI: 1.12,1.65) and with BL EDSS ≥3.5 vs. <3.5 (HR 1.66, 95% CI: 1.27, 2.14). Presence of Gd+ lesions at baseline was also associated with increased risk of relapse (HR 1.37, 95%CI: 1.14, 1.66). Risk of new MRI activity was higher in younger participants (HR 1.56, 95%CI: 1.34, 1.86) and those taking either single agent arms compared to the combination (GA: HR 1.48, 95%CI 1.22, 1.80; IFN: HR 1.43, 95%CI 1.18, 1.74). Similarly, higher preexisting lesion burden greater than the median lesion count with ≥71 T2 hyperintense lesions vs. <71 (HR 1.50, 95%CI 1.27, 1.78) and presence of BL Gd+ lesions (HR 1.75, 95%CI: 1.49, 2.06) were also associated with a higher risk of developing new MRI activity. Risk of disease worsening was higher for those with BL EDSS < 2 (HR 2.79, 95%CI 2.14, 3.67). There were no associations between sex and disease duration on clinical or radiological disease activity or worsening.

Conclusions

Both clinical and radiological disease activity are predicted by younger age and presence of Gd+ lesions. Additionally, relapses are also predicted by higher EDSS, and there is some protective evidence of the combination therapy in lowering risk of new MRI activity. Only baseline EDSS level was associated with disease worsening.

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Clinical Outcome Measures Poster Presentation

P0060 - Descriptive study on recruitment effort for a remote monitoring study in Multiple Sclerosis: RADAR study (ID 1529)

Abstract

Background

There is a growing body of literature highlighting the role that wearable and mobile remote monitoring technology (RMT) can play in the assessment of Multiple Sclerosis (MS) and how it could improve clinical care and improve efficiency of research.

The Remote Assessment of Disease and Relapse in the Central Nervous System (RADAR-CNS) study is a pan-European consortium aimed to improve the management of different CNS disorders such as MS, Epilepsy or Major Depression using smartphones and wearable devices.

Most of the available data are based in small monocentric studies, however the full validation of these digital devices requires multicenter, well designed studies providing information on feasibility and acceptability.

Objectives

We aimed to describe the outcomes of the recruitment process in the Multiple Sclerosis (MS) RADAR-CNS disability and fatigue study (D&F).

Methods

The study was run in three European centers. Main eligibility criteria for D&F study were patients with relapsing-reminting or secondary progressive MS with an EDSS score between 2.0 and 6.0. Passive and active data were continuously collected through wearables (FitBit) and mobile phones (Android) and compared to the on-site visit every 3 months. The study duration is 2 years. The study sample size was 400 patients.

Results

The enrolment of the D&F study extended for a period of 18 months. We identified 4094 potential candidates (min-max 885-1789). At the end of the recruitment period, 678 (16.6%; min-max 0-24.2%) remained in the pre-screening phase. 3416 (min-max 885-1454) patients were assessed for eligibility. Out of those, 2372 (69.4%; min-max 53.3-87.1%) were excluded for not fulfilling the eligibility criteria: 1520 (64.1%; 15.0-87.1%) did not meet the EDSS score, 254 (10.7%; 0.2-49.6%) would not be suitable in the investigators opinion and 598 (25.2%; 3.0-60.3) did not have an Android. Out of the 1044 (30.6%; 12.9-46.7) eligible candidates, 644 (61.7%; 13.8-79.7%) declined to participate. A total of 400 (90-162) patients, 9.8% of the potential candidates, were enrolled into the study.

Conclusions

Our study illustrates the primary challenges in recruiting MS patients in RMT studies related to eligibility, both clinical and technological criteria, followed by reasons related to patients preferences. There is variability in the recruitment approach between centers. In future studies, developing technology for all types of phones and more attractive assessment for patients should be considered.

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Biomarkers and Bioinformatics Poster Presentation

P0061 - Determining the effect of blood anticoagulants on the detection level of neurobiomarkers in headache and control patients on the SIMOA platform (ID 1833)

Speakers
Presentation Number
P0061
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In the development of the sensitive single molecule array (SIMOA) technology, serum and blood plasma from EDTA collection tubes were used to verify and validate blood levels of NFL, GFAP, Tau and UCHL1 across healthy controls[1]. As the need arises to establish extensive baseline levels of these neurobiomarkers in order to better evaluate neurodegeneration in a wide variety of patients including multiple sclerosis (MS) patients, a validation study across a variety of blood collection anticoagulants is necessary to ensure there are no significant differences in blood levels due to the additives themselves.

Objectives

To determine whether SIMOA results are reliable and comparable within patients and between cohorts, we measured blood levels of the neurobiomarkers neurofilament (NFL), glial fibrillary acidic protein (GFAP), tau and ubiquitin C-terminal hydrolase L1 (UCHL1) in samples collected with different blood collection additives.

Methods

Serum and blood plasma were collected voluntarily from either headache or healthy control patients in one of four different blood collection tubes representing the 4 most common types of anticoagulant: none (serum), EDTA, sodium heparin (hep) and sodium citrate (NaC). Plasma and serum were isolated from whole blood by centrifugation at 1500 x g for 20 minutes. Plasma was centrifuged at 400 x g for 10 minutes to further deplete cells. Biomarker levels of NFL, GFAP, Tau and UCHL1 were measured via SIMOA with the Neuro4Plex A Advantage kit in the Quanterix SR-X machine according to manufacturer instructions. Statistical comparisons were made using GraphPad Prism analysis software.

Results

No statistically significant differences in blood concentrations were found between the anticoagulants for the NFL, GFAP or UCHL1 biomarkers in either the headache patients or the healthy control patients. However, Tau levels were significantly lower in all serum samples (p value <0.0001) from both patient cohorts with average levels 65-80% lower than plasma.

Conclusions

Use of serum should be avoided when establishing baseline blood levels of the neurobiomarker Tau on the SIMOA platform.

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Clinical Outcome Measures Poster Presentation

P0062 - Developing standard data of cognitive function using Processing Speed Test in Japanese healthy volunteers and comparison to the US normative data (ID 1616)

Speakers
Presentation Number
P0062
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction can be observed early in the disease course of multiple sclerosis (MS) patients and has important consequences for daily activities. International guidelines recommend annual screening with the Symbol Digit Modalities Test (SDMT) and use of electronic administration to increase clinical adoption. The Processing Speed Test (PST) is a self-administered, iPad®-based validated adaptation of the SDMT in MS. The PST is not yet widely used in Japan, and there are few reports of its usage in Japanese subjects.

Objectives

To develop normative data of the PST score on Japanese healthy volunteers (HVs) in order to utilize it as a cognitive function test on Japanese patients with MS, and to characterize the PST score distribution between Japanese HVs and United States (US) HVs.

Methods

A single arm, cross-sectional study was conducted in Japanese HVs. The primary endpoint was the distribution of PST score. The secondary endpoints were distribution of PST scores stratified by age, educational status, and gender. Comparison of the PST scores between Japanese and US HVs collected in a previously reported study was evaluated using an age, gender, and education matched analysis.

Results

Of 254 subjects who participated in this study, 242 subjects with a Mini Mental State Examination score ≥ 27 were analyzed. The mean age was 44.1 years, 51.2% were male and 60.7% were educated over 13 years (vocational school, university, or more educated). Mean PST score (±SD) was 61.8±10.0, median of 62.0 (min 37, max 88). The mean PST score (±SD) significantly decreased with age, with scores of 69.6±8.8 (20-29 years, n=52), 64.9±10.9 (30-39 years, n=45), 63.5±6.1 (40-49 years, n=46), 57.1±8.7 (50-59 years, n=44) and 54.3±6.7 (60-65 years, n=55). The mean score (±SD) with education over 13 years (63.9±9.8) was significantly higher than with education 12 years or less (58.7±9.7) (p<0.0001). There was no significant difference in PST score between males (61.6±10.9) and females (62.0±9.1) (p=0.75). Mean (95% CI) difference between Japanese and US HV PST scores from the matched analysis was 10.2 (8.2, 12.2) (p<.0001), with Japanese > US.

Conclusions

The PST score in healthy Japanese subjects significantly decreased with age and was significantly higher in subjects with higher educational background. The average PST score was higher in Japanese HVs compared to US HVs. Use of country specific normative data may contribute to more accurate cognitive screening in Japanese MS patients.

Study supported by: Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0063 - Development of a Custom Multivariate Proteomic Serum Based Assay for Association with Radiographic and Clinical Endpoints in MS (ID 833)

Abstract

Background

Multiple Sclerosis (MS) is a complex and heterogeneous disease. Investigating the biological pathways and cell types involved in MS pathophysiology as represented by protein biomarker expression can help inform the development of tools to monitor disease activity, disease progression, identify early evidence of relapse, and monitor treatment response.

Objectives

To develop a blood based multiplex proteomic assay that associates with clinical and radiographic endpoints in patients with MS. These endpoints include the presence of gadolinium-enhanced (Gd+) lesions, Annualized Relapse Rate (ARR) and clinically defined relapse status (active versus stable).

Methods

Serum samples (n=690 in total) from multiple deeply-phenotyped cohorts (ACP, CLIMB and EPIC) were tested in immunoassays for the measurement of 1196 proteins using Proximity Extension Assays (PEA) from OlinkTM and for 215 proteins using xMAPTM immunoassays from Myriad RBM, Inc. (RBM). Associated radiographic and clinical endpoints at the time of the blood draw were correlated with the protein levels. Twenty-one proteins were selected for inclusion in a custom assay based on their performance in univariate and multivariate statistical models, and replication across independent cohorts. Biological pathway modeling and network analysis were performed to ensure comprehensive representation of MS neurophysiology. Area under the curve (AUC) was selected as the key metric for model performance evaluation.

Results

Multivariate statistical ensembles restricted to the expression levels of the biomarkers selected for the custom assay achieved AUC performance of 0.827 for classification of the presence of Gd+ lesions, 0.802 for classification of clinically defined relapse status, and 0.930 for the classification of patients with Low ARR (≤0.2 relapses) vs High ARR (≥1.0 relapses). A multivariate model utilizing shifts in biomarker expression in longitudinally paired samples achieved the highest observed performance of 0.950 for classification of Gd+ lesion presence. In each case, the multivariate models significantly outperformed (p-value <0.05) the AUC of the highest performing univariate biomarker.

Conclusions

Multivariate models restricted to the 21 selected proteins effectively classified several radiographic and clinical endpoints with stronger performance than any single biomarker. A 21-plex custom assay panel is being developed for further investigation and validation using additional cohorts.

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Clinical Outcome Measures Poster Presentation

P0064 - Development of the international, multidisciplinary, patient-relevant standard outcome set for Multiple Sclerosis: the S.O.S.MS project (ID 1106)

Speakers
Authors
Presentation Number
P0064
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Currently, there is no consensus on which treatment outcomes need to be measured in Multiple Sclerosis (MS) care. Consequently, it is difficult to monitor and (inter)nationally compare real-world treatment outcomes of MS care. To encourage the shift towards value-based healthcare, there is need for a standard set of outcomes for MS.

Objectives

The aim of this study was to develop an international, multidisciplinary, patient-relevant standard outcome set for MS (S.O.S.MS).

Methods

A mixed method design including a systematic literature review, four patient focus groups (n=30) and consensus-driven RAND- modified Delphi process with an international, multidisciplinary MS expert panel. The expert panel consisted of seventeen MS experts of five different disciplines from seven high-prevalent MS countries. The consensus process consisted of four online consensus meetings plus three online voting rounds.

Results

A standard outcome set for MS was defined, consisting of fourteen outcome indicators divided in three domains: disease activity (3), physical functioning (5) and quality of life (6). Patient focus groups showed that outcome indicators in the quality of life domain were most important to patients. For each outcome indicator, a measurement tool was selected and the frequency of measurement was defined. Both clinical measurement tools as well as patient reported outcome measures (PROMs) were included. In addition to the fourteen outcome indicators, seven case-mix variables were selected.

Conclusions

This international, multidisciplinary standard outcome set for MS enables (inter)national measurement and comparison of patient-relevant outcomes of MS care. Results on the standard outcome set can be used for benchmarking, quality improvement, scientific research, patient information, shared-decision making and contracting care.

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Biomarkers and Bioinformatics Poster Presentation

P0065 - Differential neuroinflammation genes expression in benign and highly active multiple sclerosis (ID 1452)

Speakers
Presentation Number
P0065
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a highly heterogenous disease. Its progression rates and inflammatory activity vary from benign course with rare relapses and expanded disability scale (EDSS) scores 3 or less after more than 10 years after disease onset to highly active disease with rapid progression, high disability scores and poor response to disease modifying treatments (DMTs). Despite extensive research there are currently no biomarkers that could precisely predict MS course.

Objectives

We aimed to investigate differences in the expression of multiple genes associated with neuroinflammation in patients with benign and highly active MS.

Methods

The study included 25 patients with MS (12 with highly active disease and 13 with benign MS) and 12 healthy controls (HCs). Gene expression was analyzed in subjects peripheral blood mononuclear cells (PBMC) RNA using the Neuroinflammation gene expression panel consisting of 770 genes for the Nanostring nCounter platform. Data was processed with the nSolver Analysis Software 4.0 and IBM SPSS and Statistics 23. Gene expression levels were compared with clinical features.

Results

We identified differences in the expression of 89 genes in PBMCs of benign, highly active MS patients and HCs using ANOVA. Genes related to innate immunity, autophagy, microglia function and apoptosis were the most widely represented. Heatmap analysis showed a subset of genes that were differentially expressed in patients with benign and highly active MS. Pairwise comparison of gene expression in patients with benign and highly active MS in the post-hoc analysis revealed 28 genes with significantly different expression in the two subgroups, mostly genes related to microglia function, innate immune response and apoptosis.

Conclusions

The study identified differential expression of genes related to neuroinflammation in benign and highly active MS. The results could have potential implications for prognosis and treatment planning.

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Biomarkers and Bioinformatics Poster Presentation

P0066 - Dimethyl fumarate decreases serum neurofilament light chain in relapsing-remitting multiple sclerosis patients. (ID 924)

Presentation Number
P0066
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are associated with disease activity and prognosis in relapsing-remitting multiple sclerosis (RRMS) patients. Treatment with second-line disease modifying therapies (DMTs) leads to a reduction of sNfL, but little is known regarding first-line DMTs as dimethyl fumarate (DMF).

Objectives

To explore changes of sNfL levels in RRMS patients during treatment with DMF. To evaluate the potential role of sNfL measurement to predict an optimal treatment response.

Methods

Blood samples from 64 consecutive RRMS patients initiating DMF at Hospital Universitario Ramón y Cajal were collected at baseline and at 3, 6 and 12 months thereafter. sNfL levels were measured using a sensitive Single Molecular Array (SIMOA) assay (Quanterix). Patients were classified into No Evidence of Disease Activity (NEDA) and Ongoing Disease Activity (ODA) according the presence/absence of relapses, EDSS progression and/or MRI activity during the first year.

Results

Age at treatment initiation was 40.6 [33.2-46.3] years (median [25-75%IQR]) and EDSS was 1.5 [1.5-2.5]. Forty eight (75%) patients received other previous DMTs, seven of them were second-line DMTs. 66% of patients had evidence of disease activity at DMF initiation. Baseline sNfL levels were higher in patients who had evidence of disease activity at that time compared with patients who had not (12.2 pg/ml Vs. 8.8 pg/ml, p=0.024). No differences were found in baseline sNfL levels between naïve and previously treated patients, or between patients treated with first and second line DMTs. After 12 months of DMF treatment, 44 (69%) patients were NEDA and 20 (31%) were ODA. Baseline sNfL levels were higher in ODA patients compared to NEDA patients (14.6 pg/ml Vs. 9.2 pg/ml, p=0.016). A cut-off value of 12 pg/ml was established to predict NEDA status (OR=4.7; 95%CI: 1.6–15.7; p=0.008). After one year of DMF, sNfL levels decreased by 34.4% (p<0.0001). Both NEDA and ODA patients experienced a progressive sNfL reduction during the first year of treatment. However, this reduction was observed earlier in NEDA patients (three months after DMF initiation) than in ODA patients (six months).

Conclusions

DMF induced a progressive decrease in sNfL concentration during the first year of treatment. This reduction was delayed in ODA patients. Patients with basal sNFL values ≤ 12 pg/ml showed increased probability to achieve NEDA status at 12 months.

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Clinical Outcome Measures Poster Presentation

P0067 - Disability improvement by Multiple Sclerosis Functional Composite in progressive MS patients and MRI features (ID 1729)

Speakers
Presentation Number
P0067
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disability improvement is an important functional measure in progressive MS. The MRI features of disability improvement have not been explored.

Objectives

To assess quantitative brain and spinal cord MRI measures, including volumetric features, that correlate with improvement in the T25FW or 9HPT compared to multiple sclerosis (MS) patients with stable or worsening features.

Methods

A nested cohort from the SysteMS substudy of Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) Study was selected to match inclusion criteria for patients enrolling in a phase 2 trial of repeat dose intrathecal Mesenchymal Stem Cells-Neurotrophic Factor (MSC-NTF) cells in patients with progressive MS (NCT03799718). 3T MRIs at baseline and at follow-up timepoint (12-24 months later) underwent brain and lesion volumetric analysis by Icometrix, as well as mean upper cervical cord area (MUCCA) which generated 34 measures. These 34 MRI volumetric measures (ml) were compared in patients with improved versus patients with worsening or stable 9-hole peg test (9HPT) or timed-25-foot-walk (T25FW) scores. Results were not corrected for multiple comparisons due to the exploratory nature of this study.

Results

48 patients met inclusion criteria. 17 patients had improved 9HPT score, while 29 had worsened or had stable 9HPT score from baseline to 12-24 months later. Whole brain volume at baseline for these 3 cohorts (Improved 9HPT:1505±51 vs. stable-worse 9HPT:1471±62;p=0.069;t-test) and follow-up (Improved:1501.555±52.039 vs. stable-worse:1461.304±63.562);p=0.03;t-test) differed between the two groups, as did gray matter volume at follow-up (Improved 1505.059 ±50.961 vs. stable-worse 865.57±41.352); p=0.063:t-test). For T25FW, 18 patients had an improved score, while 27 were worsened or stable over the 12-month period. Deep white matter FLAIR/T2 lesion volume at baseline (Improved:0.43±0.507 vs. stable-worse:0.827±0.561;p=0.03;t-test) and follow-up (Improved:0.429±0.503 vs. stable-worse:0.864±0.603;p=0.02) differed between two T25FW groups. MUCCA was not associated with improvement measures.

Conclusions

Improved 9HPT measures over a 12-month period correlated with baseline brain volume, while T25FW improvements correlated with baseline deep white matter T2 lesion volume. These results will inform analysis of clinical outcomes in the ongoing phase 2 clinical trial of MSC-NTF cells in progressive MS.

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Clinical Outcome Measures Poster Presentation

P0068 - Disability Progression in MS Participants Treated with Delayed-release Dimethyl Fumarate: Age-related Subgroup Analysis of the NARCOMS Registry (ID 397)

Speakers
Presentation Number
P0068
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Dimethyl fumarate (DMF) clinical trials excluded relapsing-remitting multiple sclerosis (RRMS) patients aged >55 years (yrs). The limited data on DMF use in this age group evaluated relapses but not disability. Unlike relapses, which often decrease as MS patients age, disability progression often increases.

Objectives

To characterize long-term disability outcomes over 4.5 yrs of DMF treatment in RRMS participants based on age at time of DMF initiation.

Methods

We identified NARCOMS participants (pts) with RRMS, living in the US, and initiating DMF from Fall 2013–Spring 2018 with ≥1 yr follow-up. We dichotomized age at DMF initiation as <55 (younger) and ≥55 yrs (older). Disability was measured using the Patient Determined Disease Steps (PDDS). Time to 6-month confirmed PDDS progression (≥1-point increase) and conversion to SPMS were estimated using the Kaplan-Meier method and compared using a log rank test. Cox proportional hazards regression models were adjusted for sex and initial PDDS level. Pts were censored at last follow-up or DMF discontinuation, whichever came first. Safety data were not collected.

Results

647 RRMS pts initiated DMF. In the younger subgroup (n=351, 54%), median age was 47 yrs, 88% female, and 24% reported a relapse in the last 6 months. In the older subgroup (n=296, 46%), median age was 60 yrs, 82% female, and 22% reported a relapse in the last 6 months. Compared to the younger subgroup, older pts had longer MS disease duration (11 vs 17 yrs, p<0.001) and significantly greater disability at baseline as measured by PDDS. Median treatment duration was 2.5 yrs in younger pts and 2 yrs in older pts. At last follow-up, 283 (81%) younger pts and 236 (80%) older pts remained on DMF. Most pts in both groups were estimated to remain free of disability progression over 4.5 yrs: 64% (95%CI: 57-71) of younger pts vs 74% (95%CI: 67-80) of older pts (p=0.12). Most pts in both subgroups also were estimated to remain free from conversion to SPMS over 4.5 yrs: 90% (95%CI: 85-94) of younger pts vs 86% (95%CI: 79-91) of older pts (p=0.17).

Conclusions

Conclusions: As expected, older pts (≥55 yrs) had significantly longer MS disease duration and higher baseline disability compared with younger pts (<55 yrs). Despite these baseline differences, most pts in both groups remained free of PDDS progression and free from conversion to SPMS over 4.5 yrs of DMF treatment.

Supported by: Biogen; NARCOMS is a project of the CMSC

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Biosensors Poster Presentation

P0069 - dreams: developing a comprehensive, sensitive and validated set of digital biomarkers for MS (ID 1323)

Speakers
Presentation Number
P0069
Presentation Topic
Biosensors

Abstract

Background

Smartphones and watches and their inbuilt sensors allow for the collection of a near to infinite amount of data about their owners. Taking advantage of these capabilities to improve disease characterisation and monitoring and to support treatment decisions in MS seems obvious but faces a number of challenges: Selection and validation of a comprehensive and meaningful set of tests, managing the immense amount of data and identifying the useful information, data privacy and ascertainment of long-term adherence.

Objectives

To assess systematically the feasibility of a comprehensive smartphone and smartwatch based set of digital biomarkers for disease monitoring in patients with MS (PwMS) and validate this tool against currently available state of the art clinical, imaging and body fluid assessments.

Methods

The dreams App is a software application including multiple biomarkers for each of the domains movement, dexterity, cognition and vision as well as questionnaires for fatigue and other patient reported outcomes. Compliance is enhanced through a gamification-approach. We are currently conducting a feasibility study with a group of PwMS and matched healthy controls to further evaluate the technical reliability of a larger set of digital biomarkers and select those best suited for the validation studies. Early next year, the first of two independent validation studies including 400 PwMS, recruited from participants in the Swiss MS cohort (SMSC) is planned to further validate the digital biomarkers through correlation with established standardized clinical, imaging and body fluid markers already implemented in the SMSC.

Results

Preliminary in-house reliability testing with healthy controls showed intra class correlation coefficients of >60% for the digital biomarkers included in the feasibility study and >80% for at least one in every domain. These results were derived through unguided repetitions over multi-day-timeframes and not optimal laboratory conditions in order to truthfully reflect future use.

Conclusions

With this program, we aim at establishing dreams as a novel smartphone-based comprehensive, modular, validated, independent and broadly accepted digital assessment tool for PwMS. Integrated into a data management and precision medicine based decision support system this assessment tool would improve every day management and allow for better assessment of new therapies in the setting of clinical trials.

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Biomarkers and Bioinformatics Poster Presentation

P0070 - Effect of evobrutinib, a BTK inhibitor, on immune cell and immunoglobulin levels in relapsing MS: an open-label extension to a phase II study (ID 1683)

Speakers
Presentation Number
P0070
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evobrutinib (EVO), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, has a dual mode of action on B cells and myeloid cells involved in multiple sclerosis (MS) pathogenesis. A Phase II randomized study (NCT02975349) investigated the effect of EVO on immune cells and immunoglobulins (Ig). After a 48-week randomized, double-blind period (DBP), relapsing MS (RMS) patients treated with EVO showed no evidence of B cell depletion or clinically relevant changes in memory or mature-naïve B cell subsets. IgG levels remained stable and slight elevations and reductions, respectively, in IgA and IgM levels were observed.

Objectives

To investigate the long-term effects of EVO on B cells (total, mature-naïve and memory subsets), T cells (total, helper and cytotoxic subsets), NK cells, and Ig levels after 48 additional weeks in the ongoing open-label extension (OLE).

Methods

Adults with RMS were randomized double-blind to EVO 25 mg QD, 75 mg QD, 75 mg BID, or placebo (PBO). PBO patients switched to EVO 25mg QD at Week 24. At Week 48, all patients were OLE-eligible, and received EVO 75 mg QD (median ≈48 weeks), then 75 mg BID. Safety of EVO, including assessment of total B cell counts and Ig levels, was a secondary endpoint; effects on B cell subsets, T cells, and NK cells were exploratory. Immune cell counts were assessed at OLE Week 48 relative to DBP baseline, and Ig levels at OLE Weeks 24 and 48.

Results

Of 213 patients receiving EVO during the DBP, 164 (77%) entered the OLE and 148 (90%) completed ≥60 additional treatment weeks. Investigation of total CD19+ B cells and B cell subsets revealed a decrease in CD19+ B cells and in mature-naïve B cells in all groups originally randomized to EVO. The decrease in mature-naïve B cells was consistent with that observed for CD19+ B cell counts, however no evidence of a change in the memory B cell levels was observed. No relevant changes in IgG levels relative to DBP baseline were observed. Mean IgA and IgM levels remained increased and decreased, respectively, but mean values were within normal ranges. Furthermore, there was no evidence of a change in T or NK cell parameters. Overall, EVO treatment was not associated with an increased risk of infections.

Conclusions

Immune cell numbers and Ig levels seen in patients receiving EVO for 48 weeks of the OLE were consistent with those in the DBP. The results suggest a gradual decline of B cells over time with consistent BTK inhibition, however the clinical meaningfulness of these changes remains to be determined. The observed changes in B cells, IgA and IgM levels were not associated with an enhanced risk of infections. These findings suggest that the continuous pharmacological inhibition of BTK over 96 weeks with EVO does not lead to substantial B cell reductions or changes in Ig levels.

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Clinical Outcome Measures Poster Presentation

P0071 - Effect of oral ponesimod on clinical disease activity and MRI-based outcomes in patients with relapsing multiple sclerosis: Phase 3 OPTIMUM study (ID 1570)

Abstract

Background

Ponesimod (PON), an orally active, highly selective and reversible modulator of sphingosine-1-phosphate receptor 1, reduces circulating lymphocytes by sequestration in lymphoid organs. In the phase-3 OPTIMUM study (NCT02425644), PON showed superior efficacy vs teriflunomide (TER) in patients with relapsing multiple sclerosis (RMS).

Objectives

To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.

Methods

Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive PON 20 mg or TER 14 mg for 108 weeks. MRI endpoints included: percentage change from baseline to week 108 in brain volume (SIENA, Structural Image Evaluation, using Normalization of Atrophy), mean number of new gadolinium-enhancing (Gd+) T1 lesions and volume/count of new/enlarging T2-weighted (T2) lesions. NEDA-3 (absence of confirmed relapse, 12-week confirmed disability accumulation, Gd+T1 and new/enlarging T2 lesions on annual MRIs) and NEDA-4 status (NEDA-3 and no average annual brain volume decrease ≥0.4%) were evaluated from baseline to week 108.

Results

985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean percent change from baseline in brain volume: −0.91% vs −1.25% (difference: 0.34%, 95% CLs: 0.17;0.50, p<0.0001); LS mean difference (PON−TER) in change from baseline in total T2 lesion load: −399.2 mm3 (95% CLs: −651.5;−146.8, p=0.002); mean number of new/enlarging T2 lesions per year: 1.40 vs 3.16 (rate ratio [RR]: 0.44, 95% CLs: 0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (RR: 0.42, 95% CLs: 0.31;0.56, p<0.0001); PON vs TER (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, 95% CLs: 1.27;2.28, p=0.0004) achieved NEDA-3; 15.0% (79/526) PON vs 8.5% (45/532) TER patients (OR: 1.85, 95% CLs: 1.24;2.76, p=0.0026) achieved NEDA-4. The most common reason for not achieving NEDA-3 or NEDA-4 status was presence of new/enlarging T2 lesions.

Conclusions

PON showed benefit vs TER for all MRI outcomes including brain volume loss and a significantly higher proportion of patients achieved NEDA-3 and NEDA-4 status, supporting the effects observed on clinical endpoints.

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Clinical Outcome Measures Poster Presentation

P0072 - Effect of switching disease modifying drugs on relapse rate in stable relapsing remitting multiple sclerosis patients planning for pregnancy. (ID 580)

Speakers
Presentation Number
P0072
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The decision to have children is complex for multiple sclerosis patients due to the range of aspects that affect it. One of the most important aspects is the use of disease modifying drugs (DMDs) when planning or during pregnancy and how continuing, stopping or switching them may affect the disease course. It is always better to avoid the use of medications during pregnancy but in patients with severe disease stopping their medium or high potency medications imposes high risk of disease recurrence, rebound or Immune Reconstitution Inflammatory Syndrome (IRIS),specifically when stopping Natalizumab (NTZ) or Fingolimod. Switching to another medication that can be used up to conception and even during pregnancy which are either Glatiramer acetate (GA) or Interferons (IFNs) may be an option.

Objectives

To review available evidence on the effect of different switching strategies in stable relapsing remitting MS (RRMS) patients on clinical and radiological disease activity.

Methods

We searched MEDLINE, EMBASE, EMCARE, CINAHL, SCOPUS, Cochrane Library up to March 2020. No limits or restrictions on time or study design were applied, but only papers written in English were included. We used the revised Cochrane risk of bias tool for randomized trials (ROB2), and national heart, lung and blood institute (NIH) quality assessment tool for before-after (pre-post) with no control group cohort studies.

Results

Seven articles that matched the inclusion criteria were included: 4 cohorts, 2 case reports and one RCT. Results were synthesized narratively and Meta-analysis was not possible due to high heterogeneity (limited treatment overlap) between the studies. Four different switching strategies were identified, the first three were considered de-escalation from high to low potency DMDs, (NTZ to GA), (NTZ to monthly methylprednisolone for three months then GA) which is called (bridging) and (NTZ to IFN). All studies measured the mean change in annualized relapse rate after switching as disease activity measure. These switches showed some protection from rebound and IRIS but not from disease recurrence. The fourth strategy IFN to GA (switching between first line injectables), showed disease stability in two case reports.

Conclusions

Evidence on switching strategy effect on disease course in stable RRMS patients is scarce, available data suggests partial activity in case of de-escalation, and stability in case of switching between first line injectables.

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Clinical Outcome Measures Poster Presentation

P0073 - Effectiveness of peginterferon beta-1a versus non-pegylated interferons and glatiramer acetate in a real-world setting using propensity score matching (ID 1659)

Speakers
Presentation Number
P0073
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Peginterferon (pegIFN) beta-1a with a prolonged half-life and increased systemic exposure was developed for the treatment (tx) of relapsing-remitting multiple sclerosis (RRMS) resulting in less frequent dosing intervals without attenuating the biological or pharmacodynamic properties associated with existing IFN treatments. Real-world data with pegIFN beta-1a in clinical practice are limited. NeuroTransData GmbH (NTD) is a Germany-wide network of neurologists and psychiatrists. The NTD MS registry is a database capturing demographic, clinical history, and clinical variables from MS patients in a real-world setting.

Objectives

To compare pegIFN beta-1a populations with populations using the following injectables: SC IFN beta-1a, IM IFN beta-1a, SC IFN beta-1b, glatiramer acetate (GA).

Methods

NTD registry data from adult patients with RRMS who initiated tx no earlier than 2014, had ≥12 months of tx exposure, and ≥1 EDSS measurement or a relapse after index therapy initiation were retrospectively analyzed. Primary endpoints were annualized relapse rate (ARR) and time to first relapse. The secondary endpoint was time to confirmed disability progression (CDP). Patient characteristics between treatment groups were compared using propensity-score matching (PSM).

Results

In total, 175 pegIFN beta-1a patients, 308 from the IFN group (SC IFN beta-1a, IM IFN beta-1a, SC IFN beta-1b), and 287 GA patients were included in the analysis set. Mean tx duration was 2.5, 2.7, and 2.4 years, respectively. After PSM, no difference was found in the ARR and time to relapse between pegIFN beta-1a patients and patients from the IFN group (estimated ARR ratio 1.18; 95% CI 0.72, 1.94; p= 0.5047; relapse hazard ratio [HR] 1.14; 95% CI 0.71, 1.84; p=0.5790) or the GA group (estimated ARR ratio 0.74; 95% CI 0.45, 1.24; p=0.2608; relapse HR 0.76; 95% CI 0.47, 1.25; p=0.2813). For time to CDP, a significantly higher estimated treatment effect in favor of pegIFN beta-1a was found compared to both, the IFN (CDP HR 0.43; 95% CI 0.21, 0.89; p=0.0234) and the GA group (CDP HR 0.46; 95% CI 0.22, 0.97; p=0.0425).

Conclusions

Statistically significant superiority of pegIFN beta-1a was demonstrated for time to CDP. However, the current analysis is limited by small sample sizes and follow-up time. Updated results with larger sample sizes and longer follow-up time will be presented in order to assess if superiority of pegIFN beta-1a in other endpoints can be supported by statistical evidence.

This study was funded by Biogen.

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Clinical Outcome Measures Poster Presentation

P0074 - Effects of Ocrelizumab on Cognition-Real World Evidence Using the CogEval App (ID 504)

Speakers
Authors
Presentation Number
P0074
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction in MS patients is common, with up to 65% of patients experiencing cognitive difficulties during the course of the disease. The effects of ocrelizumab on cognition have not been studied in a real-world setting.

Objectives

We sought to determine the effects of ocrelizumab on cognition in patients with relapsing multiple sclerosis (MS) or active secondary progressive multiple sclerosis (aSPMS) using the CogEval app's Processing Speed Test (PST), a validated analogue of the Symbol Digit Modalities Test (SDMT). The PST has three major advantages over the SDMT: 1) PST takes only 2 minutes to complete, and does not require a healthcare professional to be present with the patient during testing, 2) PST has been shown to be more sensitive to T2 lesion volume compared to SDMT, and 3) There is a smaller learning effect with PST compared to SDMT.

Methods

We performed the PST on patients in our clinic currently receiving ocrelizumab or who were started on ocrelizumab from January 2019 to April 2020. Only patients who had received at least two doses of ocrelizumab and had at least 3 PST scores were included in the analysis. 28 patients met these criteria. Based on the average of subsequent PST tests performed (Range: 2-5) we analyzed the proportion of patients who improved on PST (>4 points) were stable (no change >4 points or <4 points) or worsened (< 4 points). We performed univariate regression analyses based on age (>40 and <40), gender, smoking, and educational attainment (four-year college degree vs. no college degree). We also performed a sub-group analysis on nine patients starting ocrelizumab therapy with a PST score prior to initiation of ocrelizumab.

Results

Average time on treatment for the cohort was 430 days. 32.1% of patients showed improvement of their PST scores, 50% of patients had stable PST scores, and 17.9% of patients had a worsening of their PST scores. Univariate regression analyses were performed based on age, gender, smoking, and educational attainment (four-year college degree vs. no college degree) and there were no significant trends with any of these analyses. In the sub-group analysis of nine patients with a PST score prior to initiation of ocrelizumab, three patients showed improvement in their PST scores, four patients were stable, and two patients worsened.

Conclusions

To our knowledge, this is the first real-world analysis of the effects of ocrelizumab on cognition using the PST, a validated analogue of SDMT. A substantial majority of patients showed stability or improvement on PST during the course of their treatment with ocrelizumab. Univariate regression analyses looking at age, gender, smoking and educational attainment showed no significant trends, suggesting baseline demographics/disease characteristics did not affect the outcome of PST scores. Longer-term real-world analyses are necessary to determine the effects of prolonged B cell depletion on cognition in MS patients taking ocrelizumab.

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Clinical Outcome Measures Poster Presentation

P0075 - Efficacy of Rituximab in Adult and Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Systematic Review and Meta-analysis (ID 1932)

Speakers
Presentation Number
P0075
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Myelin-oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) is an emerging disease entity related to a broad spectrum of acquired inflammatory demyelination of the central nervous system. Previous studies have demonstrated the efficacy of rituximab (RTX), an anti-CD20 monoclonal antibody, in neuromyelitis optica spectrum disorder, and multiple sclerosis. Although RTX is commonly used in MOGAD as well, the benefit of this therapy is still underinvestigated.

Objectives

To evaluate the effect of RTX in adult and pediatric MOGAD including the change in annualized relapse rate (ARR), and expanded disability status (EDSS), the post-treatment ARR, as well as the prevalence of freedom-from-relapse and EDSS progression.

Methods

A literature search was conducted on MEDLINE, EMBASE, and Cochrane databases. Eligibility criteria included observational studies that evaluated the efficacy of RTX in adult and pediatric MOGAD. We excluded review articles, case reports, studies that included fewer than 2 patients, and unpublished studies. We performed meta-analysis using Comprehensive Meta-analysis version 3.3 software from Biostat, Inc (Eaglewood, NJ, USA). Study results were statistically combined using a random-effect model and displayed with forest plots. The standard mean differences (SMD) with 95% confidence interval (95%CI) of ARR and EDSS, mean post-treatment ARR as well as the prevalence of freedom from relapse and EDSS progression were calculated.

Results

The initial search yield 398 articles. Forty articles underwent full-text review. Twelves cohorts and case series (259 MOGAD patients) were included in the meta-analysis. The SMD of pre- and post-treatment ARR was - 0.629 (95% CI -0.874 to -0.384, p <0.001) for all MOGAD patients, -0.440 (95% CI -0.648 to -0.231, p <0.001) in adults, and -0.957 (95% CI -1.450 to -465, p <0.001) in pediatric population. Post-treatment ARR were 0.893 (95% CI 0.174 to 1.612) in adults, and 0.468 (95% CI 0.181 to 0.754) in children. The prevalence of freedom-from-relapse were 68.8% (95% CI 40.2% to 87.8%) and 59.7% (95%CI 37.0% to 78.8%) in adult and pediatric subgroups, respectively. Although EDSS was not significantly changed, 82.7% (95%CI 63.0% to 93.1%) of MOGAD patients had no increasing in EDSS after RTX therapy

Conclusions

This meta-analysis of the cohorts and case series demonstrated the effects of RTX in adult and pediatric MOGAD patients. Although RTX reduced the relapse rate significantly, a large portion of patients continued to relapse. There was substantial heterogeneity in treatment regimens among studies. Prospective controlled studies are needed to validate these results as well as investigate the safety and tolerability of this treatment.

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Clinical Outcome Measures Poster Presentation

P0076 - Evaluation of diagnosis and treatment practices in patients with Multiple Sclerosis by Brazilian neurologists’ experts in demyelinating disorders. (ID 994)

Abstract

Background

Recent changes in Multiple Sclerosis (MS) diagnostic criteria and new medications promoted a major impact on the way specialists manage the disease.

Objectives

This study aimed to give an insight into the factors considered by Brazilian neurologists in the management of MS, and to identify how these factors contribute to diagnosis and treatment.

Methods

Potential participants were selected by a Steering Committee, which was assembled of MS experts from eleven Brazilian states and was responsible to development the Survey. Only MS specialists were included in the study (neurologists who have completed a neuroimmunology fellowship or who treat more than 30 patients with MS). Links to the online survey were distributed between March 2019 and January 2020. The questionnaire was composed of 11 question sections with hypothetical scenarios, as radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS).

Results

Neurologists from 13 Brazilian states responded to Survey (n=94). In CIS scenario, respondents agreed to treat patients with high risk of MS diagnosis, results that was not founded in RIS case, which half of the respondents opted to not treat, even in high risk patients. In RRMS and high-risk CIS, choice of treatment was distributed among interferon beta, glatiramer acetate and teriflunomide, which were changed to dimethyl fumarate and fingolimod as RRMS severity increased. In PPMS case, almost all respondents agreed to start treatment with ocrelizumab or rituximab. In contrast, the majority of respondents opted to treat SPMS only if there is evidence of disease activity. Reasons for switching medication, in a 12-month period, were appearance of one new or enlarging brain T2 lesion; one gadolinium-enhancing lesion in brain imaging; and one clinical relapse. Almost all specialists perform lumbar puncture for diagnoses, and monitor disease through a 12-months interval neuroimaging. Furthermore, almost all specialists check levels of vitamin D and prescribe supplements for low levels.

Conclusions

This study allowed the identification of areas of agreement among Brazilian neurologists on different scenarios related to patients with MS. These results can be used to promote debate among Brazilian experts, with the goal of helping update future protocols and improve patient management.

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Clinical Outcome Measures Poster Presentation

P0077 - Evaluation of Quality of Life and Fatigue in Patients Followed in Multiple Sclerosis Outpatient Clinic (ID 249)

Speakers
Presentation Number
P0077
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Fatigue in multiple sclerosis (MS) is a common disabling symptom that may have a major impact on quality of life (QoL) of MS patients, however it frequently is overlooked in daily clinical practice. Moreover, the studies exploring the QoL and fatigue have mostly been limited to the MS patients. Currently, we are unaware of any data exploring the QoL and fatigue in the clinical subtypes of MS and other demyelinating diseases. This study aims at bridging this gap.

Objectives

Our objective is to evaluate the quality of life and fatigue in the clinical subtypes of MS patients as well as in patients with other demyelinating diseases.

Methods

The clinical types, quality of life (Multiple Sclerosis Quality of Life-54 - MSQoL-54) and fatigue levels (Fatigue Severity Scale - FSS) of the patients were analyzed retrospectively. Patients were divided into two groups in terms of disability as those with EDSS scores ≥3 and <3. The quality of life of the patients was evaluated according to clinical types and disabilities. The cut‐off score for fatigue was set to be ≥4 in FSS.

Results

The mean age of the patients was 39.59 ± 9.85, and the mean disease duration was 6.30 years. Of all enrolled patients, 1.5% had Radiological Isolated Syndrome (RIS) (n = 1), 10.6% had Clinical Isolated Syndrome (KIS) (n = 7), 68.2% had Relapsing-Remitting MS (RRMS) (n = 45), 9.1% had Secondary Progressive MS (SPMS) (n = 6), 3% had Primary Progressive MS (PPMS) (n = 2), 4.5% had Neuromyelitis Optica Spectrum Disease (NMOSD) (n = 3), and 3% had other demyelinating disease (n = 2). Mean overall MSQoL-54 score was 86.79 ± 8.57, and mean Beck Depression Inventory score was 10.39 in all patients. MSQoL-54 score was 88.36 ± 8.54 in RRMS patients; 81.25 ± 5.78 in SPMS patients; 84.57 ± 10.84 in CIS patients; 82.75 ± 6.71 in PPMS patients; 83.50 ± 7.05 in NMOSD patients; 75.50 in RIS patient; and 90.50 ± 2.12 in patients followed up with the diagnosis of demyelinating disease. Although the QoL scores of the progressive forms were lower; no statistically significant difference between clinical types was found (p = 0.281). The mean MSQoL-54 score was 82.61 ± 5.70 in patients with EDSS scores ≥3 (n = 13) whereas it was 87.82 ± 8.89 in patients with EDSS scores <3 (n = 53) (p = 0.014). The prevalence of fatigue in our cohort was 65.2%. 57.8% of patients with RRMS; 83.3% in SPMS patients; 85.7% in CIS patients; 100% in RIS patients; 50% in PPMS patients; 66.7% in NMOSD patients; and 100% in patients who were followed up with the demyelinating disease reported fatigue (FSS ≥4).

Conclusions

Despite the several limitations including the small number of the patients in subgroups, our results show the higher fatigue levels regardless of clinical types and the association of increased disability and reduced quality of life in MS patients. In addition to medical treatments, periodic evaluation of patients' quality of life with appropriate support programs and taking necessary measures may contribute positively to the course of the disease.

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Clinical Outcome Measures Poster Presentation

P0078 - Evidence for the efficacy of nabiximols oromucosal spray in the management of patients with spasticity: A systematic review (ID 1609)

Speakers
Presentation Number
P0078
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Spasticity is a common symptom for people with multiple sclerosis (MS), and increases in prevalence and severity throughout the disease course. Worsening spasticity is associated with impaired mobility and other symptoms and negatively impacts quality of life, increasing health resource utilization and costs. Nabiximols oromucosal spray, containing mainly tetrahydrocannabinol (THC) and cannabidiol (CBD), and also other CBD and non-CBD components is approved in >25 countries outside of the US as add-on therapy in people with moderate-to-severe MS spasticity who do not respond adequately to other antispasticity medications.

Objectives

To evaluate the efficacy and safety of nabiximols spray as add-on therapy to antispasticity treatment in people with moderate to severe treatment-resistant MS spasticity.

Methods

The review was undertaken following principles published by the Centre for Reviews and Dissemination. A comprehensive search of Medline, Embase, and Cochrane Library databases was conducted. Randomised controlled trials (RCTs) and non-randomised trials investigating the effect of adding nabiximols to standard antispasticity treatment in people with moderate-to-severe MS spasticity were included. Evaluated outcomes included proportion of patients with improvement (30%) in Numeric Rating Scale (NRS) spasticity, mean change in NRS spasticity, quality of life, adverse events. When appropriate data were pooled using meta-analysis.

Results

A total of 7 RCTs with 1,570 participants were eligible for inclusion. Studies scored low risk of bias. Of these studies, data from 4 studies (468 participants) evaluated nabiximols within the approved dose, 1–12 sprays/day: 2 (n=347) were appropriate for pooling (after a 4-week single-blind period, almost half of the enrolled participants met early response criterion [improvement of 20%, label condition] and were randomised). Of these early responders, a greater proportion of patients were clinically relevant responders (30% NRS improvement) with nabiximols than placebo at the end of a 12-week double-blind period (pooled: 75% vs 45%, RR 0.55 [0.33, 0.92]), with a statistically significant reduction in mean NRS spasticity (NRS 0-10) from baseline compared with placebo (pooled: mean difference -1.30 [-2.33, -0.27]). Adverse events were generally mild-to-moderate in severity, transient and rarely required treatment discontinuation. One systematic review of non-randomised studies was identified which reported results in line with those from RCTs.

Conclusions

Add-on nabiximols provides clinically relevant improvement of MS spasticity in patients who do not respond adequately to antispasticity medications both in clinical trial and daily practice settings.
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Clinical Outcome Measures Poster Presentation

P0079 - Experience in Multiple Sclerosis Patients with SARS CoV-2 Infection (ID 1508)

Speakers
Presentation Number
P0079
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The new coronavirus SARS-CoV-2 infection has spread worlwide becoming a pandemic never before seen. Multiple Sclerosis (MS) patients in a state of immunosuppression (IS) may be exposed to a greater risk of COVID-19 complications, although there is increasing evidence postulating a possible protective role of selective IS.

Objectives

To describe the real-world experience in MS patients with SARS-CoV-2 infection at a MS Unit of a hospital in Madrid, Spain. We describe clinical evolution and MS treatment actions

Methods

Observational, prospective and usual clinical practice study in MS patients affected by SARS-CoV-2 infection with clinical diagnosis (at least three of the following: fever, anosmia, cough, diarrhea, myalgia) and/or microbiological diagnosis (PCR in nasopharyngeal swabs and/or serology).

Results

41 SARS-CoV-2 infection cases were registered. 21 were women with a mean age of 39,4 years old (DS10,3). 38 were relapsing-remitting MS patients and 3 had a progressive MS. The mean MS time course was nine years (DS1,4). 39 patients were treated with disease-modifying therapies (DMTs): 46,3% with oral agents, 39% with monoclonal antibodies and 10% with injectable agents. 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2,5 (DS0,7). 11 patients had clinical activity the previous year. 18 cases were confirmed by PCR and/or serology and 23 were clinically diagnosed. 17% of the patients were admitted to hospital (6 were diagnosed with pneumonia) and none required admission to the intensive care unit. There were no deaths.Three patients had other comorbidities. Admitted patients were older and had higher EDSS score without statistical significance. MS got worse in 7 patients. DMTs were stopped or delayed in 10 patients due to the SARS-CoV-2 infection.

Conclusions

All the MS patients studied had a good outcome of the SARS-CoV-2 infection. Only 17% of them required admission to hospital and 14,6% of the cases were asymptomatic. 95% of the patients were treated with DMTs. From our experience, the SARS-CoV-2 infection does not seem to entail a more aggressive form of the disease in this group of patients. Selective IS may favor the good evolution. Larger clinical registers are needed to establish solid conclusions.

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Biomarkers and Bioinformatics Poster Presentation

P0080 - Exploring neurofilament light in CSF as a biomarker for multiple sclerosis in clinical practice (ID 586)

Speakers
Presentation Number
P0080
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light (NFL), a biomarker of axonal damage and disease activity in multiple sclerosis (MS), has been increasingly recognized for prognostic and therapeutic decisions.

Objectives

To assess the sensitivity and specificity of cerebrospinal fluid (CSF) NFL for disease activity and to evaluate its prognostic value in predicting disease severity and conversion from relapsing-remitting (RRMS) to secondary progressive MS (SPMS).

Methods

Patients with a confirmed diagnosis of RRMS (n=769) who had determined NFL in CSF as part of the diagnostic work-up or from assessments as part from regular clinical visits between 2001 and 2018 were retrospectively identified in the Swedish MS registry. Measurements over time of disease activity (clinical relapses and lesion formation on MRI) and disability (EDSS) were retrieved. We assessed NFL levels in relation to concomitant clinical and MRI activity and as outcome for treatment response.

Results

Patients with a concurrent clinical relapse had significantly higher NFL concentrations (median NFL no relapse 278 ng/L, relapsed 1122 ng/L, p<0.001) and a correlation with relapse severity was observed (p<0.001). Patients with gadolinium-enhancing lesions had higher median NFL levels (1414 ng/L) than those without (426 ng/L, p<0.001) and NFL levels correlated with the number of gadolinium enhancing lesions (p<0.001). CSF NFL showed sensitivity of 93.3% and specificity of 77.4% to disease activity (relapses and/or MRI activity). High NFL at diagnosis (n=414) was independently associated with worsening of disability and predicted progression to EDSS≥3 (n=128, p<0.001, HR 0.566 95% CI 0,413-0,711) and conversion to secondary progressive MS (n=39, p=0.0003, HR=0,380 95% CI 0,225-0,641). In a subset of patients (n=159), NFL was analysed at baseline and at follow-up (median time between LPs 23.7 months). Patients who switched from a first-line to a second-line therapy (n=65) exhibited significant reduction in NFL concentrations (p<0.001). However, patients who did not receive disease modifying therapy (DMT) (n=32), had first-line therapy (n=40), or switched to a third-line treatment (n=22) between baseline and follow-up did not show a significant decrease in their CSF NFL levels (p=0.975, p=0.658, and p=0.059 respectively).

Conclusions

Since 2001 CSF NFL has been part of the clinical assessment at Sahlgrenska University Hospital, Gothenburg. Thus, the results of this study are based on a real-life material and we can confirm the utility of NFL as a biomarker in MS. Our data underline NFL as a sensitive biomarker of disease activity, its usefulness for prediction of disability and clinical course and for monitoring DMT response. Serum/plasma NFL is most likely to show similar properties but probably at a lower precision.

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Biomarkers and Bioinformatics Poster Presentation

P0081 - Exploring the usability and patient satisfaction of a virtual rehabilitation program in multiple sclerosis: The RehabVR study protocol (ID 210)

Speakers
Presentation Number
P0081
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: There is an association between motor and cognitive impairment in patients with multiple sclerosis (MS) over their disease course and strong evidence that physical therapy can prevent disability progression in these patients. Virtual reality (VR) has emerged as a promising treatment approach in rehabilitation for patients with MS due to its potential to increase patient motivation and rehabilitation adherence. However, there is a lack of studies about its safety, feasibility and effectiveness in MS patients.

Objectives

Objectives: The objective of this study protocol is to evaluate the feasibility, adherence, safety and effectiveness of a virtual reality rehabilitation (VRR) program in MS patients compared to a conventional rehabilitation (CR) program.

Methods

Methods: A randomized, prospective, open-label, controlled feasibility study will be conducted in a sample of 48 individuals diagnosed with MS. Participants will be allocated 2:1 to the VRR group (32) or CR group (16). Both groups will perform 8 in-hospital physical therapy sessions of 2 hours each, twice a week over 4 weeks. The VRR group will perform half of these sessions with a VRR tool. In addition, both groups will continue rehabilitation at home for 5 months. The VRR program was designed by a multidisciplinary group of healthcare professionals (neurologists, physiatrists, physiotherapists, neuropsychologists) according to a validated CR program. Feasibility will be assessed by the User Satisfaction Evaluation Questionnaire (USEQ). Secondary outcomes include adherence, disability, spasms and spasticity, balance, fatigue, activities of daily living, depression, anxiety, work status, cognition, demographic and clinical characteristics (in the VRR and CR groups), and safety (in the VRR group). Outcome measures will be assessed at baseline and at 1 and 6 months from the start of rehabilitation.

Results

Results: Due to the present comunication is a description of an ongoing study protocol there are stil not results to present.

Conclusions

Conclusions: A better understanding of long-term patient satisfaction with a VRR program specifically designed for MS patients would allow us to optimize the rehabilitation program and to collect valuable information for its implementation in the clinical practice. Additionally, the study will provide information on long-term adherence, changes in motor symptoms, cognitive function and patient-reported outcomes after the rehabilitation program. Altogether, the results from this study will help to gather valuable knowledge on the use of rehabilitation with a new VR tool in MS patients.

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Biomarkers and Bioinformatics Poster Presentation

P0082 - From proteome to interactome: a mechanistic approach to MS biomarker discovery (ID 1215)

Speakers
Presentation Number
P0082
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a multifaceted disease with an intricate pathophysiology that lies at the intersection of autoimmunity, inflammation, redox imbalance, demyelination, and neurodegeneration. The varying interplay of distinct and converging mechanistic profiles in MS is believed to contribute to the heterogeneity observed in disease course and outcomes, clinical presentation, and therapeutic response. With this high degree of undeciphered molecular complexity, identifying biomolecular markers that are reproducible as well as specific to even the major subclasses of MS has been problematic. These difficulties have hindered the clinical translation of biomarkers and their use to aid in disease assessment and treatment strategies for individual MS patients.

Objectives

We posit that a biocentric framework can be leveraged to augment the prognostic capacity of MS biomarkers. By coupling machine learning findings with a computational illustration of their dynamical interactions within disease-perturbed networks, we hope to extract biomarkers that convey the full spectrum of MS pathophysiology—from disease activity to worsening and progression. Furthermore, by honing in on biomarkers that reflect the true underlying biology, we may be able to expand on the standard list of MS clinical and surrogate endpoints, further guiding patient stratification and informing targeted therapeutic selection and drug repurposing.

Methods

Using a panel of 21 protein serum biomarkers that were pre-selected per radiographic and clinical endpoints, we ran spatial expression correlation to extract a proteomic signature specific to MS organs and cell types. We modeled the functional connectivity of these proteins and then performed unsupervised clustering and network centrality analysis to identify motifs of interconnected proteins. Network motifs were later annotated using significantly enriched gene ontology terms and pathways in order to contextualize their mechanism-of-action with respect to MS.

Results

Topological mapping of protein functional interactions uncovered 10 major pathological profiles in MS: (1) myelin integrity; (2) lipid metabolism; (3) immune modulation; (4) inflammation; (5) cerebrovascular function; (6) cell-cell communication; (7) cellular energetics; (8) synaptic dynamics; (9) neuroaxonal integrity; and (10) gut microbiota. Their shifting degree of involvement was captured to characterize the different paths to disease activity and progression. A rich repertoire of immune, glial, and neuronal cells was implicated as being critical in orchestrating the synergistically evolving crosstalk between these various disease mechanisms.

Conclusions

Through a complementary integration of data analytics and systems biology, we were able to shift the focus from that of single proteins to disease processes, identifying clinical biomarkers that appear to fully recapitulate hallmarks of MS.

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Biomarkers and Bioinformatics Poster Presentation

P0083 - Gadolinium improves detection of central vein lesions in MS using 3T FLAIR*. (ID 1404)

Abstract

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

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Biomarkers and Bioinformatics Poster Presentation

P0084 - Gene expression profiling and TCR diversity of ATA188, an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy for progressive MS (ID 1770)

Speakers
Presentation Number
P0084
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development and pathogenesis of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J, et al. Mult Scler 2012]. We have developed a novel allogeneic T cell therapy targeting EBV-encoded antigens, ATA188. Preliminary data from a phase 1 study (NCT03283826) suggests ATA188 is well tolerated and has shown initial efficacy in patients with progressive forms of MS [Pender MP et al. EAN 2020; LB130].

Objectives

The goal of this study was to characterize ATA188 allogeneic EBV-targeted T cells to delineate activated gene sets, molecular signatures and underlying functional pathways associated with effector cell function and therapeutic potential.

Methods

ATA188 T cells were profiled with a curated 326-gene panel using the NanoString nCounter® platform. Total RNA from control and antigen-activated EBV-specific CD8+ T cells were sorted following EBV stimulation, sequenced, and analyzed. Individual genes differentially expressed were identified and further subjected to enrichment analyses. Furthermore, deep TCRβ chain sequencing (TCR-seq) was conducted to define TCR clonal diversity and identity in ATA188 cells.

Results

Despite being derived from unrelated healthy donors, the ATA188 T cells showed considerable concordance in expression profiles (Spearman>0.80; p<E-10) within the control and activated states. Significantly differentially expressed genes (fold change>1.5, p<0.01) were identified, representing a distinct activation signature for ATA188 cells. The activated states were associated with upregulation of IL-2, IFNG, XCL1, CCL4, CSF2, TNFRSF9, and downregulation of KLF2. These patterns were consistent with activation of cytokine-receptor, JAK-STAT, T-cell receptor, and chemokine signaling pathways. Finally, TCR-seq analysis showed that ATA188 cells contain varying EBV-specific TCR clonotypes associated with specific restriction through one or more HLA alleles.

Conclusions

Transcriptional and TCR repertoire profiling of ATA188 revealed T-cell-intrinsic signatures and clonotypes associated with defined EBV-specific TCR repertoire, EBV-specific T-cell activation, and functional signaling pathways. These data are consistent with the proposed mechanism of action of ATA188 targeting EBV infected B cells by recognizing EBV antigens presented by defined TCRs.

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Clinical Outcome Measures Poster Presentation

P0085 - Harmonization of real-world studies in multiple sclerosis: retrospective analysis from the RIReMS group (ID 687)

Abstract

Background

Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.

Objectives

In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods

RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ2).

Results

Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ2=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ2=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ2=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ2=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ2=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ2=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ2=1.00).

Conclusions

We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.

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Biomarkers and Bioinformatics Poster Presentation

P0086 - Highly sensitive quantitation of CXCL13 as an intrathecal biomarker in optic neuritis (ID 718)

Speakers
Presentation Number
P0086
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

CXCL13 chemokine is a key regulator of B cell chemotaxis and CXCL13 in cerebrospinal fluid (CSF) is of pathophysiological relevance in multiple sclerosis (MS).

Objectives

To assess the potential value of a highly sensitive CXCL13 assay in acute optic neuritis (ON) patients for prediction of MS.

Methods

A Simoa CXCL13 assay was used to measure CXCL13 in CSF and serum of two independent, treatment-naïve ON cohorts: A training cohort (TC) derived from a population-based cohort (n = 33) and a validation cohort (VC) of patients collected consecutively in line with the population study precepts (n = 30). Prospectively, 14/33 patients from the TC and 12/30 patients from the VC showed progression to MS (MS-ON). The remaining 19/33 from TC and 18/30 from VC were considered as isolated ON (ION). A group of healthy controls (HC, n = 11) were used for comparison.

Results

CXCL13 was detectable in all samples. General ON patients had higher CXCL13 than HCs (p = 0.012). In the TC, CXCL13 in MS-ON patient CSF was higher than in ION and HC (p = 0.0001 and p<0.0001, respectively). This was confirmed in the TC, where MS-ON patients too showed increased CSF CXCL13 relative to ION (p = 0.0091). Logistic regression analysis showed area under curve of 0.83 (95% confidence interval: 0.73-0.93) and an odds-ratio of 19.6 at the optimal cutoff.

Conclusions

Increased ability to detect CSF CXCL13 using the Simoa assay allowed identification of ON patients and segregated MS-ON from ION. These data indicate a promising potential of this assay, and further studies are warranted.

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Biomarkers and Bioinformatics Poster Presentation

P0087 - Identification of proteins associated with ageing in patients with progressive multiple sclerosis (ID 1589)

Abstract

Background

Similar to other neurodegenerative disorders, the onset of progressive MS is related to age, a factor known to amplify neurodegeneration. Recent studies have shown that exposure of aged mice to a young blood circulation through parabiosis or administration of young blood plasma (plasma from 3-month-old mice) reverses cognitive deficits observed with normal ageing.

Objectives

We aimed to search for soluble factors in the serum of patients with progressive MS that are affected by age and are differentially decreased in patients compared to healthy controls (HC) of similar age.

Methods

Protein levels were determined in serum samples from a cohort of 30 untreated MS patients (15 patients with secondary progressive MS - SPMS - and 15 with primary progressive MS - PPMS) and 25 HC. Progressive MS patients were classified according to age and clinical characteristics into the following three groups (each group containing 10 patients, 5 with SPMS and 5 with PPMS): (i) 40 ± 3 years old, disease duration <10 years, EDSS <4.5; (ii) 50 ± 3 years old, disease duration between 10-20 years, EDSS between 4.5-6; and (iii) 60 ± 3 years old, disease duration >20 years, EDSS >6.5. HC were classified based on age into the following groups (each group containing 5 individuals): 20, 30, 40, 50, and 60 ± 3 years old. To maximize the breadth and depth of serum proteome coverage, the top 70 abundant proteins in serum were depleted. Afterwards, samples were subjected to mass spectrometry.

Results

After depletion of the most abundant proteins in serum, a total of 2,059 molecules were detected in all 55 samples. The maSigPro package (R Bioconductor) was used to identify proteins with significantly divergent expression profiles as a function of time. A quadratic regression model was fit for each molecule and 823 proteins, among the 2059 analyzed, were found differentially expressed (FDR < 0.05) between the MS group and HC. The serum levels of the following proteins were significantly decreased by ageing in progressive MS patients compared with HC and were selected for further studies: PLXDC2, Neudesin, Myostatin, Myocilin, and EMMPRIN.

Conclusions

Protein expression profiling associated with ageing in progressive MS patients and HC lead to the identification of number of promising candidates associated with neurotrophic functions, myelination, and nervous system development. Results obtained by mass spectrometry need to be validated by targeted immunoassays.

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Biomarkers and Bioinformatics Poster Presentation

P0088 - Identification of putative multiple sclerosis biomarkers in CSF by targeted-mass spectrometry (ID 913)

Speakers
Presentation Number
P0088
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The individual expression of Multiple Sclerosis (MS) is highly heterogeneous. One of the greatest potential benefits of biomarkers is to predict disease severity and guide therapeutic choices.

Objectives

Our objective is to evaluate the predictive value of soluble brain-specific proteins of 10-year MS clinical outcomes.

Methods

This retrospective study analyzed cerebrospinal fluid (CSF) from 35 MS patients (mean age: 42; 79% female) and 23 non-MS controls (mean age: 35.5; 68% female) collected within 5 years of disease onset. We quantified 63 brain-specific proteins in the CSF of these patients using a targeted liquid-chromatography tandem mass spectrometry assay. This assay was previously developed in-house by mining of the Human Protein Atlas database and experimental search of CSF to establish brain-enriched proteins.

Results

Our parallel reaction monitoring assay (PRM) used in this study had high assay reproducibility (median across peptides CV = 5.7%). Twelve proteins significantly differentiated MS from controls (p<0.05). The levels of 6 proteins at baseline were significantly associated with CIS, RRMS or PPMS. We also observed a trend with a number of proteins negatively predicting evolution of CIS to RRMS or SPMS. Finally, we observed an association between 3 proteins and the rate of EDSS progression rate over 10 years (Spearman rank correlation: r=-0.59, r=-0.36, r=-0.44; p=0.0006, p=0.046, p=0.0151 respectively).

Conclusions

We identified 12 CSF brain-specific proteins that are unique to MS patients and 3 proteins that seem to predict disease course over the next decade. These proteins also highlight putative pathways implicated in MS pathogenesis and can be targets for future therapeutic regimes.

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Biomarkers and Bioinformatics Poster Presentation

P0089 - IFP35 as biomolecular marker of neuroinflammation and treatment response in Multiple Sclerosis (ID 196)

Speakers
Presentation Number
P0089
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The innate immunity in clinically isolated syndrome (CIS) and Multiple Sclerosis (MS) is poorly studied, but very important for both initiation and progression of the disease. In a predisposed subject, the activation of damage-associated molecular patterns (DAMPs) mediated by Toll-like receptors provides a micro-chemical inflammatory environment resulting in the self-maintaining neuroinflammation. IFN-beta is one of the most prescribed agents for MS’ treatment. Its heterogeneous response is individual and urges defining biological marker. The Rio Score (RS) provided a clinical assessment tool for predicting the one year-response in IFN-treated MS, but no pharmacodynamic biomarker is available. Interferon induced protein 35 (IFP35) is a zinc-finger factor correlating with the biological IFN activity, also serving as proinflammatory DAMP via the Janus kinase/signal transducers on the transcription of JAK-STAT protein.

Objectives

The primary aim of this study is to profile the IFP35 expression in CIS and clinically defined MS (CDMS) patients; furthermore, to assess the IFP35 differential profile to individuate the responder (RS=0) and non-responder (RS≥1) subjects among the IFN-treated MS group.

Methods

30 CIS-patients, 50 relapsing remitting (RR) MS-patients treated with IFNbeta-1b and IFNbeta-1a, 10 Secondary Progressive (SP) MS-patients along with 20 healthy controls (HCs) were enrolled. All patients underwent the blood sample, clinical and MRI evaluation, obtaining lesion load (LL), white/grey matter fraction (W/GMF) and RS definition over a 30-months observational period. Quantitative assessment of IFP35 was obtained by western-blot technique from peripheral blood mononuclear cells.

Results

IFP35 from the CIS-patients was 2.06-fold up-regulated than HCs (p<0.0001) and 1.67-fold up-regulated than SPMS-patients (p=0.035); IFP35 from IFNbeta-1a-treated patients was higher than IFNbeta-1b (p=0.006). Furthermore, IFP35 from the RS=0 group was 1.88-fold up-regulated than RS ≥ 1 (p<0.0001). IFP35 expression also inversely correlated to RS (r=0.60; p<0.0001), WMF (r=-0.50; p=0.0017) and LL (r =-0.51; p=0.0026). Finally, Kaplan-Meier analysis sorted a cut-off value of IFP35 ≥ 65% for RS=0 (p<0001).

Conclusions

We demonstrated for the first time the IFP35 biological pattern as predictive indicator of drugs efficacy in IFN-treated MS, but also of disease activity, thus reflecting the innate immunity-dependent neuroinflammation.

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Biomarkers and Bioinformatics Poster Presentation

P0090 - Immune cell profiles associated with CIS progression and stability using RNA-seq single-cell analysis (ID 577)

Speakers
Presentation Number
P0090
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Clinically Isolated Syndrome (CIS) can be an initial multiple sclerosis (MS) presentation, but the risk for developing future demyelinating episodes is often uncertain. The singular clinical episode of demyelination is thought to be driven by acute inflammation brought about by proinflammatory macrophages, autoreactive CD8+ and CD4+ T cells, and B cells crossing the blood-brain-barrier.

Objectives

To use single-cell transcriptome analyses to identify immune cell profiles in CIS patients associated with a higher risk of developing an MS relapse or new central nervous system (CNS) disease activity on brain MRI.

Methods

Cryopreserved peripheral blood mononuclear cells (PBMC) were collected at study entry and six months from six CIS participants from the ITN020AI STAyCIS trial of atorvastatin. Three participants met the primary endpoint defined as ≥ 3 new T2 lesions on MRI or an MS relapse within 12 months, while the other three did not. RNA from about 10,000 PBMC per sample were sequenced at the single-cell level using the 10X Genomics Chromium platform and analyzed using Cell Ranger software. Seurat R software package was used for downstream analysis, with cell type annotated both computationally (SingleR) and by matching differentially expressed genes with canonical markers using online genomics databases.

Results

Approximately 30 clusters of differentially expressed transcripts were assigned as specific cell types; baseline frequencies of seven clusters enriched >2-fold for macrophage, NK, NKT, CD4+ T cell, and B cell transcripts were associated with disparate outcomes at six months. Several clusters assigned as B cells, CD4+ and CD8+ T cells were expanded from baseline at six months in participants with CNS disease activity at that time point, while no notable changes were observed in those with stable disease.

Conclusions

An understanding of the immunological changes associated with future disease activity in CIS may be useful for making early treatment decisions. Our preliminary data suggest that participants with disparate clinical outcomes exhibited different frequencies of innate and adaptive leukocyte populations in PBMC, which may represent a predictive biomarker for aggressive early intervention. Also, expanded clusters of CD4+ and CD8+ T cells and B cells in blood at the time of disease activity may identify biomarkers that contribute to acute demyelination. Follow-up studies are underway to increase sample size and incorporate protein expression data to better define cell subtypes and clonality of T and B cells associated with disparate outcomes in the STAyCIS trial.

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Clinical Outcome Measures Poster Presentation

P0091 - Improving patient outcomes through a comprehensive care management platform (MOVING MS) (ID 364)

Speakers
Presentation Number
P0091
Presentation Topic
Clinical Outcome Measures

Abstract

Background

When standard of care neurology visits are 6 months apart, there can often be gaps in care and missed opportunities to improve patient function; the result is poor follow-up for care management or low medication adherence. MS care can be comprehensively approached with a human-tech platform that supports symptom and medication tracking, nursing interventions, laboratory monitoring for subclinical disease activity and curated MRI reports to ensure accurate data at return visits.

Objectives

To test the Octave integrated MS care platform for efficacy in reducing unplanned healthcare utilization (UHU) and improving patient and physician satisfaction.

Methods

This prospective, randomized study with a within-subjects, waitlist-control trial design aims to reduce UHU costs and increase patient and physician satisfaction with their MS care. Secondary endpoints include determining the feasibility of the human-tech service, blood-based disease activity tests and enhanced MRI reports. Approximately 80 participants will be randomized to a case or waitlist group. Case subjects will have access to the platform for all 12 months of enrollment; waitlist subjects will have access for the second 6 months of enrollment. The platform includes medication and symptom tracking, check-ins every 2 weeks with an MS-certified nurse and curated physician/MRI reports. UHU will be qualified by events captured in the EHR and monetary value assigned to these events. Satisfaction will be measured through participant and physician questionnaires. Subject’s blood tests will be correlated to symptomology and MRI findings to assess subclinical disease activity.

Results

UHU was created by Octave and is a composite metric of unplanned office visits and communication by phone or e-message, weighted by expense per interaction as collected in the EHR. Our analysis aims to quantify the UHU difference between 1) case vs. control samples over the first 6 months of the study, and 2) waitlist control patients for the first vs. second 6 months of the study. Satisfaction will be measured between case and control groups using a Likert scale and quantified with a 2-sample t-test.

Conclusions

This trial aims to improve MS disease management, reduce UHU and increase patient/physician satisfaction through a mobile platform intervention, using a waitlist design.

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Clinical Outcome Measures Poster Presentation

P0092 - Incidence of recurrence of disease activity after fingolimod discontinuation in older patients (ID 264)

Speakers
Presentation Number
P0092
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Discontinuing fingolimod (FTY) in older patient is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.

Objectives

We investigate the incidence of RDA and rebound in MS patients who discontinued fingolimod for any reason, and looked for risk factors influencing this risk. Of particular interest was the subgroup of older patients who discontinued FTY for other reasons than disease progression. Our hypothesis was that these patients, older at treatment discontinuation, previously stable on treatment, would have a statistically lower risk of recurrence of activity given their age.

Methods

Retrospective analysis of 288 MS patients on FTY. Recurrence of disease activity (RDA) was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal; among these patients with RDA, we considered rebound when the levels of disease activity surpassed pretreatment activity. We defined a subgroup of patients older than ≥ 50 years at FTY discontinuation and with NEDA-3 status during FTY treatment.

Results

128 patients discontinued FTY from 2011 to 2019 mainly for estimated high PML risk (3.6%), inefficacy (26.6%) or pregnancy planning (18%). RDA occurred in 45 patients (35.2 %) within 3.4 months (SD 2). Younger age at disease onset (p=0.008), highly active disease at baseline (p=0.037) and previous treatment with natalizumab (p=0.050) increased the risk of RDA at FTY discontinuation. Sixteen patients (12.5%) experienced rebound with a mean of 9 Gd enhancing lesions. Baseline MRI activity (p=0.008) and longer wash-out period (p=0.001) correlated with rebound. Twenty-two patients were older than 50 years at FTY withdrawal and discontinued FTY for other reasons than disease progression. The incidence of RDA was lower, yet not statistically significant, from younger patients (18.2 % RDA, p=0.068).

Conclusions

RDA occurred in 35.2% of our patients including 12.5% with rebound. Older age at FTY discontinuation may be associated with a lower risk of disease reactivation, although the incidence of RDA remains high, as 1/5 of the older patients, previously stable on treatment, experienced RDA.

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Biomarkers and Bioinformatics Poster Presentation

P0093 - Increased serum GFAP associates with microstructural white matter damage in multiple sclerosis (ID 1066)

Speakers
Presentation Number
P0093
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Astrocytes and microglial cells are now recognized as active players in contributing to the diffuse neuroaxonal damage associated with disease progression of multiple sclerosis (MS). The serum level of glial fibrillary acidic protein (GFAP), a biomarker for astrocytic activation, is increased in MS and associated with the disease progression and disability. Similarly, diffusion tensor imaging (DTI) parameters for microstructural changes in brain, including demyelination and axonal loss, associate with disability. The association between brain DTI parameters and serum GFAP has not been previously explored in MS.

Objectives

To get insights into DTI-measurable pathological correlates of elevated serum GFAP in the normal appearing white matter (NAWM) of MS.

Methods

A total of 62 MS patients with mean age of 49.4 years were included in the study. Study patients underwent DTI-MRI and blood sampling for GFAP determination by single molecule array (Simoa). MS patients were subdivided to GFAP(high) and GFAP(low) groups based on the median value of GFAP (97.7 pg/ml). Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the NAWM and six segmented NAWM regions. The associations between the DTI parameters and GFAP levels were analyzed within the GFAP(high) and GFAP(low) subgroups using Spearman correlation analysis and multiple regression model with sex and disease modifying treatment (no, 1st line or 2nd line) as adjustments performed with the R statistical software (version 4.0.0).

Results

Elevated serum GFAP levels correlated significantly with decreased FA values within the entire, frontal, temporal and cingulate NAWM (R=-0.39, p=0.03; R=-0.42, p=0.02; R=-0.37; p=0.04 and R=-0.38, p=0.03) and increased MD and RD within the frontal NAWM (R=0.36, p=0.046 for both) in the GFAP(high) subgroup. Associations between higher GFAP and lower FA in frontal and cingulate NAWM were sustained in the multiple regression model corrected for confounding variables (standardized regression coefficient r = -0.29, p = 0.045 and r = -0.33, p = 0.025).

Conclusions

Our results give evidence that increased serum GFAP levels are associated with DTI-measurable micro-damage in the NAWM in MS. Our work supports the use of serum GFAP as a biomarker for MS pathology-related astrocytopathy and related diffuse white matter damage.

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Biomarkers and Bioinformatics Poster Presentation

P0094 - Inter-laboratory evaluation of cerebrospinal fluid and serum kappa free light chain measurements (ID 966)

Abstract

Background

The kappa index, calculated by dividing the cerebrospinal (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as an indirect marker of intrathecal activation of the humoral immune response. The demonstration of intrathecal synthesis is of particular relevance in the diagnostic work-up of suspected Multiple Sclerosis. However, the lack of consistent data on inter-laboratory agreement in CSF and serum KFLC measurements is one of the factors that hamper the use of kappa index in routine practice.

Objectives

Aim of this study was to assess agreement in CSF and serum KFLC measurements and kappa index values across different laboratories.

Methods

Fifteen paired CSF and serum samples were analyzed in all participating laboratories (nr=8). Four centers used Binding Site instruments and assays, 3 centers used Siemens instruments and assays, and one center used a Siemens instrument and a Binding Site assay.

Absolute individual agreement between laboratories was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen's kappa coefficient was used to measure inter-laboratory agreement on positive (5.8) kappa index values.

Results

Within Binding Site laboratories, ICC for KFLC measurements was 0.96 (95%CI: 0.9-0.98) for CSF, 0.93 (95%CI: 0.63-0.98) for serum and 0.97 (95%CI: 0.94-0.99) for kappa index values. Within Siemens laboratories, ICC for KFLC measurements was 0.99 (95%CI: 0.97-100) for CSF, 0.93 (95%CI: 0.48-0.98) for serum and 0.95 (95%CI: 0.89-0.98) for kappa index values. ICC calculated for all laboratories was 0.93 (95%CI: 0.87-0.97) for CSF KFLC, 0.81 (95%CI: 0.53-0.93) for serum KFLC and 0.65 (95%CI: 0.43-0.84) for kappa index. Cohen's kappa coefficient for a positive kappa index was 0.89 across Binding Site laboratories, 0.70 across Siemens laboratories, and 0.77 across all laboratories.

Conclusions

There was an excellent agreement in CSF KFLC measurements and in kappa index values within laboratories using the same instrument and assay (Binding Site or Siemens), while serum KFLC measurements were less concordant. Agreement across all laboratories was decreased when including the laboratory using a Siemens instrument coupled with a Binding Site assay in the analyses. Concordance for a positive kappa index was substantial across all laboratories and within Siemens laboratories, and very good within Binding Site laboratories.

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Clinical Outcome Measures Poster Presentation

P0095 - Intracortical motor conduction is associated with dexterity in progressive multiple sclerosis (ID 1841)

Speakers
Presentation Number
P0095
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Hand dexterity dysfunction is a key feature of disability in people with progressive multiple sclerosis (PMS). It underlies corticospinal tract (CST) and cerebellar integrity but also disruption of cortical networks, which are hardly assessed by standard techniques. Transcranial magnetic stimulation is a promising tool for evaluating the integrity of intracortical motor pathways.

Objectives

to investigate neurophysiological correlates of motor hand impairment in PMS and assess intracortical motor conduction through the use of a innovative TMS protocol.

Methods

Antero-posterior (AP) stimulation of the primary motor cortex activates the CST indirectly through polysynaptic pathways, while a direct CST activation occurs with latero-medial (LM) directed current. 30 PMS and 15 healthy controls underwent dominant hand motor evoked potentials (MEP) using AP and LM-directed stimulation, and a clinical assessment of dexterity (nine-hole peg test) and strength (MRC scale, grip and pinch).

Results

PMS with AP-LM latency difference 2.5 standard deviation above the mean of controls (33%) showed worse dexterity but no difference in upper limb strength. Accordingly, AP-LM latency shortening predicted dexterity (R2 0.538, p<0.001), but not strength impairment. On the contrary, absolute MEP latencies only correlated with strength (grip: R2 0.381, p=0.014; MRC: R2 0.184, p=0.041).

Conclusions

AP-LM latency shortening may be used to assess the integrity polysynaptic intracortical networks implicated in dexterity impairment.

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Biomarkers and Bioinformatics Poster Presentation

P0096 - Intrathecal immunoglobulin M synthesis is associated with higher disease activity and severity in Multiple Sclerosis (ID 1101)

Abstract

Background

Additional biomarkers reflecting disease activity and predicting severity of multiple sclerosis (MS) are urgently needed.

Objectives

To explore whether intrathecal immunoglobulin (Ig) M synthesis is associated with time from disease onset to first relapse, MS Severity Score (MSSS) and time to first initiation of high efficacy disease modifying treatments (DMT) in patients with relapsing MS in the Swiss Multiple Sclerosis Cohort study.

Methods

487patients were categorized by presence of CSF oligoclonal IgG bands (OCGB) and quantitative intrathecal IgG and IgM production (Intrathecal Fraction, IF). Treatments were classified according to "no therapy", "platform", "oral" and "high efficacy". Multivariable Cox proportional hazard models or a multivariable linear model, adjusted for relevant covariables, were used to assess time from disease onset to described endpoints and associations with the MSSS.

Results

OCGB were present in 89.3%, IgGIF in 66.3%, IgMIF in 26.9% and IgAIF in 11.9% of patients. Patients with IgMIF had a shorter interval from disease onset to first relapse (HR 1.887 [CI 1.181, 3.014], p<0.01) compared to those without OCGB and IgGIF and IgMIF. Quantitatively, patients with IgMIF above versus below the median had a 1.75- fold increased hazard of occurrence of a first relapse (HR 1.746 [CI 1.097, 2.781]; p=0.019). IgMIF positive patients had on average a 1.24 steps higher MSSS compared with those without any intrathecal Ig synthesis (estimate: 1.243 [CI 0.501,1.986], p<0.01), followed by patients with OCGB and quantitative production of IgGIF (estimate: 0.966 [CI 0.283, 1.650], p<0.01) and patients with only OCGB (estimate: 0.716 [CI -0.030, 1.461], p=0.060). Accordingly, patients with IgMIF production had a shorter interval to initiation of high efficacy DMT (HR 2.788 [CI 1.306, 5.951], p<0.01). Quantitatively, above versus below median IgMIF was associated with a 2.36-fold risk of escalation to a high efficacy DMT (HR 2.361 [CI 1.304, 4.277]; p<0.01).

Conclusions

In relapsing MS, presence of intrathecally produced IgM is associated with higher disease activity, more severe disease course and earlier use of high efficacy treatments. Intrathecally produced IgM may qualify as useful prognostic biomarker for therapeutic decision making in early stage of disease.

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Biomarkers and Bioinformatics Poster Presentation

P0097 - Intrathecal immunoglobulin M synthesis is associated with higher serum neurofilament light chain levels and increased MRI disease activity in MS (ID 1089)

Abstract

Background

Intrathecal IgM synthesis was reported to be associated with higher clinical disease activity and severity. We found an association also with earlier use of high efficacy treatments in relapsing MS (RMS).

Objectives

To explore whether patients with intrathecal IgM synthesis show a) higher serum neurofilament light chain levels (sNfL) as a reflection of neuronal damage, or b) signs of increased disease severity in cerebral MRI, in patients with RMS followed in the Swiss MS Cohort Study.

Methods

487 patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecally produced IgG/M:

1) OCGB-/IgG-/IgM- (reference [ref]);

2) OCGB+/IgG-/IgM-;

3) OCGB+/IgG+/IgM- and

4) OCGB+/IgG+/IgM+.

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modelled in 8865 healthy control samples to reflect the deviation of a patient sNfL value compared to mean values observed in same age healthy controls. Yearly T2 lesion number and occurrence of new/enlarging T2 lesions were automatically assessed in cerebral MRIs and checked manually. Contrast enhancing lesions (CEL) were manually quantified. Linear or negative binomial mixed models were used to investigate the associations between the four CSF Ig patterns and longitudinal sNfLz and MRI measures, adjusted for DMT and other covariates.

Results

IgM+ patients had higher sNfLz vs reference (estimate 0.50 [CI 0.12, 0.89], p=0.011), whereas those with only OCGB+ (0.11 [-0.28, 0.50], p=0.582) or with OCGB+/IgG+ (0.20 [-0.16, 0.56], p=0.270) did not (n=2970 observations). This was confirmed when analyzing only untreated patients adjusting for T2 and CEL numbers (1.16 [0.47, 1.86], p<0.01 vs 0.58 [-0.11, 1.27], p=0.1022 vs 0.51 [-0.11, 1.13], p=0.108 vs ref, respectively) (n=234).

IgM+ patients had 2.28-fold more T2 lesions ([1.51, 3.44], p<0.01) vs ref; for patients with only OCGB+ (1.61 [1.07, 2.43], p=0.0237) or OCGB+/IgG+ (1.58 [CI 1.08, 2.32], p=0.0179) (n=1580) this association was weaker.

IgM+ was associated with a 2.47-fold risk for new/enlarging T2 lesions on yearly follow-up MRIs vs ref (2.47 [1.28, 4.78], p<0.01) but not the two other patient groups (1.84 [CI 0.93; 3.65], p=0.0799 and 1.61 [CI 0.87; 2.95], p=0.1280) (n=861).

Conclusions

Intrathecal IgM synthesis was consistently associated with quantitative measures of neuro-axonal injury and disease severity in RMS. Our findings strongly support the clinical utiliy of this biomarker.

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Biomarkers and Bioinformatics Poster Presentation

P0098 - Investigation of biomarkers in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders (ID 1302)

Speakers
Presentation Number
P0098
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In neuroimmunology; biomarkers have been determined as having a pivotal role. Among them, Neurofilament Light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Interleukin-6 (IL-6), Osteopontin, Growth-associated protein 43 (GAP-43) have been examined for different central nervous system autoimmune disorders. It has been shown that each of them has a potential role for a different immunopathogenesis.

Objectives

In our study, we aimed to evaulate NfL, GFAP, Osteopontin, IL-6, GAP-43 in different subgroups of Multiple Sclerosis(MS). Relapsing-Remitting MS(RRMS)(n=38), Secondary-Progressive MS(SPMS)(n=16), Primary-Progressive MS(PPMS)(n=8), were included in this study. The samples from aquaporin-4(AQP4)-Ab-positive NMOSD(n=7), Myelin Oligodendrocyte Glycoprotein(MOG)-Ab-positive(n=9) patients and healthy controls(HC)(n=20) were also studied. All biomarkers were evaluated both in serum and cerebrospinal fluid (CSF).

Methods

Serum (n=98) and available CSF (n=20)(paired with serum,only MS subtypes) samples have used this cross-sectional study. For measuring NfL and GFAP concentrations in sera and CSF samples, we used SIMOA technology and assays on the Quanterix SIMOA HD-X ANALYZER. IL-6 measurements were performed on the Roche Cobas e-411 analyzer with the electrochemiluminescence method. Osteopontin and GAP-43 levels determined with the ELISA assays. Clinical and radiological data at sampling were collected for each case.

Results

We observed a significant positive correlation between serum NFL,GFAP and CSF NFL,GFAP levels in MS patiens(NfL,p=0,001,rho=0,686; GFAP,p=0,006,rS=0,594). For serum samples, there was a very strong positive correlation between treatment-naive GFAP and treatment-naive NFL levels in MS patients (p<0,001, rS=0,828). Additionaly, we have found negative correlation between serum IL-6 and GFAP levels in MS patients (p<0,01, rS =-0,356). Also there was a negative correlation between serum IL-6 and NfL levels in MS patients (p<0,01, rS =-0,422). When compared with HC, there was a significant incrase in terms of serum IL-6 levels in central neuroimmunological disorders(p<0,001).Mean value of AQP4-Ab-positive NMOSD serum GFAP levels(111,7±29,39 pg/mL) were signififantly higher than MOG-Ab-positive serum GFAP levels(80,39±32,53 pg/mL)(p<0,05). MOG-Ab-positive serum IL-6 mean values(42±52,17 pg/mL) were found to be higher than AQP4-Ab-positive NMOSD group(6,17±4,36 pg/mL)(p<0,05).

Conclusions

NfL and GFAP are certainly promising biomarkers in MS patients. NMOSD and MOG-Ab-positive patients have to be assessed in prospective studies that have a large number of patients. Our study is the first that Single Molecule Array (SIMOA) technology has been used in Turkey to evaluate NfL, GFAP levels both in serum and CSF levels.

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Clinical Outcome Measures Poster Presentation

P0099 - Is disease activity prior to fingolimod initiation in treatment-naive patients predictive of response?  (ID 323)

Speakers
Presentation Number
P0099
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Randomized controled trials, post-hoc analysis and real-world post-marketing studies have confirmed fingolimod (FTY) efficacy over placebo as second-line therapy in case of persistent disease activity and in treatment-naive patients with rapidly evolving highly active RR-MS. In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity.

Objectives

To evaluate and compare the incidence of NEDA-3 status at last follow up according to the baseline MS disease activity.

Methods

Retrospective analysis of clinical and radiological data of 54 RR-MS patients treated with FTY. The patients were divided into highly active patients (HΑ) if ≥ 2 relapses in the year before treatment initiation and ≥1 Gd-enhancing T1 lesion or “not highly active” (NHA). NEDA-3 status at endpoint was defined as no relapses, no EDSS progression and no new T2 or Gd-enhancing lesions during the follow-up.

Results

Mean follow-up duration was 48.2, SD 18.4 months. FTY efficiently reduced relapses (NHA 90.3% reduction, p<0.001, HA 84.9%, p<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, p=0.019, HA 92.3%, p=0.043). 53.7% reached NEDA-3 status at endpoint, although the distribution was different in the two subgroups with 62.2%, (n=23/37) of the NHA patients reaching NEDA 3 status compared to 35.3% (n=6/17) of the HA. The proportion of patients reaching NEDA-3 status decreased over time (first line : 80% at 2 years and 66% at 4 years, HA : 58% at 2 years and 38% at 4 years, p=0.042). 63% of patients were still on FTY at last follow-up (n=34/54). Main reason for discontinuation was lack of efficacy (75%, n=15/20).

Conclusions

Chances of reaching NEDA-3 status reduce over time with the highest relative benefit from FTY treatment observed when prescribed as a first line disease-modifying drug in treatment-naïve MS patients, which may favour its indication in that context rather than for HA patients only.

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Clinical Outcome Measures Poster Presentation

P0100 - Italian prospective multicentric observational real-life study of aggressive Relapsing Remitting Multiple Sclerosis treated with alemtuzumab (ID 1730)

Abstract

Background

Alemtuzumab(ALEM) is an anti-CD52 monoclonal antibody approved for the treatment of active Multiple Sclerosis(MS) which showed an overall high efficacy in clinical trials, also in the highly active subgroup of patients.

Objectives

The aim of this multicenter obervational study is to evaluate efficacy and safety of ALEM-treatment in a population of aggressive MS naïve-patients at year 2 and 3 after a complete cycle of treatment.

Methods

We conducted a multicenter prospective observational study in a cohort of ALEM-naïve MS patients. Clinical and neuroradiological parameters were collected from patients’ clinical records in 26 Italian MS Centers from October 2015 to May 2020.

Results

133 naïve patients were treated with ALEM: 60,2% females, mean age 31,4(± 8,9) years, mean disease duration 18,5(± 22,7) months, mean follow-up(FU) 34,2(± 12,1) months, median EDSS 3(0-6,5), ARR in the year preceding treatment 1,8 (± 0,9), mean number of brain T2/FLAIR-hyperintense lesions 29,8 (± 20,8) and mean number of Gd-enhancing lesions 3,4(± 5,1). Regarding ALEM efficacy, we report data obtained after the first complete cycle of treatment (2 ALEM-courses) because the occurrence of disease activity between the first and second course is not indicative of a therapeutic failure. 99 and 61 over 133 patients have at least 24 and 36 months FU respectively: 97% and 82% were relapse-free, ARR was 0,02 and 0,1, 92.9% and 82% were MRI activity-free and 97,7% and 91,8% progression-free with median EDSS of 2,0 and 1,5 (IQR 1 – 2,5) at year 2 and 3. The mean time to first relapse was 27,6(± 6,4) months 89,2% and 69,4% of patients reached NEDA-3 at year 2 and year 3 respectively. 5,3% of patients needed a third cycle of therapy. Overall 74,4% of patients had adverse events. Infusion-reaction and infections occurred respectively in 70,1% and 9,8% of patients; regarding secondary autoimmune disease the most frequent was thyroid dysfunction (15,8%).

Conclusions

In our very active MS-population after ALEM-treatment a strong reduction of both relapse rate and MRI activity was achieved. These results strengthen the assumption that aggressive naïve patient is an ideal candidate for immune system resetting, likely due to young age, short disease duration and low disability. Furthermore, absence of previous immunomodulating/immunosuppressant drugs altering the immune system could play a key role in determining effectiveness of this powerful drug. However, longer FU is needed to confirm our data and evaluate whether an early induction therapy could be worthy in this specific population, balancing benefit-risk ratio.

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Biosensors Poster Presentation

P0101 - Kinematic assessment of upper limb function in progressive multiple sclerosis (ID 201)

Speakers
Presentation Number
P0101
Presentation Topic
Biosensors

Abstract

Background

Upper limb dysfunction is common in progressive forms of multiple sclerosis (MS) leading to increased dependency and reduced quality of life. Clinicians and researchers need tailored outcome measures to quantify upper limb dysfunction, and evaluate potential deterioration or intervention efficacy. Current assessments rely on coarse measures and subjective evaluation. This is particularly disappointing as advances in digital technologies allow precise measurement of upper limb function in well constrained tasks.

Objectives

We will use novel kinematic assessment tools to explore the extent and progression of upper limb dysfunction in patients with progressive MS

Methods

We developed a kinematic assessment system that could accurately track arm movements over time and space and provide precise objective measures of function. The ‘gold-standard’ system allows infrared tracking of arm movements but is integrated with a ‘performance’ system that captures kinematic milestones (e.g. movement duration) alone.

Results

We have successfully built the kinematic assessment systems. Participants reach, grasp and move pre-designed cylindrical objects from one docking station to another on a manufactured board. Reaction times, hand velocity, hand trajectory and grip aperture are measured using a low cost and portable dual infrared camera system, capturing quantifiable trajectories in 3D space. We are now testing our systems with a sample of primary and secondary progressive MS patients (n=40) from the local outpatient population. Performance on our system will be calibrated against: the Expanded disability status scale (EDSS); the nine hole PEG test (9HPT); the ABILHAND; and AMSQ-SF10 questionnaire. The measures are taken over the course of a year (baseline, six months and twelve months).

Conclusions

It is possible to build low cost portable systems capable of providing rich kinematic data that capture upper arm function. Our current study will determine whether a simple performance system (that does not require infrared tracking) might provide rich measures in an even easier to deploy clinical assessment tool. This work will establish the extent to which these detailed kinematic measures map to the current clinical standard assessments. This provides an important first step in the development and evaluation of reach to kinematic analysis in the quantification of upper limb function in progressive MS.

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Clinical Outcome Measures Poster Presentation

P0102 - KonectomTM smartphone-based digital outcome assessment of cognitive and motor function in multiple sclerosis (ID 815)

Speakers
Presentation Number
P0102
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The next generations of MS therapies aim at enhancing remyelination, protecting neurons/axons and altering the slowly progressive course of MS from its inception. To evaluate their efficacy, it is essential to develop novel, patient-centric outcome assessments that can quantify patient’s function with high frequency in their everyday life.

Objectives

To develop a digital solution that enables patients to quantitatively self-assess their function at high frequency in free-living environment in complement to in-clinic supervised administration and derive outcome measures that are able to detect the subtle changes during MS evolution.

Methods

KonectomTM smartphone application was designed and developed with patient-focused user experience insights to assess cognition, upper extremity function, ambulation/mobility and MS-related quality of life. To optimize accuracy and adherence of self-assessments, tutorials, vocal instructions and completion reward features were built into the app. KonectomTM was developed under IEC 62304 / ISO 13485 standards. KonectomTM digital outcome assessments (DOAs) will derive digital features processed from iPhone X accelerometer, gyroscope, touch, force touch, and GPS sensor information. KonectomTM formal usability study was completed in September 2019, in Chicago and in Paris (N=14 participants). KonectomTM is being evaluated in two Phase 2 studies in patients with relapsing MS (NCT04079088, N=300, 72 weeks of treatment period; undisclosed RMS Ph2 study).

Results

KonectomTM DOAs include 9 active test modules (mood/physical state 5-point Likert scale, multiple sclerosis impact scale 29-item questionnaire version 2 [MSIS-29v2], cognitive processing speed test, pinching test, drawing test, grip force test, static balance test, U-turn test and 6-min walk test) and a passive continuous monitoring of mobility behaviour. In the user experience testing, KonectomTM received a system usability scale (SUS, range 0-100, mean [SD]) score of 87.7 [8.7] which is much above the benchmark average of smartphone applications with a likelihood to recommend (LTR, range 0-10, mean [SD]) of 8.1 [2.0]. Results were consistent between French and US participants.

Conclusions

KonectomTM provides a patient-centric modular digital platform for ecological monitoring of neurological disability in MS clinical trials and real-world use with potential to be extended to other neurological disorders affecting cognitive and motor functions

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Biomarkers and Bioinformatics Poster Presentation

P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)

Speakers
Presentation Number
P0103
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.

Objectives

To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.

Methods

We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.

Results

Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.

Conclusions

Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.

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Clinical Outcome Measures Poster Presentation

P0104 - Long term disability trajectories in multiple sclerosis: a group-based trajectory analysis of the AusLong cohort (ID 1920)

Speakers
Presentation Number
P0104
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Understanding progression of disability in multiple sclerosis (MS) is essential to design preventive and therapeutic strategies.

Objectives

We analyzed data from the Ausimmune Longitudinal (AusLong) Study to investigate the existing heterogeneity in long-term disability accumulation in a prospective cohort of People with MS (PwMS) followed over 10 years from the date of their first clinical diagnosis (FCD) and identify clinical and demographic factors associated with these trajectories.

Methods

We used a group-based trajectory model (GBTM) to measure the heterogeneity in the disability trajectories based on Expanded Disability Status Scale (EDSS) in a prospective cohort of 263 participants followed from FCD.

Results

We identified three distinct clinically meaningful disability trajectories: no or mild, moderate and severe disability trajectories. Those in the minimal disability trajectory did not show any appreciable progression of disability (median EDSS ~ 1 at 10-year review), those in moderate and severe disability trajectories experienced disability worsening (median EDSS~ 2.5 and 6, respectively). The relative probability of being in a worsening disability trajectory was higher for older age at onset, those experiencing a higher number of relapses within five-year post FCD and those having a shorter interval between the first two attacks. High annual relapse rate was associated with an upward shift in moderate disability trajectory, whereas non-smoking status was associated with reducing the EDSS score in minimal and severe disability trajectories.

Conclusions

Those at highest risk of rapid disability progression can be identified based on their early clinical information with potential therapeutic implications.

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Biomarkers and Bioinformatics Poster Presentation

P0105 - Longitudinal proteomic analysis of MS patients before and after autologous hematopoietic stem cell transplantation (ID 1549)

Speakers
Presentation Number
P0105
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum markers which reflect MS disease activity could help personalize MS therapeutics. Longitudinal samples from patients undergoing autologous haematopoetic stem cell transplantation (HSCT) for aggressive MS represent a valuable cohort to search for such biomarkers, as these patients had very active disease prior to treatment followed by durable supression of inflammatory disease activity after treatment.

Objectives

To investigate changes in candidate serum proteins in patients with active MS compared to controls as well as before and after HSCT in relation to clinical and MRI outcomes.

Methods

97 proteins of interest were identified including established markers of inflammation and neurodegeneration. Levels were quantified using an in-house antibody colocalization microarray in 24 MS patients with aggressive relapsing MS at baseline compared to 10 controls. Pre-post HSCT changes were analyzed over 10 timepoints pre and up to 36 months post HSCT. We used principal componant analysis for data reduction prior to correlation as well as mixed effects models of individual proteins to compare changes in levels to clinical and MRI covariates of interest (age, EDSS score, relapses, sustained progression, lesional and volumetric MRI measures).

Results

Levels of 19 proteins differed between MS patients at baseline and controls and 17 proteins differed comparing baseline and 12-months post HSCT (simple t tests, p<0.1); we focused on the levels of these proteins for subsequent analyses. 7 proteins were identified in both comparisons including amphiregulin, cathepsin, CRP, GRO, HAI-1 and leptin, which may indicate normalization post HSCT. 8/24 patients developed sustained EDSS progression in the absence of ongoing relapses post HSCT; using mixed effects models, of the 17 candidate proteins, the longitudinal trajectory of CRP levels differed in patients who developed sustained progression compared to those who did not (B=-0.003, p=0.045). Component analysis was used to summarize clusters of proteins into a single value based on internal correlation/discordance. At baseline, one cluster of proteins (CRP, KLK14, PAI-1, IGFBP-7, PDGF) correlated with preceding rapid progression from diagnosis to EDSS 6 (p=0.011, r=0.80) and EDSS worsening in the preceding 24 months (p=0.047, r=0.46). A different cluster of proteins (HAI-1, amhiregulin, FAS, capthespsin B, e-cadherin, GFAP) correlated with the pretreatment rate of brain atrophy. Comparing pre-post changes, one cluster correlated with rate of brain atrophy in the first year post HSCT (p=0.024, r=0.059).

Conclusions

This exploratory analysis of longitudinal serum biomarkers changes pre and post HSCT provides hypothesis generating observations worthy of future investigation.

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Clinical Outcome Measures Poster Presentation

P0106 - Long-term single-centre experience with natalizumab. (ID 365)

Speakers
Presentation Number
P0106
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (NZB) is a disease-modifying treatment (DMT) used in persons with MS (PwMS) with an active relapsing course, either as a first-line, or after previous treatments.

The principal biological effect of NZB is thought to be the blockade of the molecular interaction between α4β1-integrin (also known as very late antigen-4) expressed by mononuclear inflammatory cells, and vascular cell adhesion molecule-1 (CAM-1) expressed by cerebral vascular endothelial cells.

NZB is a potent DMT which must be monitored with caution, its use being hampered by the risk of opportunistic infections, mostly progressive multifocal leukoencephalopathy (PML).

Objectives

To document the efficacy and safety of NZB for the treatment of RRMS in a population of persons with MS (PwMS) followed in a regular MS Clinic setting.

Methods

We report our single-centre experience over a period of 13 years: from JAN 2007 through the end of May 2020.

All PwMS treated with NZB were included, regardless of the treatment duration.

The retainment of patients in our MS Clinic is 95%.

We use the iMed database, an international MS registry. .

Results

We report on 230 PwMS, 159 women, 71 men treated with NZB since 2007, up to 30 April 2020.

We had no PML case. We had 2 PML 'clinical alerts', but CSF search for JC virus (JCV) was negative.

There was no rebound of activity, nor IRIS, after NZB cessation, as we usually quickly switch to an alternative DMT.

Median age at MS onset: 26.3 years. Median age at NZB initiation: 35 years. Median disease duration before treatment: 8.07 years.

First line use: 94. Previous BRACE DMT: 136.

Risk factors: previous immuno-suppression: 7; NZB duration > 24 months: 112; JCV index > 1: 81.

Median treatment duration: 23 months; still active: 71 including 7 after > 6 years.

ARR at NZB onset: 1.5; during NZB: 0.27; current: 0.89.

Median EDSS at NZB start: 3.0. Current median EDSS: 2.8. EDSS stable: 65, worsened: 58; improved: 60.

MRI: stable: 133 (58%) ; improved: 5 (2%); worsened: 35 (25%).

Conversion to SPMS: 48 (20%) 29 W, 19 M.

Reasons for NZB cessation: planned: 27; pregnancy: 3; loss of efficacy: 39; increased JCV index: 62. No blood toxicity (CBC, ALT).

We had 9 pregnancies: 4 planned interruptions; 5 full term, with normal babies.

Treatment after NZB cessation: 48 fingolimod, glatiramer: 17; ocrelizumab: 16; others: 29; none: 32 (no rebound observed).

One patient had COVID 1 year after NZB: complete recovery; needed only nasal O2 during 3 day hospital admission.

Conclusions

NZB, when used with caution, is an effective and safe MS DMT during the RRMS phase, even after extended disease and treatment durations.

NZB is most effective to reduce relapse frequency, less effective against progression, as 20% of PwMS transited to the secondary progressive phase.

Gender, disease duration, and age do not influence outcomes.

We encountered no significant toxicity, in particular no PML.

Clinical, JCV index measures, and MRI monitoring are paramount to maintain safety.

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Clinical Outcome Measures Poster Presentation

P0107 - Lymphocyte response in standard and extended interval dosing of natalizumab (ID 312)

Speakers
Presentation Number
P0107
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (Tysabri) is a humanised monoclonal IgG4 antibody used in the management of severe relapsing remitting multiple sclerosis (RRMS). It is the first in its class of selective adhesion molecules.

The four-weekly standard interval dosing (SID) of natalizumab is based on initial phase 3 trials showing that a4 integrin receptor saturation remains >70% four weeks following a 300mg infusion. Extended interval dosing (EID) e.g. six weekly infusions, can be associated with a lower integrin receptor saturation however this may not result in any clinical difference. A recent study by Yamout et al confirmed that both regimens had similar impact on MRI inflammatory activity and Expanded Disability Status Score (EDSS) outcomes. Additionally EID may be linked with a lower risk of progressive multifocal leucoencephalopathy (PML), the most worrying adverse event in natalizumab use.

Natalizumab use results in elevation of serum levels of lymphocytes, through their sequestration in peripheral blood. The lymphocytosis response has been established as a marker for therapeutic efficacy- patients displaying lower levels of natalizumab induced lymphocytosis are at greater risk for relapse.

Objectives

Given the established evidence of peripheral blood lymphocyte count as a marker of therapeutic efficacy, we sought to establish the lymphocyte response in our cohort of patients on SID, EID and those who transitioned from SID to EID.

Methods

We collected lymphocyte levels on all patients on tysabri (on standard and extended interval dosing). Lymphocyte count was tracked at three monthly intervals during natalizumab use. Lymphocyte levels on ten patients who were switched from standard dosing to extended interval dosing was also analysed.

Results

We had 92 patients using tysabri. Ten of the patients were transitioned from SID to EID.

The average lymphocyte count prior to commencement of natalizumab was 1.89.

Post two infusions at SID, this increased to 2.66, and after five infusions increased to 3.46. There was no significant change after this, with average lymphocyte counts maintained between 3 and 3.5 for the remainder of the therapy.

Of the eight patients who were transitioned from SID to EID:

-Average pre natalizumab lymphocyte level was 1.88.

-Average lymphocyte level on SID was 3.23

-Average level post two infusions on EID was 3.41

Conclusions

Our data confirms that there is no significant difference in lymphocyte count between patients on SID and EID, and similarly between patients who transition between SID and EID.

EID has been shown to be at least as effective as SID in treatment of RRMS while also lowering the risk of progressive multifocal leucoencephalopathy (PML). Studies have shown no increase in relapses. The Expanded Disability Status Scale (EDSS) also shows no difference between patients on SID and EID. Our data contributes to the evidence underlying the safety of EID use in patients with highly active relapsing remitting MS.

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Clinical Outcome Measures Poster Presentation

P0108 - Meta-analysis of randomized controlled trials and real-world evidence comparing natalizumab and fingolimod for relapsing-remitting multiple sclerosis (ID 681)

Speakers
Presentation Number
P0108
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (NTZ) and fingolimod (FTY) are effective treatments for patients with relapsing-remitting multiple sclerosis (RRMS), yet comparative randomised controlled trials (RCTs) of their effectiveness have been limited.

Objectives

To compare the effectiveness of NTZ versus FTY in a network meta-analysis (NMA) of studies in RRMS patients, including indirect evidence from RCTs and direct real-world evidence from non-randomized studies (NRSs).

Methods

RCTs and NRSs were identified in a systematic literature review of studies assessing the effectiveness of NTZ and FTY. An NMA was employed to synthesize the evidence. RCTs indirectly compared treatments via placebo. Outcomes evaluated at 2 years included relapse rate (3 RCTs, 10 NRSs), relapse free patients (3 RCTs, 7 NRSs), 6-month confirmed disability worsening (CDW) (3 RCTs, 3 NRSs), 6-month confirmed disability improvement (CDI) (2 RCTs, 3 NRSs), and no evidence of disease activity (NEDA-3; defined as no relapses, no CDW, and no active magnetic resonance imaging lesions) (2 RCTs, 5 NRSs). Incidence rate ratios (IRRs), odds ratios (ORs) and hazard ratios (HRs) summarised relative effects; values <1 favoured NTZ. Sensitivity analyses employed design-adjusted NMA models; NRSs were down-weighted according to their risk of bias with the ROBINS-I tool.

Results

The relapse rate (IRR [95% confidence interval (CI)]) was lower in patients treated with NTZ than with FTY in RCTs (0.67 [0.51–0.88]), NRSs (0.65 [0.50–0.85]) and the NMA (0.67 [0.55–0.82]). The probability (OR [95% CI]) of remaining relapse free was higher with NTZ than with FTY in RCTs (0.88 [0.62–1.25]), NRSs (0.48 [0.35–0.67]) and the NMA (0.52 [0.39–0.70]). The probability (OR [95% CI]) of CDW was lower with NTZ than with FTY in RCTs (0.66 [0.42–1.05]), NRSs (0.80 [0.54–1.17]) and the NMA (0.74 [0.55–0.99]). The probability (HR [95% CI]) of CDI was similar with NTZ and FTY in RCTs (0.98 [0.53–1.81]) but was higher with NTZ than with FTY in NRSs (0.52 [0.24–1.14]) and the NMA (0.59 [0.33–1.05]). NEDA-3 was more often achieved (OR [95% CI]) with NTZ than with FTY in RCTs (0.55 [0.32–0.93]), NRSs (0.38 [0.29–0.50]) and the NMA (0.41 [0.32–0.52]). Design-adjusted NMAs did not substantially alter the clinical interpretation of results.

Conclusions

NTZ was more effective than FTY across a range of key effectiveness measures. In the absence of head-to-head trials, these results provide evidence about the comparative effectiveness of NTZ and FTY.

This study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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Biomarkers and Bioinformatics Poster Presentation

P0109 - microRNA expression and its association with disability and brain atrophy (ID 1255)

Abstract

Background

MicroRNAs (miRNAs) are endogenous, non coding, small RNAs with post-transcriptional regulating functions. They participate in several cellular processes, including inflammation, neurodegeneration and remyelination

Objectives

To correlate serum miRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis (RRMS)

Methods

Cross-sectional study in RRMS patients on stable treatment with glatiramer acetate (GA) during at least 6 months.

We selected the 20 best miRNAs candidates for RRMS and cognitive dysfunction through simple topological analysis (Anaxomics ®). MiRNAs profile was determined with LNA-based PCR (Exiqon). Clinical variables were Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) and brain volume (whole brain volume, grey matter volume, white matter volume, cerebellum volume, basal ganglia volume and T1 lesion load volume) (automatic software NeuroQuant ®). Correlation was analyzed with Spearman correlation coefficient (r) (p<0,05; software: SPSS)

Results

We included 20 patients (13 women), age 38,2 (29,4, 47,8) years, duration of disease: 5,1 (1,5, 8,5) years, and time on GA 2,1 (0,8, 6) years. We found a pathogenic association between miR.146a.5p and has.mir.9.5p with EDSS (r:0,434, p=0,03; r:0,516, p=0,028); miR.146a.5p with SDMT (r:-0,476, p=0,016); has.mir.9.5p with thalamus (r:-0,545, p=0,036), and miR.200c.3p with pallidum and cerebellum (r:-0,675, p=0,002; r:-0,472, p=0,048).

Conclusions

MiRNAs could be useful biomarkers in multiple sclerosis. We would like to highlight the association of proinflammatory has.mir.9.5p with EDSS and thalamus volume. They are needed more studies to confirm this findings.

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Biomarkers and Bioinformatics Poster Presentation

P0110 - Modulation of cerebrospinal fluid immunoglobulins by ocrelizumab treatment (ID 1597)

Abstract

Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3+ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

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Biomarkers and Bioinformatics Poster Presentation

P0111 - Monitoring Multiple Sclerosis Treatment with Plasma Biomarkers: NfL, GFAP, UCH-L1, and Tau (ID 909)

Speakers
Presentation Number
P0111
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Blood neurofilament light (NfL) levels have been linked to multiple sclerosis (MS) activity and progression but are affected by factors such as age and body mass index (BMI). Less is known about what factors affect blood levels of Glial Fibrillary Acid Protein (GFAP), Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1), and Tau. Single Molecule Array (SIMOA) platforms allow multiplex measurement of these biomarkers with high sensitivity.

Objectives

To evaluate factors associated with higher levels of four plasma biomarkers—NfL, GFAP, UCH-L1, and Tau—in individuals with MS on immunotherapy.

Methods

Subjects with MS between 18-65 years taking dimethyl fumarate (n=40), fingolimod (n=37), natalizumab (n=47), or rituximab (n=90) for at least 1 year were identified from Rocky Mountain MS Center Biorepository. Neuro 4-plex A plasma assays were conducted on the Quanterix SR-X SIMOA platform. Biomarker concentrations were log transformed. For each biomarker, summary statistics were generated, and logistic regressions on the probability of having a level in the top quartile, adjusting for age, were performed with different explanatory variables including gender, BMI, disease duration, length on disease modifying therapy (DMT), DMT type, and MS subtype (relapsing MS [RMS] or progressive MS [PMS]). All statistics were generated in SAS.

Results

Included were 214 subjects (194 RMS, 20 PMS; 70.3% female; 86.9% Caucasian) with mean age of 44.1(SD 9.8). Mean disease and treatment durations were 150.7(SD 95.7) and 49.7(SD 33.5) months, respectively. Means (IQR) for NfL, GFAP, UCH-L1 and Tau were 6.6(3.9-7.1), 66.9(45.5-81.4), 11.5(7.1-13.8), and 1.2(0.8-1.5) pg/ml, respectively. NfL, GFAP, and UCH-L1 increased with age. (Remainder of results are given age-adjusted.) PMS was more likely than RMS to be in the top quartile for NfL (OR 3.5,p=0.01), GFAP (OR 2.6,p=0.06), and UCH-L1 (OR 2.8,p=0.04). Longer disease duration (5 years) increased the likelihood of elevated NfL (OR 1.3,p=0.02) and elevated GFAP (OR 1.3,p=0.03). Higher BMI (5 units) decreased the likelihood of elevated NfL (OR 0.6,p=0.0007) and GFAP (OR 0.8,p=0.03) but increased the likelihood of having an elevated Tau (OR 1.4,p=0.002). Ethnicity and treatment duration had no effect, but men were more likely to have elevated UCH-L1 (OR 2.1,p=0.03) and lower Tau (OR 0.2,p=0.0004). Comparing DMTs, no biomarker differences were observed except subjects on rituximab and dimethyl fumarate were less likely to have elevated Tau.

Conclusions

Plasma NfL, GFAP, and UCH-L1 are promising biomarkers to differentiate relapsing from progressive MS. Age and BMI should be incorporated into biomarker models to determine normal thresholds. No differences were observed between treatments for NFL, GFAP, or UCH-L1, but subjects on dimethyl fumarate and rituximab were less likely to have elevated Tau. Lack of randomization or repeated measures limited comparative effectiveness analyses.

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Clinical Outcome Measures Poster Presentation

P0113 - MRI activity as a predictor of suboptimal response to natalizumab treatment: single center prospective cohort trial (ID 850)

Speakers
Presentation Number
P0113
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Second line disease modifying drugs are widely used in clinical practice, the most common is natalizumab. NTZ have usually reduced the annualized rate of relapse and MRI lesion load in clinical trials but sometimes clinical and MRI activity was still present. Defining the predictors of suboptimal response is still needed to decide which second line treatment drug is optimal for patient.

Objectives

To determine the early clinical and MRI predictors of suboptimal treatment responses at one year of natalizumab (NTZ) therapy.

Methods

Clinical assessment (EDSS, relapses) and MRI (T2, T1Gd+) on start, after 6 and 12 months were made. All patients receive NTZ as second line therapy. RRMS patients undergoing treatment with NTZ for at least 12 months were classified as optimal responders if they have no EDSS score increase, no relapses and stable MRI (<3 new T2 and no Gd+(GELs)).Statistical analysis: one-way ANOVA, ROC-curve.

Results

43 patients (34 female) were included in analysis, RRMS, age–35.9-41.6 (95%CI) years, with disease duration of 58-131(95%CI) months;25-31(95%CI) NTZ infusions. On month 12 30.2% have a suboptimal response: 3 patient have a clinical relapse, 4–increasing of EDSS, 13–MRI activity. The comparison of the groups did not reveal statistically significant differences in age, sex, duration of the disease, duration of therapy before starting NTZ, relapse rate on baseline. Patients in suboptimal response group have more severe previous year MRI activity (before NTZ): more severe T2 lesion load (F=6.3,p=0.016) and high number of GELs (F=4.1,p=0.051). Predictors of suboptimal response are: more than 4 new T2 lesions during last year and more than 2 GELs on MRI before NTZ.

Conclusions

High previous year MRI activity is a strong predictor of suboptimal NTZ response. This cohort of patients probably needs more powerful therapy, for example, alemtuzumab or cladribine.

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Biomarkers and Bioinformatics Poster Presentation

P0114 - MS Biomarker Discovery: a multi-modal approach to identify biomarkers of myelin repair by leveraging a preclinical rodent model of MS (ID 485)

Speakers
Presentation Number
P0114
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Analysis of remyelination and repair therapies in preclinical models for Multiple Sclerosis (MS) has historically relied mainly on histological examination, which provides limited clinical translatability. To overcome the challenge, we aimed to set up preclinical models, initiated with the cuprizone demyelination model, and to integrate multi-modal longitudinal biomarker evaluations.

Objectives

Employ multi-modal biomarker approaches to longitudinally and sensitively monitor myelin changes by leveraging the cuprizone mouse model.

Methods

C57BL/6 male mice are fed with cuprizone diet (demyelinating toxin) for either 4 weeks or 12 weeks followed by recovery for 2 weeks and 4 weeks, respectively. During demyelination and remyeination, animals undergo either MRI or evoked potential recording for structural and functional assessment of myelin. All readouts are assessed in conjunction with histological examination to correlate multi-modal biomarkers for measuring remyelination.

Results

Cuprizone preclinical model of MS was successfully established that reproduced histological changes in myelin content during the remyelination and demyelination phases. MRI based imaging measurements (MTR and T1/T2 ratio) and electrophysiology (transhemispheric and sensory evoked potentials) were highly consistent with cellular level changes in myelin content and correlative with each other. Of interest, during de- and re-emyelination, MTR and T1/T2 demonstrated a reduction and trend to rebound respectively, while DTI was increased and stayed high during the measurement timeframe. Ongoing evaluation to further explore and study the correlation between multiple biomarker modalities and serum neurofilament analyses is underway.

Conclusions

A platform to longitudinally monitor multi-modal biomarkers in the context of demyelination/remyelination in a preclinical model of MS has been established by this study. Ultimately this platform willserve to evaluate efficacy of remyelinating therapeutics by implementing translational biomarkers for faster readouts.

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Clinical Outcome Measures Poster Presentation

P0115 - mSteps: A pilot study using a phone application with GPS, accelerometers and Wi-Fi positioning to measure walking distance in MS, indoors and outdoors (ID 1102)

Speakers
Presentation Number
P0115
Presentation Topic
Clinical Outcome Measures

Abstract

Background

There is to our knowledge few validated electronic tool in MS that measures the distance walked by a person with MS (PwMS). Utilising global positioning systems (GPS), WI-FI positioning and an in-built smartphone accelerometer to measure distance walked by a PwMS outdoors or indoors, could alleviate the uncertainty around using pedometers in those with gait disturbances, and is an attractive option.

Objectives

To pilot an accurate measure of distance walked using a smartphone application (mSteps) to facilitate Expanded Disability Status Scale (EDSS) measurement, indoors and outdoors, using both an MS and a control cohort.

Methods

The pilot study recruited 25 PwMS and 10 controls. mSteps utilised the iPhone’s inbuilt accelerometer and GPS functionalities to calculate the distance walked and time taken, indoors and outdoors. Due to unpredictable weather the physician monitored walk took place indoors which was fitted with location beacons to allow for WI-FI indoor positioning. The control cohort did the same walk indoors and outdoors to validate the use of the GPS functionality.

The participant was instructed to walk 25 feet, without rest, whilst the study phone was attached to their arm using a runner’s arm band and study personnel walked alongside them with a trundle wheel. Measurements were taken at 3 separate time points within a 3-month period.

95% levels of agreement between app and trundle wheel (gold standard) were calculated using the Bland-Altman repeated measures analysis. Levels of agreement, app vs trundle, were calculated for indoor measurements on both PwMS and controls with additional app vs trundle outdoor measurements for controls only. The a priori defined clinically acceptable difference was 1.52m.

Results

The 95% levels of agreement for indoor measurements on PwMS were -2.46 to 2.27m; and for controls were -2.02 to 2.71m. The 95% levels of agreement for outdoor measurements on controls were -0.45 to 0.43m.

Conclusions

The outdoor GPS functionality of mSteps is very accurate as shown by the 95% levels of agreements compared to the a priori clinically determined difference. The indoor WI-FI positioning function of mSteps however, was not accurate enough and shows that it is not reliable enough for further use. The control cohort showed the same inaccuracy indoors which eliminates the possibility that an uneven gait pattern in the MS cohort contributed to the error margin. A further validity study is being carried out, looking at a cohort of PwMS walking outdoors using mSteps and a trundle wheel.

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Clinical Outcome Measures Poster Presentation

P0116 - Multiple Sclerosis and Cognitive Impairment: Computerized Cognitive Assessment and PROMIS-Cognitive Function Questionnaire: An Unfulfilled Promis (ID 1873)

Speakers
Presentation Number
P0116
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive impairment (CI) is common in people with Multiple Sclerosis (PwMS) but often not addressed in routine care. Disease burden/progression in PwMS is traditionally measured by reported relapse, EDSS, and MRI change. CI is a source of significant disability independent of findings on examination. Use of a validated multi-domain screening cognitive assessment battery (NeuroTrax, CAB-NT) provides quantitative patient centric information to track CI longitudinally. Patient self-reported outcome measures (PRO) are also often used to gauge disability progression. PROMIS–Cognitive Function Short Form (CF-SF) is a validated disease agnostic PRO that can be incorporated to evaluate patient perception of disease impact. The relationship of the PROMIS PRO to a multi-domain quantitative cognitive assessment tool has not been explored in PwMS.

Objectives

To examine the cross-sectional relationship between PRO PROMIS-Cognitive Function (CF-SF) scores and CAB-NT scores.

Methods

Retrospective review of consecutive PwMS who completed both the CAB-NT and PROMIS-CF-SF in the course of routine care on the same day. CAB-NT included 7 cognitive domains: memory (Mem), executive function (Exe), attention (Att), information processing speed (Inf), visual spatial (Vis), verbal function (Ver), motor skills (Mot) as well as a global cognitive summary score (GCS). Cognitive domains impaired (CDI, domain score’s <85) are also calculated.

Results

147 PwMS, average age 49+/- 12, 70% female. Significant relationships (p<0.05) were identified through regression analysis with Pearson’s correlation coefficient (r) only for the following Cognitive Domain scores: GCS (r=0.27), Mem (r=0.23), Exe (r=0.27), Att (r=0.27), Inf (r=0.42), and Mot (r=0.27), CDI (r=0.4).

Conclusions

The PROMIS-Cognitive Function Short Form PRO does not provide a meaningful alternative to objective measures of CI in PwMS. Computerized Multi-domain Cognitive Testing provides an accurate tool to evaluate the degree of cognitive impairment across multiple relevant cognitive domains as well as the combination of domain impairment and accumulative cognitive impairment. The promise of the PROMIS-Cognitive Function Short Form to provide an effective PRO to evaluate cognitive impairment in PwMS has not been fulfilled.

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Biomarkers and Bioinformatics Poster Presentation

P0117 - Mystery of MRZ reaction in multiple sclerosis   (ID 1449)

Speakers
Presentation Number
P0117
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: Multiple Sclerosis (MS) is an immune mediated disease of the central nervous system (CNS). Epstein-Barr virus (EBV) is among the most well-established environmental risk factors in MS. MS patients also make low affinity antibodies against neurotrophic viruses such as measles (M), rubella (R), and zoster (Z), and they make these intrathecally. This phenomenon is quite specific for MS and it is called MRZ reaction. The pathophysiological role of MRZ reaction currently remains unclear.

Objectives

Objectives: Because EBV induces differentiation of infected B cells in antigen-nonspecific manner, the aim of this project is to test the hypothesis that the extent of MRZ reaction correlates with the amount of EBV infected B cells in the intrathecal compartment of MS patients and with the MS severity.

Methods

Methods: In a pilot cohort of 80 patients with broad range of MS severity, we blindly analyzed MRZ reaction by enzyme-linked immunosorbent assay (ELISA) applied to matched cerebrospinal fluid (CSF) and serum samples. To derive a single measure of the extent of MRZ reaction, we summed antibody indexes (AI) for each reaction component (M, R and Z) to MRZ score.

Results

Results: Upon unblinding the MS severity outcomes and diagnostic subgroups, the MRZ scores did not significantly correlate with B cell/plasma cell biomarkers known to be increased in MS CSF (i.e., B-cell maturation antigen/BCMA and IgG index) and were not significantly different between relapsing remitting, primary progressive and secondary progressive MS. Finally, the MRZ scores did not correlate with clinical outcomes of MS severity (MS disease severity scale: MS-DSS and brain damage severity: principal component of brain parenchymal fraction and the symbol digit modalities test normalized for patient’s age).

Conclusions

Conclusions: The study proved null hypothesis (i.e., MRZ reaction is not associated with intrathecal biomarkers of B cell/plasma cell expansion and with MS severity). The association between MRZ reaction and MS remains a mystery.

Acknowledgments: The research was supported by the Intramural Research Program of the NIH, NIAID.

Notice: This study involved patients and it was approved by NIAID IRB.

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Biomarkers and Bioinformatics Poster Presentation

P0118 - Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials (ID 1211)

Speakers
Presentation Number
P0118
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.

Objectives

To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.

Methods

In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.

Results

At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).

Conclusions

Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.

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Biomarkers and Bioinformatics Poster Presentation

P0119 - Neurofilament light chain levels correlate with lesion activity and axonal damage in MS (ID 902)

Speakers
Presentation Number
P0119
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The level of neurofilament light chain (NfL), a major component of the neuronal cytoskeleton, in plasma or cerebrospinal fluid (CSF) is considered a promising biomarker in multiple sclerosis (MS) for inflammation-mediated axonal damage.

Objectives

The relation between NfL levels and MS specific neuropathological measures is not yet known, and is the subject of this study.

Methods

In this autopsy study (n=105), CSF NfL levels were measured using a Simoa assay and were correlated with hallmarks for acute and chronic damage axonal damage, clinical and pathological donor characteristics, and to proportions and activity of MS white matter lesions determined with myelin and HLA stainings.

Results

CSF NfL levels correlated with presence of acute axonal damage features (APP+ bulbs: p=0.04, APP+ axons: p=0.03) and correlated negatively with axonal density (Bielschowsky+ axons: p=8.3e-3) in the normal appearing pyramid tract. As CSF NfL levels were confounded by stroke (<1 year before death, p=2.0e-3), these donors were excluded from further MS specific clinical and neuropathological analysis. NfL correlated negatively with disease duration (p=6.9e-3), thus with more severe MS. NfL levels positively correlated with the proportion of active MS lesions containing foamy microglia (p=9.85e-10) and not those containing ramified microglia. NfL levels of donors without atrophy at neuropathological examination were positively correlated with the proportion of mixed lesions with foamy microglia (p=1.75e-3), and negatively correlated with the proportion of inactive lesions (p=5.66e-3) and remyelinated lesion presence (p=0.04).

Conclusions

We validated that CSF NfL levels reflect pathological hallmarks of acute disease activity and concomitant axonal degeneration. These observations support the clinical use of NfL to monitor these neuropathological processes in people with MS.

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Clinical Outcome Measures Poster Presentation

P0120 - Neuroperformance test outcomes as predictors of employment in a large, heterogeneous real world MS populations: Results from MS PATHS (ID 1758)

Speakers
Presentation Number
P0120
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Neuro-performance testing has been used extensively in MS clinical trials, resulting in a large literature on processing speed (Symbol Digit Modalities Test [SDMT]), manual dexterity (9-Hole Peg Test [9HPT]), and walking speed (25-foot walk [25FW]). Computer adapted versions were developed and validated, to support widespread use in clinical practice. The Multiple Sclerosis Performance Test (MSPT) includes a self-administered Processing Speed Test (PST), simulating SDMT; Manual Dexterity Test (MDT), simulating 9HPT; and Walking Speed Test (WST), simulating 25FW. MSPT is deployed within the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network. Optimal test thresholds associated with employment status in a real-world population have not been reported.

Objectives

To determine thresholds for standardized test scores of processing speed, manual dexterity, and walking speed as predictors of employment status in a real world MS population.

Methods

Neuroperformance testing was done as part of clinical visits in MS PATHS. Employment status was collected via standardized questionnaire. Patients aged 18 to 60 in the US were divided into a training set (n=3210) and a test set (n=1605). PST, MDT and WST benchmarks predicting unemployment at baseline and employment worsening at 2 years were identified as the test scores with the minimum p-value in logistic regression models adjusting for age, sex and education. Odds ratios representing the risk of unemployment or employment worsening were calculated based on the identified benchmarks.

Results

4815 of 9585 participants (50%) were employed full-time at baseline. In the training set benchmarks for unemployment were: PST ≤44 correct, OR (95% CI) 5.3 (4.7, 6.0); MDT >28.7 seconds, OR 7.2 (6.3, 8.1); and WST >8 seconds, OR 6.7 (5.8, 7.7). For patients employed at baseline, benchmarks for worsening employment status were: PST ≤44 correct, OR 4.3 (3.1, 6.0); MDT >24 seconds, OR 3.3 (2.3, 4.6); and WST >7.6 seconds, OR 6.4 (4.7, 8.8). Benchmarks were confirmed in the validation set.

Conclusions

Clinically relevant neuroperformance test benchmarks for predicting unemployment and employment worsening were identified in a training set and confirmed in a validation set using a large real world MS population. Future research will determine early risk factors for these benchmarks in order to identify potential employment preservation strategies.

Disclosures: MS PATHS is sponsored by Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0121 - Objective measurement of speech correlates with disease status and quality of life in people with MS without dysarthria (ID 1681)

Speakers
Presentation Number
P0121
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Objective measurement of speech has shown promising results to monitor disease state in Multiple Sclerosis (MS). Yet, it is not clear if changes in speech can be detected before overt dysarthria.

Objectives

In this study, we characterize the relationship between disease severity and objective speech metrics exclusively in people with no perceivable dysarthria.

Methods

An acoustic composite score was calculated using regression modelling of speech data from 119 people with MS (pwMS, 75% female), irrespective of dysarthria presence. That score was then tested in pwMS without dysarthria, as determined by blinded perceptual rating, for correlations with the Expanded Disability Status Scale (EDSS), brain volume and lesion load from magnetic resonance imaging, and quality of life scores from the Multiple Sclerosis Impact Scale (MSIS-29) .

Results

PwMS without dysarthria (n=77) were more likely to be female (82% vs 62%, p=0.017), were on average 5.7 years younger (age mean ± standard deviation 53.5±11.4, p=0.009), had MS for 2.5 years shorter (11±8.5 years, p=0.034) and scored EDSS 1.7 step lower (2.7±1.9, p<0.001) than pwMS with dysarthria (n=42). The acoustic composite score correlated with EDSS scores (r=0.45, p<0.001) and quality of life (r=0.4, p=0.01) in pwMS without perceivable dysarthria, but not with brain volume or lesion load.

Conclusions

Acoustic analysis offers a valuable insight into the subclinical development of speech impairment in MS. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.

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Clinical Outcome Measures Poster Presentation

P0122 - Ocrelizumab in patients with multiple sclerosis: A single center experience.  (ID 668)

Speakers
Presentation Number
P0122
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple Sclerosis is a progressive demyelinating autoimmune disorder that can lead to significant morbidity and mortality. It can be either relapsing remitting i.e Relapsing Remitting Multiple Sclerosis (RRMS) or progressive in nature like Primary Progressive Multiple Sclerosis (PPMS). Several Disease Modifying Treatments (DMT) are used to treat this disorder. Ocrelizumab is a humanized CD20 monoclonal antibody which was approved for management of RRMS and PPMS in 2017. Trials such OPERA I and II as well as ORATORIO has shown improved clinical outcomes in patients with RRMS and PPMS respectively.

Objectives

We aim to study the clinical disease progression including disability scores and imaging findings such as volumetric analysis of several central structures in patients being treated with Ocrelizumab at baseline and 12 months.

Methods

We enrolled a total of 124 patients that were seen at our institute, who are currently being treated with Ocrelizumab (92 with RRMS and 32 with PPMS) between August 2017 to July 2020. Clinical data was obtained from their medical records including Expanded Disability Status Scale (EDSS) and Timed 25 Foot Walk (T25FW) at baseline and 12 months. MRI of the brain, which included T1-w, T2-w, T2-FLAIR, post gadolinium T1-MRAGE sequences were also collected. LesionQuant software, developed by CorTechs laboratory will be used to obtain volumes of the cortical gray matter, white matter, hippocampi and white matter lesion load in the periventricular, juxtacortical, infratentorial and deep cerebral white matter areas.

Results

When independent paired t- test was performed there was significant improvement in the T25FW over time (t= 3.19, n=47; p=0.003 Cohen’s d= 0.46) but no such changes were observed with the EDSS scores (t= 1.58, n= 120; p=0.118 Cohen’s d= 0.14). Means of T25FW before and after intervention were 10.98 seconds and 9.49 seconds respectively. Means of EDSS scores before and after interventions were 3.58 and 3.52 respectively. We’re currently in the process of obtaining volumetric measure of the structures mentioned above and correlating them with the clinical scales in the near future.

Conclusions

In 31 participants with PPMS, EDSS score improved in 6 (19%), was stable in 22 (71%), and deteriorated in 3 (10%). In 89 participants with RRMS, EDSS score improved in 3 (3%), was stable in 76 (86%), and deteriorated in 10 (11%). We hope to further explore the effect of medication by computing imaging features in the near future.

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Biomarkers and Bioinformatics Poster Presentation

P0123 - Ocrelizumab reduces thalamic volume loss and clinical progression in PPMS and RMS independent of baseline NfL and other measures of disease severity (ID 1621)

Speakers
Presentation Number
P0123
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS). Thalamic atrophy occurs early and may be a sensitive marker of overall brain damage. Ocrelizumab (OCR) reduced brain atrophy and NfL in patients with relapsing MS (RMS) and those with primary progressive MS (PPMS).

Objectives

To examine the independent impact of OCR and baseline (BL) NfL on thalamic volume (TV) and clinical progression in patients with PPMS and RMS, including those with RMS without acute BL activity (i.e. no gadolinium–enhancing [Gd+] lesions or relapse in the last 3 months).

Methods

Patients were from OPERA I/II (RMS, n=1,421) and ORATORIO (PPMS, n=596). Thalamic atrophy was calculated as annualized percentage TV change (PTVC) from Wk 24 to the end of controlled treatment (ORATORIO, Wk 120; OPERA I/II, Wk 96). OCR treatment (vs IFNβ-1a [RMS] or placebo [PPMS]) and log-transformed BL NfL were examined for associations with PTVC (linear regression) and 24-week confirmed disability progression (Cox regression) adjusting for BL demographic and disease characteristics.

Results

In patients with PPMS and RMS, OCR treatment (PTVC: +0.47% and +0.33%, respectively) and lower BL NfL (+0.20% and +0.33% per 2-fold lower NfL) independently associated with a smaller TV reduction (all p<0.005). Adjusting for BL NfL level, Gd+ lesion count, T2 lesion volume and BL disability, OCR still reduced disability progression on Expanded Disability Status Scale (EDSS) (PPMS, hazard ratio [HR]=0.73; RMS, HR=0.65; both p<0.05]), 9-Hole Peg Test (9HPT) (PPMS, HR=0.53, p=0.002; RMS, HR=0.52, p=0.059), Timed 25-Foot Walk (T25FW) (PPMS, HR=0.79, p=0.063), Symbol Digit Modalities Test (RMS, HR=0.54, p=0.002) and time to EDSS 6 (RMS, HR=0.42, p=0.009). In patients with PPMS, higher BL NfL was associated with worsening on 9HPT (HR=1.34 per 2-fold higher NfL), T25FW (HR=1.19) and time to EDSS 7 (HR=1.78) (all p<0.05). In patients with RMS without acute BL activity, higher BL NfL was associated with EDSS worsening (HR=1.49), progression independent of relapse activity (PIRA) (HR=1.61), 9HPT (HR=2.1) and time to EDSS 6 (HR=2.24) (all p<0.05).

Conclusions

Ocrelizumab treatment remained associated with reduced thalamic atrophy and clinical progression after adjusting for baseline NfL and other factors. Higher BL NfL was associated with increased rates of thalamic atrophy and clinical progression in patients with PPMS and those with RMS without acute disease activity.

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Clinical Outcome Measures Poster Presentation

P0124 - Ocrelizumab treatment in patients with relapsing-remitting multiple sclerosis: a single-center real-world experience (ID 1619)

Speakers
Presentation Number
P0124
Presentation Topic
Clinical Outcome Measures

Abstract

Background

ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with relapsing-remitting multiple sclerosis (RRMS) was associated with high clinical efficacy and safety. However, real word data on efficacy and safety are still scarce

Objectives

To provide first experience on patients with RRMS treated with OCR in a single center real-world setting (MS Center of University of Genoa)

Methods

We collected safety and efficacy data from pts with RRMS treated with OCR. The probability of disability worsening-free survival, relapse-free survival, MRI-activity free-survival and NEDA-3 status was calculated with the Kaplan-Meier estimator and Cox proportional hazards regression analysis.

Results

96 RRMS pts [60 females (62.5%), mean (SD) age 37.3 (10.2) years] with a mean disease duration (DD) of 9.6 (9.3) years, a median (IQR) baseline EDSS of 2.5 (2-4) and a mean ARR of 0.79 (0.73). Median (IQR) number of previous DMTs was 1 (0-2). The mean time from previous DMT discontinuation and OCR start of 209 (661) days. Reasons for previous DMTs discontinuation were (i) lack of efficacy for 45 (67%), (ii) occurrence of adverse events for 7 (10%) and (iii) high JCV titer during natalizumab treatment for 5 (7.5%) pts. 28 pts (29.5%) had not received any DMT prior to OCR. Naïve pts had significantly shorter disease duration (2.6 vs 12.5 years; p<0.0001), had higher ARR (1.1 vs 0.7; p=0.002) and more frequently exhibited inflammatory activity on baseline MRI scan (96.3% vs 74.6%; p=0.019). Mean follow-up (FU) was 1.4 (1.2) years.

At 1-year FU, MRI-inflammatory activity free survival was 75.9%, relapse free survival was 95.9%, progression free survival was 98.7%. 2-years NEDA-3 status was achieved in 73.6% of pts. At multivariate analyses, adjusting for DD, ARR and baseline MRI activity, 2-years NEDA-3 status was significantly higher in naïve compared with treated pts [90.7% versus 60.8% at the end of the observation period; HR (CI 95% ) 0.14 (0.03-0.65); p=0.012]. We recorded 55 adverse events in 39 pts (4 lower respiratory tract infections; 18 upper respiratory tract infections; 7 herpes simplex-1 reactivation; 1 shingles; 8 upper urinary tract infections; 2 breast cancers). No serious infusion-associated reactions were reported

Conclusions

OCR treatment allows complete disease control in a high proportion of real-world RRMS pts, with a manageable safety profile. Although ocrelizumab can control disease activity after failure of highly efficacy DMTs, its efficacy seems to be higher in naïve patients

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Biomarkers and Bioinformatics Poster Presentation

P0125 - Ocrelizumab treatment induces a sustained blood NfL reduction in patients with PPMS and RMS (ID 1865)

Speakers
Presentation Number
P0125
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Blood neurofilament light chain (NfL) is a biomarker of neuroaxonal injury associated with acute disease activity and may be prognostic for disability progression in patients with multiple sclerosis (MS). Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody indicated for relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To assess the impact of OCR on blood NfL distribution in patients with RMS from the OPERA I and II trials and those with PPMS from ORATORIO.

Methods

Pretreatment and posttreatment NfL levels (measured using the SiMOA assay) with OCR vs interferon β-1a (OPERA I and II; n=1,421) or placebo (ORATORIO; n=596) were compared using geometric mean (GM) and GM ratios (GMR). Patients were stratified by presence/absence of acute disease activity at baseline (BL) (T1 gadolinium [Gd]-enhancing lesions and/or relapse in prior 3 months for RMS; T1 Gd-enhancing lesions for PPMS). Age-adjusted NfL distributions (using a linear model for log-NfL and age derived from a healthy donor [HD] cohort) at BL and after OCR were compared with HD using the Kolmogorov-Smirnov test.

Results

Significant reductions in NfL were observed 3 months after OCR initiation (RMS, GMR=0.80; PPMS, GMR=0.89) and sustained through the end of controlled treatment (RMS [96 weeks], GMR=0.56; PPMS [120 weeks], GMR=0.81; all p<0.0001). Age-adjusted BL serum NfL was elevated in patients with RMS disease activity (GM [95% CI]=12.7 [11.9–13.6] pg/mL) vs those without (5.5 [5.3–5.7] pg/mL) and HD (4.1 [3.9–4.4] pg/mL; all p<0.0001). In OCR-treated patients with RMS, GM [95% CI] serum NfL levels after 96 weeks (with activity at BL, 4.4 [4.2–4.6] pg/mL; without activity at BL, 4.1 [4.0–4.3] pg/mL) were comparable to HD (4.1 [3.9–4.4] pg/mL; all p>0.1). Age-adjusted BL plasma NfL was also elevated in PPMS patients with disease activity (GM [95% CI]=8.7 [7.5–10.1] pg/mL) vs those without (4.9 [4.6–5.2] pg/mL) and HD (3.1 [2.9–3.3] pg/mL; all p<0.0001). In OCR-treated patients with PPMS, GM [95% CI] plasma NfL levels after 120 weeks (with activity at BL, 4.6 [4.1–5.1] pg/mL; without activity at BL, 4.2 [4.0–4.4] pg/mL) were reduced from BL (all p<0.005) but remained elevated vs HD (all p<0.001).

Conclusions

NfL is highly elevated in patients with acute MS disease activity, and more subtle elevations are observed in RMS and PPMS patients without detectable disease activity. Ocrelizumab significantly reduces NfL in RMS and PPMS patients with and without detectable disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0126 - Olfactory threshold as a biomarker predicting treatment response in relapsing multiple sclerosis (ID 296)

Speakers
Presentation Number
P0126
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Olfactory threshold impairment is transiently occurring in patients with active multiple sclerosis (MS) and during acute MS relapse resolving in phases of clinical stability and after initiation of disease-modifying treatment (DMT). Thus, threshold impairment is a marker of short-term inflammatory activity in relapsing multiple sclerosis (RMS).

Objectives

The objective of this study was to investigate the potential of olfactory threshold for prediction of treatment response in RMS.

Methods

In this 4-year prospective observational study on 113 RMS patients, olfactory threshold was measured at DMT initiation (M0) and after 3 (M3) and 12 months (M12) of follow-up by the Sniffin’ Sticks test. Inclusion criteria included adherence to DMT for at least 2 years. Treatment response was defined as absence of relapse during the observation period. Best possible cut-off values of olfactory threshold for predicting treatment response were determined by receiver-operating characteristics (ROC) analyses. Odds ratios (OR) for treatment response were calculated by stepwise multivariate logistic regression models correcting for age, sex, and disease duration at baseline.

Results

A combination of threshold score ≥6.0 at M3 and ≥1.0 points improvement from M0 to M3 sustained to M12 displayed the best prediction of treatment response (OR 5.1; 95% CI: 2.3 – 7.8; p<0.001; specificity 90%, sensitivity 83%) followed by threshold score ≥6.0 at M3 alone (OR 3.6; 95% CI: 1.3 – 7.0; p<0.001; specificity 83%, sensitivity 76%), ≥1.0 points improvement from M0 to M3 sustained to M12 alone (OR 3.5; 95% CI: 1.2 – 6.8; p<0.001; specificity 82%, sensitivity 70%). Threshold score at M12 alone and improvement from M3 to M12 was not significantly predictive. Also, adding threshold score at M12 to the model did not improve predictive accuracy.

Conclusions

Olfactory threshold impairment predicts relapse activity upon DMT initiation. Pending validation, olfactory threshold may be a useful and easily obtainable biomarker of treatment response in RMS.

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Clinical Outcome Measures Poster Presentation

P0127 - Oral therapies for treatment of relapsing-remitting multiple sclerosis in Austria (ID 252)

Speakers
Presentation Number
P0127
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Studies matching the clinical efficacy between fingolimod (FTY), dimethylfumarate (DMF) and teriflunomide (TERI) provided conflicting results. These discrepancies ask for further investigations to confirm or rebut the published findings, especially by real-life experiences.

Objectives

To compare the efficacies, frequencies and reasons for treatment interruption of FTY, DMF or TERI in a nationwide observational cohort.

Methods

Twocohorts of patients with relapsing-remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study.

Results

Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption (p=0.023) and reduced sustained EDSS regression for 12 (p=0.016) and 24 weeks (p=0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks (p=0.02).

Conclusions

Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lowerprobability for treatment interruptionas compared to TERI treated patients.

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Clinical Outcome Measures Poster Presentation

P0128 - Outcomes in Alemtuzumab-Treated Patients With Thyroid Adverse Events: 6-Year Pooled CARE-MS Data (ID 736)

Abstract

Background

Over 6 years in the CARE-MS core and extension trials (NCT00530348; NCT00548405; NCT00930553), alemtuzumab improved outcomes in RRMS patients, but many experienced thyroid adverse events (AEs).

Objectives

To characterize thyroid AEs over 6 years in alemtuzumab-treated patients from the CARE-MS core and extension trials.

Methods

Patients received 2 alemtuzumab courses, with as-needed additional alemtuzumab ≥12 months after the most recent course. An expert panel of 3 independent endocrinologists reviewed all reported cases of thyroid-related laboratory abnormalities and AEs to assess diagnosis, start date, and outcome through a consensus approach. Cases for which consensus was not reached, or those that were preexisting or occurred after Y6 were excluded.

Results

Over 6 years, 378/811 (47%) alemtuzumab-treated patients had a thyroid AE or laboratory abnormality (342 [42%] with thyroid AE; 44 serious AEs). After panel review, 292 cases had a consensus diagnosis as a thyroid AE, no consensus diagnosis could be reached in 60 cases, 2 cases were deemed pre-existing, and 24 occurred after Y6. Cases with a consensus diagnosis were adjudicated to Graves’ disease (40%), Hashimoto’s disease (17%), transient thyroiditis (8%), Graves’ disease switching to hypothyroidism (6%), Hashimoto’s disease switching to hyperthyroidism (3%), or uncertain (27%). Oral thyroid medications were given to 245/292 (84%) patients, primarily levothyroxine/levothyroxine sodium (n=187; 64%) or thiamazole (n=126; 43%); 32/292 (11%) patients underwent thyroidectomy and 26/292 (9%) underwent radioiodine therapy. Within 2 years of the last alemtuzumab course, 83% of thyroid AEs appeared (>97% were detected within 4 years). Patients with vs without thyroid AEs received similar numbers of alemtuzumab courses (2 courses: 62% vs 60% of patients; 3 courses: 24% in each group). From baseline to Y6, MS disease outcomes were similar in patients with vs without thyroid AEs (annualized relapse rate: 0.20 vs 0.21; mean EDSS score change: −0.04 vs +0.08; proportion with stable/improved EDSS scores: 81% vs 80%; proportions MRI disease activity-free: 60%-78% per year vs 60%-76% per year; and median cumulative brain volume loss: −1.11% vs −1.27%). Outcomes as of last follow-up were recovered (53%), ongoing (46%), and unknown (0.3%).

Conclusions

Graves’ disease was the most common thyroid AE. Most thyroid AEs were treated with oral medications. No differences in 6-year MS disease outcomes were seen when comparing patients with or without thyroid AEs.

STUDY SUPPORT: Sanofi and Bayer Healthcare Pharmaceuticals.

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Clinical Outcome Measures Poster Presentation

P0129 - Pattern of brain attack occurrence in neuromyelitis optica spectrum disorder: effect of treatment   (ID 1626)

Speakers
Presentation Number
P0129
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Brain involvement in neuromyelitis optia spcectrum disorder (NMOSD) is well recognized and some characteristic magnetic resonance imaging (MRI) abnormalities are incorporated into the recently proposed diagnostic criteria for NMOSD. However, little is known about clinical implication of brain attacks in NMOSD.

Objectives

To analyze patterns of frequency and timing of brain attacks with regard to treatment compared to those of optic neuritis or myelitis in patients with NMOSD.

Methods

This study retrospectively reviewed 260 consecutive aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD patients who were on immunosuppressive therapies (IST) more than 6 months between October, 2005 and April, 2020 at National Cancer Center, Korea. Brain attack was defined as newly developed acute neurological symptoms lasting ≥24 hours with corresponding acute NMOSD-characteristic brain lesion(s). The following demographic and clinical variables were collected: sex, onset age, disease duration, types (optic neuritis [ON], myelitis, brain attack and area postrema syndrome [APS]) and date of each attack, and treatment history.

Results

A total of 1738 attacks occurred in 260 patients during median 143 months (interquartile range 84-195 months) of observation period: 1377 and 361attacks before and after initiation of IST, respectively. Brain attacks were observed in 95 (37%) patients: 147 attacks in 93 (36%) patients before IST and 13 attacks in 11 (4%) patients after IST. APS was observed in 25 (9.6%) patients before IST especially at the disease onset, but no one experienced APS after IST. Before IST, ON, myelitis and brain attack were observed at 36.8, 78.7 and 14.1 per 100 patient-years, respectively, while decreased to 4.5, 12.1 and 0.6 per 100 patient-years after IST, respectively. The reduction rates of each attack frequency after IST were significantly greater in brain attack than in ON or myelitis (mean 78% vs. 95%, p=0.014). Patients with brain attacks despite IST showed higher mean annualized relapse rate (ARR) compared to those without brain attacks (p=0.029).

Conclusions

Impact of IST appeared to be greater on the reduction of brain attack than that of ON and myelitis in AQP4-IgG seropositive NMOSD, resulting in rare occurrence of brain attacks after IST. ARR was higher in patients with brain attack than in those without brain attack particularly after IST. These results suggest brain attack may allude high disease activity in NMOSD.

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Clinical Outcome Measures Poster Presentation

P0130 - Pediatric MS: different disease course, different impact, different measurement approach needed (ID 972)

Speakers
Presentation Number
P0130
Presentation Topic
Clinical Outcome Measures

Abstract

Background

To understand the impact of pediatric mulitple sclerosis (MS), generic health related quality of life (HRQL) measures have been used. However, generic measures do not always reflect the relevant domains of health that are affected by MS. Specific areas of concern of youths with MS are not known and are assumed to be the same as parents, clinicians, or children with other disabilities or children in general.

Objectives

The objectives of this study were to identify the domains of life that are important to youth with pediatric MS and to contribute evidence towards the development of a condition-specific measure for children and adolescents with MS.

Methods

In conjunction with patient partners, an online survey for youths with MS and parents was developed based on the Patient Generated Index (PGI). Text threads generated by the PGI were mapped onto the International Classification of Functioning, Disability and Health (ICF) and the Comprehensive ICF Core Set for MS.

Results

A total of 19 people completed the PGI survey of which 10 were youths with MS aged 14 to 22 years with a median onset age of 13.5 years. Over 80% of the areas nominated by youths with MS related to activities and participation and only 20% related to impairments. In contrast, 62% of the areas nominated by parents related to impairments. This input indicated that a measure of HRQL would need to include both the impairments associated with MS that need to be targeted with therapies and the activities and roles that are important that need to be encouraged and celebrated. The new approach has a disability component covers MS related impairments and is completed using the PGI system where the youth (or parent for young children) selects 5 disability areas affected by MS, rate severity, and prioritize each area for improvement. The “quality of life” component, to be completed only by the youth, queries those areas that are going well.

Conclusions

In a rare disease like pediatric MS, progress is slow in this area as condition-specific measures are not available. The rarity of the conditions makes it difficult to adhere to best practice guidelines developing measures for these unique populations. The use of this new measurement approach could prove useful in overcoming challenges of measurement development for children with rare diseases.

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Clinical Outcome Measures Poster Presentation

P0131 - Predicting long-term sustained disability progression in multiple sclerosis: application in the CLARITY trial (ID 1071)

Speakers
Presentation Number
P0131
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Prevention of disability over the long-term is the main treatment goal in multiple sclerosis (MS), however, randomized clinical trials provide only short-term (3-6-month) treatment effect on disability.

Objectives

To externally validate the previously developed sustained progression score which established 6-month confirmed disability progression events as indicators of long-term disability worsening in randomized double-blind CLARITY (Cladribine Tablets Treating MS Orally) trials. A higher score indicates a greater probability of a progression event to be sustained over the long-term.

Methods

Data from the CLARITY and CLARITY 2-year Extension study were used. The 3-and 6-month confirmed disability progression events and the time over which progression remained sustained were identified. Patient characteristics at the time of progression previously associated with the likelihood of improvement after confirmed progression event (age, primary progressive MS, a relapse in previous month, expanded disability status scale score≥6 and its change from baseline, number of affected functional system domains, and worsening in pyramidal, brainstem and sensory domains) were used to calculate the sustained progression score for each progression event. A Cox proportional hazards model was used to validate the association of the score calculated for each 6-month confirmed disability progression event with time to improvement. To demonstrate application of the score in trial setting, the analysis of the CLARITY study were repeated estimating the effect of therapy on long-term disability outcomes. Effect of cladribine on 3-month confirmed progression events with any score and score˃1.5 was evaluated.

Results

A total of 667 6-month confirmed disability progression events were identified in the combined dataset, of which only 12 were followed by a 6-month confirmed disability improvement. The external validation of the score illustrated a trend towards a decrease in the likelihood of disability improvement in progression events with higher score (Hazard Ratio HR=0.72, 95% CI: 0.21-2.42). Results of the original trial were confirmed in addition to that oral cladribine reduced the risk of disability progression that was likely to be sustained over the long-term (only events with score˃1.5; HR: 0.64; 95% CI: 0.47-0.87).

Conclusions

The sustained progression score, estimated using the characteristics of confirmed progression events, provides important complementary information that will allow future trials to establish the effect of therapy not only on short-term but also on long-term disability accrual.

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Biomarkers and Bioinformatics Poster Presentation

P0132 - Prediction of 15-year MS outcomes in BENEFIT trial patients using serum neurofilament light chain concentrations (ID 1726)

Speakers
Presentation Number
P0132
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are a promising biomarker for quantifying neuro-axonal injury in multiple sclerosis (MS). Recent studies showed sNfL levels relate to disease activity and treatment response.

Objectives

To analyze the predictive capacity of baseline (BL) sNfL levels for disease outcomes in the 15-year BENEFIT study long-term follow-up

Methods

Monofactorial regression analyses were conducted on outcomes at Year 15, including sNfL age-adjusted percentiles (80th, 90th, 95th, 97.5th and 99th; Disanto et al., 2017).

Further BL covariates included sex; age; lowest EDSS up to Month 6; mono/multifocal onset; presence of optic nerve, brainstem, or spinal cord lesions; Paced Auditory Serial Addition Test 3 (PASAT-3), Timed 25 Foot Walk (T25W), and 9 Hole PEG test (9HPT) scores; number/volume of hypointense T1, gadolinium-enhancing T1, and T2 lesions; cerebral volume; and initial treatment assignment. On-study covariates at Years 1, 2, and 5 were annualized relapse rate; EDSS change; PASAT-3, T25W, and 9HPT scores; annualized rate of new lesions; lesion number/volume; brain volume change; and relative duration of treatment. Covariates with p≤0.1 (at ≥2 time points for on-study covariates) were entered into multifactorial models.

We assessed the predictive capacity of BL sNfL levels for the following outcomes: EDSS ≥4, clinically silent disease, T2 lesion volume, and cerebral volume.

Results

Patients with sNfL values at screening (N=258) above the 90th (n=176), 95th (n=157), 97.5th (n=149), and 99th (n=129) percentiles (adjusted for other relevant covariates) had a significantly higher risk of EDSS≥4 at Year 15 for BL model (odds ratio 2.45 [95% CI: 1.05,5.68] p=0.0376; 2.60 [1.18,5.75] p=0.0181; 2.61 [1.20,5.66] p=0.0154; 2.47 [1.19,5.13] p=0.0150, for the 90th, 95th, 97.5th and 99th percentiles, respectively), and for on-study models at Year 1 (3.86 [1.16,12.78] p=0.0272; 3.38 [1.13,10.14] p=0.0296; 2.92 [1.02,8.35] p=0.0461; 2.98 [1.11,8.00] p=0.0305, respectively) and Year 2 (5.36 [1.26,22.85] p=0.0231; 4.88 [1.34,17.77] p=0.0163; 3.86 [1.18,12.66] p=0.0259; 3.34 [1.17,9.48] p=0.0237, respectively). Covariates that remained statistically significant with EDSS≥4 as the endpoint in most percentile models were lowest EDSS value up to Month 6 for BL and Year 1, and change in brain volume at Year 1, 2, and 5.

Conclusions

Findings in this unique long-term BENEFIT study suggest that higher sNfL values in early MS disease stages are independent predictors of long-term disability.

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Clinical Outcome Measures Poster Presentation

P0133 - Prediction of MS disability status in Japanese claims database using principal component analysis (ID 553)

Speakers
Presentation Number
P0133
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Claims databases are widely used in MS research to evaluate clinical practice and outcome of MS treatments in real-world settings. However, disability status as indicated by Expanded Disability Status Scale (EDSS) is not available in claim databases, which makes it difficult to evaluate current healthcare situation of MS patients with higher disability status like SPMS.

Objectives

To describe healthcare situation in Japanese MS patients with higher disability status like SPMS using a score representing disability status developed by principal component analysis from claims database

Methods

We employed principal component analysis, which is a multivariate data analysis technique, for developing a score to predict the severity of MS using the information extracted from claims data. The Medical Data Vision database (a nationwide hospital-based claims database covering all diseases) was used as a data source (2009-2018, n=7067). Diagnosis and medication codes related to 7 functional systems of EDSS were selected based on the MS treatment guideline and advice of the medical expert. Additional claims (e.g. locomotorium rehabilitation fees) which are supposed to be associated with higher disability status were also included. A score for each patient in each year was calculated based on the eigenvector coefficient for each factor of the first principal component, and then divided into 4 groups by quartile values of this score. Treatment pattern, healthcare resource utilization and costs in these 4 groups were described.

Results

The average ages were 43.3 and 55.4 years in the lowest and highest score groups, respectively. The duration since first diagnosis was 6 years for the lowest group and 8.1 years for the highest group. The total healthcare costs (JPY 102,053 vs 157,387 pppm), frequency of visit (0.69 vs 1.29 pppm) and hospitalization (0.004 vs 0.066 pppm) were numerically higher in the highest group compared with the lowest group. Meanwhile, frequency of relapse was numerically higher in the highest-score group (1.1 vs 4.1% pppm), which was counterintuitive considering natural course of MS.

Conclusions

A novel method using claims database was developed to represent MS disability status of an individual patient. This method enabled to describe the current healthcare situation of Japanese MS patients with higher disability status and demonstrated increased healthcare cost and resource utilization in this population.

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Biomarkers and Bioinformatics Poster Presentation

P0134 - Preliminary validation of static posturography as a disability outcome measure in progressive multiple sclerosis. (ID 685)

Speakers
Presentation Number
P0134
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

People with multiple sclerosis (pwMS) frequently experience impairment in postural control, a multifaceted measure related but distinct to walking ability.

Objectives

To assess clinical validity of static posturography as a disability outcome measure in people with progressive MS; to assess feasibility of use of the force platform in pwMS with moderate-to-severe disability; to explore the relationship between multiple cognitive domains and postural control in pwMS with a high burden of cognitive and physical impairments.

Methods

Twenty-three pwMS with Expanded Disability Status Scale (EDSS) 3.5–6.0 stood on a force platform under various test conditions (single task: Eyes Open (EO), Eyes Closed (EC); dual-task: posturography with concurrent cognitive tasks, N-Back, and Sustained Attention Response Task) and completed a battery of ambulation, balance and cognitive tests.

Results

EO Centre of Pressure (COP) Path Length correlated with proprioceptive (r=0.65, p=0.001), cerebellar (r=0.62, p=0.002), vestibular (r=0.46, p=0.027) and visual (r=0.53, p=0.009) dysfunction, but not with age, gender, body mass index, anxiety, or standard walking measures (EDSS, Timed 25 Foot Walk). EO Path Length significantly predicted the Dynamic Gait Index (adjusted R2=25.8%, p=0.008), Dizziness Handicap Inventory score (adjusted R2=24.9%, p=0.008) and 9 Hole Peg Test score (adjusted R2=14.2%, p=0.043). Of pwMS with EDSS 6.0, EO mediolateral displacement predicted distance walked during the Two Minute Walk Test (adjusted R2=53.2%, p=0.016). Diminished postural control was associated with mediolateral direction of sway (p<0.001), EC (p=0.004), fampridine use (p=0.004) and poorer physical (p=0.039) and psychological (p=0.026) quality of life. A consistent pattern of poorer cognitive function associated with better postural control was observed across multiple cognitive domains (information processing speed, verbal memory, visuospatial memory, attentional capacity). No significant differences in postural control were detected between EO and dual-tasks. During the N-Back task, poorer postural control correlated with lower % N-Back scores (p=0.049).

Conclusions

Static posturography is a non-invasive, brief and easy-to-administer test with high construct and concurrent validity as a disability outcome measure in people with progressive MS. The finding of diminished postural control with fampridine use suggests that static posturography can identify effects of treatment in pwMS. Demonstration of cognitive-postural interference in pwMS provided insight into distinct postural control strategies adopted by pwMS with different levels of cognitive and physical disability, and may complement balance rehabilitation methods in falls prevention programmes.

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Biomarkers and Bioinformatics Poster Presentation

P0135 - Preventing multiple sclerosis misdiagnosis using the “central vein sign”: A real-world study (ID 500)

Speakers
Presentation Number
P0135
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Misdiagnosis of multiple sclerosis (MS) is common and often occurs due to misattribution of non-MS magnetic resonance imaging (MRI) lesions to MS demyelination. A recently developed MRI biomarker, the central vein sign (CVS), has demonstrated high specificity for MS lesions and may thus help prevent misdiagnosis.

Objectives

We explored the potential “real world” value of CVS in preventing MS misdiagnosis by comparing CVS in patients with MS and patients previously misdiagnosed with MS by standard clinical practice and established diagnostic tools.

Methods

30 patients (15 with MS and 15 misdiagnosed with MS) were prospectively recruited to undergo 3T brain MRI. T2-weighted fluid-attenuated inversion recovery (FLAIR) and T2*-weighted segmented echo-planar-imaging (T2*-EPI) were acquired to generate FLAIR* images, then analyzed by two independent raters blinded to clinical information. The percentage of lesions with CVS was calculated for each patient.

Results

The number of brain lesions per patient did not significantly differ between the two groups. The number of lesions with CVS, however, did differ, with a mean of 0.93 lesions (range 0-6) in the misdiagnosed group versus 6.3 (range 0-15) in the MS group. A CVS lesion threshold of 29% or higher resulted in high adjusted sensitivity of 0.79 (95% CI: 0.68-0.95) and specificity of 0.88 (95% CI: 0.68-0.95) for MS and correctly identified 87% of patients previously misdiagnosed with MS. Interrater reliability for CVS was excellent with a Cohen’s kappa coefficient of 0.86.

Conclusions

Our study found that CVS differentiated with high sensitivity and specificity patients with MS from patients who were previously misdiagnosed with MS after undergoing routine clinical evaluation. We believe that our findings further support the incorporation of CVS in the diagnostic approach to MS to increase accuracy and reduce misdiagnosis.

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Biomarkers and Bioinformatics Poster Presentation

P0136 - Profiling of small non-coding RNAs across cellular and biofluid compartments in patients with Multiple Sclerosis (ID 1195)

Speakers
Presentation Number
P0136
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Small non-coding RNAs (sncRNAs) are important regulators of gene expression at the transcriptional and post-transcriptional levels in various biological contexts, such as regulation of immune system functions, homeostasis, and autoimmunity development. While the role of microRNAs (miRNAs) in multiple sclerosis (MS) has attained major interest, studies investigating other sncRNA classes, especially in the target central nervous system compartment, are still scarce.

Objectives

We aimed to perform a comprehensive, comparative analysis of all classes of sncRNAs in matching peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from MS patients and controls.

Methods

23 relapsing-remitting (RRMS, n=12 in relapse, n=11 in remission), 6 secondary progressive (SPMS) MS patients and 16 non-inflammatory and inflammatory neurological disease controls (NINDC, n=11; INDC, n=5) were included in the analysis. We utilized Small-seq (Faridani et al., Nat Biotechnol. 2016) to quantify sncRNA transcripts.

Results

We observed distinct and variable profiles of sncRNA classes across all analyzed cellular and biofluid compartments. While miRNAs were the most abundant class of sncRNAs in PBMCs and plasma, transfer RNAs represented the most abundant class in CSF cells and cell-free CSF. Furthermore, we observed an opposing quantitative pattern of small nuclear, nucleolar, transfer RNAs, and miRNAs changes between the blood and CNS compartments. In CSF cells, 133/133 and 115/117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65/67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. These findings underscore the importance of including both the peripheral and intrathecal compartments in studies investigating the role of sncRNAs in MS.

Conclusions

Our findings demonstrate widespread alterations of several classes of sncRNAs, particularly during the relapse phase in CSF cells. Genome-wide small non-coding RNA profiling provides therefore an informative moleculer panel for addressing MS pathogenesis, where further research may lead to the identification of novel biomarkers and possible treatment targets.

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Biomarkers and Bioinformatics Poster Presentation

P0137 - Prognostic value of NK/T ratios for disease activity in multiple sclerosis (ID 1122)

Speakers
Presentation Number
P0137
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

BACKGROUND: Experimental, genetic and therapeutic studies suggest a role for natural killer (NK) cells in multiple sclerosis (MS). A study analysing the re-emergence of Th17 cells after autologous hematopoietic stem cell transplantation proposes that the relative presence of NK cells compared to CD4+ T cells is beneficial in MS, as it is associated with lower levels of Th17. As such, they propose that NK/T cell ratios may be used as a biomarker for therapeutic effect of stem cell transplantation. This ratio has not been investigated in the context of clinical outcome. Additionally, the subsets of NK cells and T cells have not been investigated in regards to this NK/T cell ratio.

Objectives

OBJECTIVES: To explore the relevance of NK cell / CD4+ T cell ratios in a cohort of MS patients treated with interferon beta by analysing NK cell subsets and T cell subsets. Additionally, to find the prognostic value of these ratios for disease activity in MS

Methods

METHODS: Baseline peripheral blood mononuclear cells of 50 relapsing remitting MS patients, participating in our vitamin D supplementation study (the SOLARIUM study), were isolated and analysed with flow cytometry for NK and T cell subsets. MS disease activity was quantified by assessment of the occurrence of new MRI-lesions, relapses, and by measuring mean plasma neurofilament light chain (NfL) levels at baseline and after 48 weeks follow-up.

Results

RESULTS: The proportion of NK cells correlated negatively with CD4+ T cells [R=-0.335 p=0.001] and IL17-A+CD4+ T cells [R=-0.203 p=0.043], which was mainly driven by the CD56bright subset. Participants with MRI activity or relapses at 48 weeks follow-up displayed lower NK/ IL-17A+ CD4+ T cell ratios [p=0.025 and p=0.006, respectively]. The NK / IL-17A+CD4+ T cell ratio correlated negatively with NfL levels [R=-0.320 p=0.050]. Vitamin D supplementation did not affect these ratios.

Conclusions

CONCLUSIONS: Our data suggests a protective role of a relatively expanded NK cell compartment compared to the CD4+ T cell subset fractions in interferon beta-treated RRMS patients. Further research is required to confirm the use of the NK cell/CD4+ T cell ratio as prognostic biomarker for disease activity in MS.

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Clinical Outcome Measures Poster Presentation

P0138 - "Progressive Multifocal Leukoencephalopathy outcomes in Multiple Sclerosis: A Systemic review and Metanalysis "  (ID 1013)

Speakers
Presentation Number
P0138
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple Sclerosis (MS) is an autoimmune, demyelinating disorder of the central nervous system (CNS), treated with disease modifying therapies (DMT). Although DMT are commonly well tolerated, a potentially fatal complication is progressive multifocal leukoencephalopathy (PML). PML is a severe, sometimes fatal disease of the CNS caused by the John Cunnigham virus (JCV) characterized by a wide range of neurologic deficits.

Objectives

This is a systemic review and metanalysis on DMT-induced PML outcomes in MS. Literature is limited and results are not uniform due to incomplete data and various treatment protocols.

Methods

We conducted a systematic review and metanalysis of articles in PubMed, SCOPUS and EMBASE database from Jan 2005 to Dec 2019 for MS patients being treated for PML. Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of >=1.0 point from the time of PML diagnosis to post PML treatment. We categorized the PML cases into two groups - people who did not improve in the EDSS score by 1 point (EDSS-NI) versus people with improved EDSS score by at least 1 point after the PML treatment (EDSS-I).

Results

A total of 569 articles were screened with 62 articles included with total number of patients were 214, out of which 158 were in EDSS-NI group and 36 were in EDSS-I group. A total of 129 women (66.5%) and 65 men (33.5%) participate in the study (20 cases gender were not available). The mean age of EDSS-NI was 44.7 while the mean age of EDSS-I was 40.5 (p-value: 0.021). In terms of DMT at the time of PML diagnosis, the most common DMT was natalizumab (185/214; 86.4%) followed by fingolimod (20/214; 9.3%) and others including dimethyl fumarate, ocrelizumab, alemtuzumab (9/214; 4.2%). Out of 214 cases CSF JCV DNA (copies per ml) were available in only 188 patients. In EDSS-NI group 108 cases had CSF JCV DNA >100 copies/ml (108/151; 71.5%). Whereas, in EDSS-I group 19 patients had CSF JCV DNA >100 copies/ml (19/37; 51.4%). There was significant difference in outcomes of the patients who had <100 copies/ml of CSF JCV DNA with p-value of 0.03, meaning that fewer CSF JCV DNA copies were associated with better outcomes.

Conclusions

The most important variables that determine outcome are age at the PML diagnosis and number of copies/ml of CSF JCV DNA. Old age and high number of copies of CSF JCV DNA are associated with worse outcome, which is either disability or death. None of the DMT are independently associated with outcome.

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Clinical Outcome Measures Poster Presentation

P0139 - Real World Clinical and Imaging Outcomes in Relapsing MS Patients treated with Alemtuzumab in a US Regional MS Center (ID 362)

Speakers
Presentation Number
P0139
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Additional data on alemtuzumab use including clinical, imaging and safety outcomes in a real-world setting can improve patient care.

Objectives

To examine clinical, imaging and safety outcomes in relapsing multiple sclerosis (MS) patients who received at least 2 courses of alemtuzumab.

Methods

This retrospective, single-center study included patients treated with at least 2 courses of alemtuzumab and at least 12 months of follow-up. Demographic, clinical (annualized relapse rate; disability progression); imaging characteristics (brain and spine MRI); previous treatment; co-morbidities and adverse events were analyzed. Patient data for 2 years prior to course 1 (index date) and for up to 4 years after initiation of alemtuzumab was available for all patients.

Results

74 patients were included. Mean age (SD) at baseline was 41.8 (9.9), diagnosis duration 11.5 (7.8) years. 33 patients needed help with ambulation; of which 11 were wheelchair-bound. 45% of patients switched from natalizumab and 23% from fingolimod primarily due to MS worsening. After Alemtuzumab treatment, ARR was significantly decreased from 1.231 (1-year pre-) to 0.392 (1-year post-) index date (P < 0.0001) and to 0.313, 0.240 and 0.291 during each of following 3 years respectively. Comparing one year prior to and 2-years post- treatment: more patients had stable spinal cord MRI (94.3% vs 62.5%) and fewer showed worsening (37.5% vs 5.7%) (p = 0.0017). On brain MRI, more patients were stable (87.7% vs. 52.1%) and fewer patients showed worsening (48.0% vs. 9.6%) (p<0.0001). On disability, 69% of patients remained stable; 3 of 11 wheelchair-bound patients became ambulatory. Safety outcomes will be available for presentation.

Conclusions

This real-world data suggests alemtuzumab is clinically and radiographically safe and effective in a wide spectrum of MS patients including those with severe disability, longer disease duration and multiple comorbidities. Long term follow-up of this cohort will help assess the clinical efficacy of alemtuzumab in a real-world setting.

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Clinical Outcome Measures Poster Presentation

P0140 - Real World Experience of Oral Immune Reconstitution therapy (Cladribine) in the treatment of multiple sclerosis in the United Arab Emirates (ID 100)

Speakers
Presentation Number
P0140
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The landscape of multiple sclerosis (MS) management is rapidly evolving in last few years . With the introduction of new MS therapies the neurologists and the patients are able to make treatment decisions based on many factors including , disease severity, modes of administration as well as efficacy and safety profiles. Oral Cladribine (MAVENCLAD), is a synthetic small molecule which selectively targets B and T lymphocytes resulting in their transient reduction. It has been suggested that Oral Cladribine is classified as immune reconstitution therapy (IRT), because of its impact on key cellular components of the immune system. Oral Cladribine was launched in United Arab Emirates (UAE) in Feb 2018.

Objectives

To study and present the real life experience of oral Cladribine in UAE. To present the clinical profile of patients selected , medications switched from , side effects and clinical outcome of patients started on oral cladribine .

Methods

Clinical data from all patients who have received oral Cladribine for treatment of Multiple sclerosis in UAE was collected and analyzed.

Results

Total of 88 patients, have been initiated on oral Cladribine for relapsing remitting Multiple sclerosis since in the period from June 2018 till January 2020 in UAE. 30 patients have completed the 2 year dose and rest have taken only one course till Jan 2020. Mean age at treatment initiation was 34 years (range 23- 54years). Average duration of Multiple sclerosis was 7.5 years (range2-20years). Average number of disease modifying agents prior to Cladribine were 1.4 (range 0-4 agents). Average EDSS was 2.4 (range 0-7). 37% were naïve, 29% were switched from Fingolimod, 12% from Natalizumab, 10.4 % from Teriflunomide, 10% from dimethyl fumarate and 3% from interferons. Mild transient headache was observed in 6 patients during first few days which did not require medications. There was no grade 4 lymphopenia, grade 3 lymphopenia was observed in 1 patient , 3 patients had grade 2 lymphopenia and 72 had grade 1 lymphopenia at month3 , all except 4 ,become grade 0 by month 7 . By month 12 only 1 had persistent grade 2 lymphopenia. 1 patient had a relapse after 2 months of first year treatment and 1 patient had persistent MRI activity end of first year. I patient had to stop therapy as she became pregnant after 6 months of first year course. No patient had progression in EDSS score

Conclusions

Oral Cladribine (MAVENCLAD) is a safe effective and well tolerated medication for the treatment of Multiple sclerosis especially for those who have had an inadequate response to, or are unable to tolerate, one or more therapies for relapsing remitting Multiple Sclerosis .

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Clinical Outcome Measures Poster Presentation

P0141 - Real-world data on the use of Ocrelizumab, among MS patients: B-cell suppression and clinical outcomes. (ID 934)

Speakers
Presentation Number
P0141
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Ocrelizumab (OCR) is an anti-CD20 B-cell-depleting agent, recently approved for treating relapsing-remitting (RR) MS.

Objectives

In a real-world population of RRMS patients, we described baseline characteristics and clinical outcomes in correlation with the level of OCR-induced B-cell suppression.

Methods

Data were retrospectively collected from 170 RRMS patients, who received 6-monthly 600mg OCR infusions at Imperial College Healthcare NHS Trust from August 2018 to March 2020. Disability progression was defined as ≥1.0 or ≥0.5 Expanded Disability Status Scale (EDSS) increase from baseline EDSS of ≤5.5 or ≥6 respectively. Patients were grouped by level of B-cell depletion after 6 months from the first OCR infusion relative to their baseline B-cell count, into categories of “depleted” (>90%) and “not depleted” (≤90%).

Results

The whole cohort (females 67%, males 33%) was followed up for 5.6 mean months (0-15 months) from OCR initiation. At baseline, the mean age was 45.5 years, the mean disease duration was 13.1 years and the mean EDSS was 4.3. While 15% of patients were treatment naïve, most patients (85%) were escalated to OCR from other disease-modifying therapies: Dimethyl Fumarate (30%), Fingolimod (16%), Alemtuzumab (15%) and Natalizumab (10%). Majority received at least 2 OCR infusions (36%, 51% and 13% with 1, 2 and 3 infusions respectively). The mean B-cell count at baseline was 272/mm3; after OCR initiation, 89% were “depleted” and 11% were “not depleted”. During the follow-up, 7% (n = 12) experienced a relapse and 20% (n = 27) showed disability progression at 4.8 and 6.5 mean months after OCR initiation, respectively. Those who relapsed had in larger proportion new MRI lesions 1 year before OCR initiation (58% vs 20%; p = 0.039) and those experiencing disability progression had longer disease duration (16.8 vs 12.1 mean years; p = 0.039). Although not statistically significant, compared to “depleted” patients, the group without adequate B-cell depletion had a worse clinical outcome, with a larger proportion experiencing a relapse (14% vs 7%; 4.5 vs 4.8 mean months to relapse; p = 0.297).

Conclusions

This study characterizes the use of OCR in a real-world population of RRMS patients. Data suggests that the level of B-cell suppression could be a potential marker of treatment response. This should be validated in further studies with longer follow-up.

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Clinical Outcome Measures Poster Presentation

P0142 - Real-world effectiveness of dimethyl fumarate versus fingolimod using novel outcomes in a heterogeneous patient cohort (ID 708)

Speakers
Presentation Number
P0142
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Prior studies suggested comparable effectiveness of dimethyl fumarate (DMF) and fingolimod (FTY) in multiple sclerosis (MS) using relapses and traditional MRI metrics. We expanded on these assessments with new outcomes, while also accounting for comorbidities.

Objectives

Compare the real-world effectiveness of DMF vs. FTY with standardized neuroperformance, MRI, and biomarker (serum neurofilament light [sNfL]) measures.

Methods

Patients were eligible if on DMF or FTY at enrollment in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network with ≥1 year of follow up and ≥1 MRI in the previous year. Sensitivity analysis included a sub-group of patients who initiated DMF or FTY within 2 years prior to MS PATHS. Propensity score weighting model covariates included demographics, MS disease history parameters, clinical and radiographic characteristics, cardiovascular disease, and diabetes. Generalized estimating equation (GEE) models assessed the differences in means and in 1-year change in neuroperformance and MRI outcomes. Logistic regression models compared sNfL with age-adjusted normative thresholds.

Results

644 DMF and 564 FTY patients had neuroperformance data, 194-354 DMF and 201-385 FTY patients had MRI assessments, 152 DMF and 118 FTY patients had NfL samples. The number of follow-up assessments was comparable between groups (approximately 2 clinical, 2 MRI, and 1 biomarker). Mean time (SD) since treatment initiation was 2.2 (1.5) years for DMF and 2.6 (2.1) years for FTY. No differences were observed in the means or slopes of change for any of the analyzed outcomes. Differences in slopes of change were minimal for processing speed (0.06, p=0.8), manual dexterity (-0.1, p=0.5), walking speed (-0.03, p=0.7), contrast sensitivity (-0.03, p=0.9), patient-determined disease steps (0.02, p=0.5), relapses (0.001, p=0.9), brain parenchymal fraction (0.0003, p=0.3), new T2 lesions (0.3, p=0.1), Gd+ lesions (0.1, p=0.1), and grey matter fraction (0.002, p=0.2). There was no difference in the proportion of patients with elevated sNfL (p=0.12). The sub-group consisted of 123 DMF and 130 FTY patients with mean time (SD) since treatment initiation of 10.2 (6.9) and 10.9 (7.2) months, respectively. Subgroup sensitivity analyses showed similar findings.

Conclusions

DMF and FTY demonstrated similar effectiveness on standardized quantitative neuroperformance, MRI, and biomarker outcomes in a heterogeneous, real-world cohort.

Supported by: Biogen

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Clinical Outcome Measures Poster Presentation

P0143 - Real-World Experience in RRMS and SPMS Patients with Higher Disability and Substantial Lymphopenia Switching from Prior DMTs to Teriflunomide (ID 1818)

Speakers
Presentation Number
P0143
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing forms of multiple sclerosis (MS).

Objectives

To describe the patient characteristics and examine the effectiveness and safety of teriflunomide in patients who switched from other disease modifying therapies (DMTs).

Methods

A retrospective, observational, cohort study was conducted using medical charts on patients ≥ 18 years of age with diagnosis of RRMS or SPMS, who switched to teriflunomide from a prior DMT at a single MS center in the US. Data were extracted at 12 months prior (M-12), at baseline (M0), at 12 months post (M12), and at 24 months post (M24) initiating teriflunomide. Descriptive statistics were conducted for all outcome measures, including relapses, disability, MRI, and cognitive assessment.

Results

Eighty patients (60% RRMS, 40% SPMS) were included in this analysis with a mean age of 44.0 ± 14.55, disease duration of 9.35 ± 6.37 years, baseline EDSS of 3.88 ± 1.76, and 30% with lymphopenia (ALC < 1000/mm3). The most common prior DMTs were dimethyl fumarate (22.5%), glatiramer acetate (18.8%), and natalizumab (16.3%). Mean number of relapses were reduced from 0.26 ±0.44 in the year prior to study entry to 0.18± 0.38 (M12) and 0.05 ± 0.22 (M24). Over the 24 months, mean (95% confidence interval) number of relapses decreased by -0.21 (-0.32, -0.11; P<0.0001), representing an 80.8% reduction. MRI was stable or improved in more patients at M12 (95.1%) and at M24 (97.6%), compared to baseline (92.5%). Mean EDSS score, Montreal Cognitive Assessment (MoCA) test score, and timed 25-foot walk (T25FW) remained stable throughout the study. The percent of patients with lymphopenia was reduced from 30.0% (M0) to 6.3% (M12) and 1.3% (M24). No unexpected or serious AEs were reported.

Conclusions

his real-world study evaluated a more challenging MS cohort with higher EDSS, including a substantial proportion with SPMS, and comorbidities including lymphopenia. Patients who switched to teriflunomide from a prior DMT demonstrated a significant decrease in relapses, and MRI was stable or improved in more patients after initiating teriflunomide compared to baseline. Mean EDSS, T25FW, and MoCA remained stable. In patients previously treated with other DMTs, the proportion of patients with lymphopenia substantially decreased with teriflunomide.

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Clinical Outcome Measures Poster Presentation

P0144 - Real-world outcomes in patients with relapsing forms of multiple sclerosis treated with intramuscular interferon beta-1a or peginterferon beta-1a (ID 794)

Speakers
Presentation Number
P0144
Presentation Topic
Clinical Outcome Measures

Abstract

Background

In clinical trials, the probability of confirmed disability worsening (CDW) is significantly lower with intramuscular (IM) interferon beta-1a (IFNβ1a) and peginterferon beta-1a (PEG) treatment than with placebo in patients with relapsing forms of multiple sclerosis (RMS). Registry data provides information on disability outcomes with long-term treatment.

Objectives

To examine the long-term effects of IM IFNβ1a and PEG on real-world effectiveness in participants with RMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry.

Methods

This analysis included NARCOMS participants diagnosed with RMS who initiated IM IFNβ1a treatment between April 2004 and October 2019 (N=760) or PEG between October 2014 and October 2019 (N=116). Patient-reported outcomes were collected every 6 months. The primary endpoint was 6-month CDW, defined as a ≥1-point increase in Patient Determined Disease Steps (PDDS) score sustained for ≥6 months. Separate analyses were conducted in the IM IFNβ1a and PEG cohorts. A Kaplan-Meier analysis assessed the cumulative probability of CDW; participants were censored if they discontinued treatment or had no additional follow-up. Only participants who completed ≥2 surveys with treatment history and ≥3 surveys with PDDS history were included in the CDW analysis (IM IFNβ1a: N=760; PEG: n=81). Progression to secondary progressive multiple sclerosis (SPMS) was analysed in IM IFNβ1a participants who completed ≥50% of their surveys (n=630) and in PEG participants (n=102).

Results

At the first survey on treatment in IM IFNβ1a and PEG participants, the mean age was 49.7 and 53.0 years, respectively, the mean (standard deviation [SD]) disease duration was 11.1 (8.6) and 15.8 (7.9) years, respectively, and 8.4% and 91.2% had prior disease modifying therapy (DMT) use, respectively. The median PDDS score at the first survey was 2.0 for both populations, indicating moderate disability. The cumulative probability of remaining free of CDW was 77.6% and 43.6% at 2 and 11 years of IM IFNβ1a treatment, respectively, and 84.4% at 2 years of PEG treatment. The cumulative probability of participant-reported progression to SPMS was 1.2% and 12.0% at 2.5 and 11 years in IM IFNβ1a participants, respectively, and 3.3% at 2.5 years in PEG participants.

Conclusions

These results support clinical trial data showing the effectiveness of IM IFNβ1a and PEG in preventing CDW and demonstrate their long-term effectiveness in RMS patients.

This study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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Clinical Outcome Measures Poster Presentation

P0145 - Relation of EDSS to patient-reported outcome measurements in MS: Real-world data from a Swedish nationwide study of fingolimod (IMSE 2) (ID 674)

Abstract

Background

Fingolimod (FGL) is an oral disease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis, introduced in Sweden 2011. Already from launch, FGL was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) in order to enable long-term surveillance of effectiveness and safety aspects in a large population-based cohort.

Objectives

To assess the relation between Expanded Disability Status Scale (EDSS) and patient-reported outcome measurements (PROMS) in patients treated with FGL.

Methods

Swedish MS patients are registered into the nationwide Swedish MS Registry. Demographic data, EDSS and the Multiple Sclerosis Impact Scale (MSIS-29), Symbol Digit Modalities Test (SDMT), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) were collected for FGL patients who agreed to participate in the IMSE 2 study. Spearman rank correlation were used to determine associations between EDSS and PROMS.

Results

From September 2011 until June 2020, 1670 MS patients (68% female) were included in IMSE 2. Mean age at treatment start was 39 years and mean treatment duration in the entire cohort was 44 months (M). Out of 1670 patients, 560 (63% female) had been treated with FGL for at least 60 M. Mean age was 40 years and mean treatment duration 81 M. Significant (p<0.05) correlations was found between EDSS and all PROMs. The strongest correlation was found between the physical component of MSIS-29 for both baseline (r=0.60, n=778) and 60 M (r=0.64, n=109). Also, for both EQ-5D and VAS, Spearman coefficient indicates a moderate correlation for baseline (EQ-5D; r=-0.48, n=744 and VAS; -0.43, n=706) and 60 M (EQ-5D; r=-0.47, n=102 and VAS; -0.48, n=102) respectively. The correlation between EDSS and SDMT and the psychological component of MSIS-29, both indicated a weak correlation for baseline (SDMT; r=-0.28, n=771 and MSIS-29 psychological; r=0.28, n=778). For 60 M the correlations were stronger and indicated a moderate correlation (SDMT; r= -0.42, n=114 and MSIS-29 psychological; r=0.33, n=109).

Conclusions

The observed correlations between EDSS and PROMs in patients treated with FGL indicate a weak correlation with SDMT and the psychological component of MSIS-29. These results highlight that different scales capture different dimensions of the physical and psychological impact of MS from the patient’s perspective and have important functions which should continue to be followed.

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Biomarkers and Bioinformatics Poster Presentation

P0146 - Reliability, concurrent and ecological validity of smartphone-based cognition and walking tests (ID 780)

Speakers
Presentation Number
P0146
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The early detection and monitoring of cognitive and ambulatory dysfunction in multiple sclerosis (MS) may be enhanced with smartphone-adapted cognition and walking tests. Contrary to clinical measures, smartphone-based assessment allows more frequent measurements in the everyday environment, which potentially better reflects daily functioning.

Objectives

To determine the reliability, concurrent and ecological validity of self-administered smartphone-adapted Symbol Digit Modalities Test (SDMT) and Two-Minute Walking Test (2MWT).

Methods

Patients with MS were recruited. At baseline the SDMT and Timed 25-foot Walk Test (T25FW) were assessed clinically. During a 28-day follow-up, patients used the MS sherpa® app to perform the smartphone SDMT and 2MWT three times a week. The smartphone SDMT was assessed through tapping numbers corresponding to symbols on the smartphone during 90 seconds. The 2MWT measured walking distance utilizing the smartphone built-in sensors during two minutes of normal walking. Reliability of the smartphone tests were assessed by calculating intra-class correlation coefficients (ICC) between scores from week 2 and 3. Concurrent validity was addressed by calculation of correlation coefficients between the smartphone tests and their clinical counterparts. MS sherpa® also included one-item self-report scores for perceived fatigue and impact of MS on daily functioning. To assess ecological validity, the temporal association between the MS sherpa® tests and self-report scores from the everyday environment were analyzed using linear mixed models with the repeated measures as random effects.

Results

102 patients with MS were included. During the 28-day follow-up 102 patients completed a mean (± SD) of 12.1 (± 6.8) SDMTs and 74 patients completed a mean (± SD) of 8.8 (± 6.1) 2MWTs. Smartphone SDMT correlated significantly with the clinical SDMT (r = 0.607, p < 0.001) and demonstrated excellent reliability (ICC = 0.923). 2MWT was significantly correlated with T25FW (ρ = -0.352, p = 0.001) and demonstrated good reliability (ICC = 0.845). Over the 28-day period, higher 2MWT scores were related with lower perceived impact of MS on daily functioning (b = -0.005, 95% CI [-0.010, -0.001]) and higher SDMT scores were related with lower perceived fatigue (b = -0.014, 95% CI [-0.026, -0.003]).

Conclusions

Smartphone-adapted cognition and walking tests can be assessed frequently from the participants’ own environment and demonstrated validity and reliability in assessment of information processing speed and ambulatory function in MS. Support for ecological validity was found for perceived fatigue and impact on functioning in the everyday environment.

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Biomarkers and Bioinformatics Poster Presentation

P0148 - Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis (ID 304)

Speakers
Presentation Number
P0148
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Retinal thinning is a biomarker of neuroaxonal degeneration in multiple sclerosis (MS) and is associated with disability progression. Recently, the term PIRA, or progression independent of relapse, has emerged purporting to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes.

Objectives

The objective of this study was to determine the association of retinal thinning with PIRA in comparison to traditional physical disability worsening and relapse.

Methods

In a 4-year prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular-ganglion-cell-and-inner-plexiform-layer(mGCIPL). Physical disability was assessed by expanded disability status scale (EDSS), cognitive disability by the symbol digit modalities test (SDMT). PIRA was defined as either an EDSS or SDMT worsening during the observation period confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening. Multivariate linear regression models adjusted for sex, age, disease duration and disease-modifying treatment regarding retinal thinning were calculated.

Results

Each PIRA event was associated with a mean additional loss of GCIPL (1.8µm) and pRNFL (1.9µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3µm) and pRNFL (1.4µm).

Conclusions

PIRA is associated with retinal thinning, likely reflecting non-inflammatory neurodegenerative processes. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.

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Biomarkers and Bioinformatics Poster Presentation

P0149 - Retinal layer thinning rate as a biomarker predicting treatment response in relapsing multiple sclerosis (ID 295)

Speakers
Presentation Number
P0149
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell plus inner plexiform layer (mGCIPL) thinning are markers of neuroaxonal degeneration in relapsing multiple sclerosis (RMS). pRNFL and mGCIPL thinning is more pronounced in patients with physical or cognitive disability progression, while it is reduced by disease-modifying treatment (DMT).

Objectives

The objective of this study was to investigate the potential of retinal layer thinning for prediction of treatment response in RMS.

Methods

In this 4-year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 (M12) and 24 months (M24) of follow-up by spectral-domain optical coherence tomography (OCT). Inclusion criteria included adherence to DMT for at least 2 years. Patients suffering optic neuritis between baseline and M24 were excluded. Treatment response was defined as absence of 6 month confirmed EDSS progression and Symbol Digit Modalities Test (SDMT) worsening during the observation period. Best possible cut-off values of retinal thinning for predicting treatment response were determined by receiver-operating characteristics (ROC) analyses. Odds ratios (OR) for treatment response were calculated by multivariate logistic regression models correcting for age, sex, disease duration and EDSS/SDMT at baseline.

Results

Thinning of mGCIPL <0.5mm at M24 displayed superior prediction of treatment response (odds ratio [OR] 4.5; 95% confidence interval [CI]: 1.8 – 7.6; p<0.001; specificity 91%, sensitivity 81%) followed by mGCIPL <0.3mm at M12 (OR 3.9; 95% CI: 1.4 – 6.9; p<0.001; specificity 85%, sensitivity 78%) and pRNFL <2mm at M24 (OR 3.7; 95% CI: 1.1 – 6.5; p=0.023; specificity 84%, sensitivity 69%), while pRNFL at M12 was not significantly predictive.

Conclusions

mGCIPL – and to a lesser degree pRNFL – thinning predict physical and cognitive disability progression upon DMT initiation. Pending validation, retinal layer thinning may be a useful and easily accessible biomarker of treatment response in RMS.

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Clinical Outcome Measures Poster Presentation

P0150 - REWORD-MS: REal WOrld study to assess the Response to Dimethyl fumarate in patients with Multiple Sclerosis (ID 1813)

Speakers
Presentation Number
P0150
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The response of relapsing-remitting Multiple Sclerosis patients (RRMSp) to disease-modifying drugs (DMDs) is heterogeneous. Tools able to predict response at the beginning of therapy are not available, but early treatment optimization is crucial to prevent disability accumulation. Scoring systems based on combination of relapse rate and new or enlarged T2 lesions (NT2) during the first year of treatment, as the MAGNIMS (Magnetic Resonance Imaging in MS) score, have been validated in RRMSp treated with interferon, to predict the individual response over time. Dimethyl fumarate (DMF) is nowadays the leading treatment prescribed among first line DMDs.

Objectives

The aim of the study is to evaluate the validity of the MAGNIMS score in predicting therapeutic failure in RRMSp treated with DMF.

Methods

Data about clinical relapses and NT2 were collected from 195 RRMSp treated with DMF for at least 12 months and with ≥ 24 months of follow-up. The MAGNIMS score was applied at month 12. Therapeutic failure was defined as EDSS (Expanded Disability Status Scale) worsening or change of therapy for inefficacy and loss of NEDA-3 status (No Evidence of Disease Activity: no relapse, no EDSS worsening, no NT2). The association between score and risk of treatment failure was evaluated by Cox proportional hazard model.

Results

At month 12, 175/195 (89.7%) patients had score=0 (no clinical relapse and <3 NT2) and 20/195 (10.3%) had score≥1 (≥ 1 clinical relapse and/or ≥3 NT2). Patients with score≥1 had a four times greater risk of EDSS worsening or change of therapy compared with patients with score=0 (HR 3.89, 95% CI 1.80-8.43; p=0.001). Similarly, the risk of losing NEDA-3 status was two times greater in patients scored ≥1 (HR 2.19, 95% CI 1.07-4.48; p=0.031). Considering RRMSp treated with DMF as first therapy (naïve, 91), patients with score≥1 had a six times greater risk of EDSS worsening or change of therapy (HR 5.86, 95% CI 2.03-16.92; p=0.001) and a two and a half times greater risk of losing NEDA-3 (HR 2.48, 95% CI 1.01 – 6.11; p=0.048).

Conclusions

Our data show that the MAGNIMS score is a reliable tool to predict response to DMF in a real world setting, even in naïve patients. Early identification of non-responders is crucial to identify candidates for a therapeutic shift to prevent disease progression. Due to the complexity of MS, future studies are needed to assess whether the addiction of other biomarkers (i.e. neurofilaments and brain atrophy) will improve the predictive power of a clinical-radiological score.

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Biomarkers and Bioinformatics Poster Presentation

P0151 - Serum contactin-1 levels as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis. (ID 1674)

Speakers
Presentation Number
P0151
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.

Objectives

To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).

Methods

Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.

Results

Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).

Conclusions

Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.

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Biomarkers and Bioinformatics Poster Presentation

P0152 - Serum Neurofilament levels of multiple sclerosis patients before and after treatment with injectable therapies (ID 1095)

Speakers
Presentation Number
P0152
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

A well-established neurochemical biomarker for axonal damage is the light chain of the axonal structural protein neurofilament (NfL), which can now also be reliably quantified in serum using highly sensitive methods. Serum NfL has been shown to correlate with neuroaxonal damage in multiple sclerosis (MS) and various other neurological diseases. While serum NfL is now regularly reported in clinical approval studies, there is a lack of longitudinal data from patients treated with established basic immunotherapies outside of study conditions.

Objectives

In this open label observational study, the dynamics of serum NfL and its potential prognostic significance will be evaluated to assess whether the longitudinal measurement of serum NfL may serve as a prognostic parameter for disease activity and therapy response.

Methods

In total 34 patients with early relapsing-remitting MS (RRMS) were included. The follow-up period was 24 months and patients received intermediate visits (including serum collection) at baseline and after 3, 6, 9, 12, 18 and 24 months. Therapy with glatiramer acetate was initiated in 20 patients and with interferon-beta in 12 patients. The course of the patients was characterized by disability progression (EDSS), disease activity and MRI parameters.

Results

Overall, serum NfL levels were higher at times with a current relapse event than at times without relapse (12.8 pg/ml vs. 9.7 pg/ml, p= 0.011). At follow-up, patients without relapse showed significantly reduced serum NfL at 9 months compared to baseline (p< 0.05), independent of the type of basic immunotherapy. This was not the case in patients with relapse activity within 12 or 24 months. In addition, serum NfL was also reduced at 12 months in patients with stable EDSS compared to baseline (p= 0.013). This effect was not seen in the group with stable EDSS at 24 months or in patients with EDSS progression.

Conclusions

In this explorative observational study, our data suggest that in addition to MRI the longitudinal measurement of serum NfL may be useful to monitor disease activity and therapy response. Stable or reduced serum NfL over time may be associated with a favourable disease course of MS.

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Biomarkers and Bioinformatics Poster Presentation

P0153 - Serum neurofilament light chain and retinal layer thickness measurements are complementary predictors of disease activity in early multiple sclerosis. (ID 1808)

Speakers
Presentation Number
P0153
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements have individually been shown to be promising biomarkers for future disease activity in multiple sclerosis (MS).

Objectives

To investigate the complementary value of sNfL and retinal OCT measurements for predicting disease activity in patients with early MS at a stable disease state.

Methods

We retrospectively screened patients with early MS or clinically isolated syndrome (CIS) from a prospective cohort study (Berlin CIS cohort). The baseline sNfL (single-molecule array (SimoaTM) assay) were determined between 12 and 24 months after initial disease onset. Inclusion criteria were the availability of baseline sNfL, OCT measurements, clinical and MRI follow-up data (new relapses, expanded disability status scale (EDSS), new T2 lesions, composing the no evidence of disease activity (NEDA-3) criteria) over a period of at least 365 days. Exclusion criteria were concomitant eye diseases interfering with OCT and a relapse within 120 days before baseline visit. For Cox regression hazard models, patients were grouped with regards to their sNfL level (abnormal/normal: ≥/< 95th percentile of age-matched reference value) and their peripapillary retinal nerve fiber layer (pRNFL: >/≤ 100 µm) and ganglion cell and inner plexiform layer (GCIP: >/≤ 1.99 mm3) in non-optic neuritis eyes. Analysis was censored after 760 days.

Results

We included 78 patients (50 females, age: 36.4 ± 7.6 years) with a median follow-up of 728 days (range: 709 – 751 days). Patients with abnormal sNfL at baseline showed a significantly higher risk for developing a new relapse (Hazard Ratio (HR): 3.33, 95% confidence interval (CI): 1.43 – 7.71, p = 0.003), a new lesion (HR: 2.64, CI: 1.35 – 5.18, p = 0.003) and violating NEDA-3 (HR: 3.22, CI: 1.73 – 6.01. p < 0.001). Patients with both thinner pRNFL and abnormal sNfL value had a greater risk for developing a new relapse (HR: 8.12, CI: 2.17 – 30.46, p = 0.002) and violating NEDA-3 criteria (HR: 4.28, CI: 1.81 – 10.14, p < 0.001) than patients with only one of the risk factors. Meanwhile, patients with thinner GCIP and abnormal sNfL not only yielded greater risk for new relapse (HR: 6.51, CI 2.06 – 20.63, p = 0.001) and NEDA-3 violation (HR: 4.48, CI: 2.11 – 9.50, p < 0.001), but also for new lesion (HR: 3.11, CI: 1.42 – 6.80, p = 0.004).

Conclusions

In patients with early MS, presence of both abnormal sNfL and OCT measurements may be a stronger risk factor for future disease activity than presence of each risk factor alone.

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Biomarkers and Bioinformatics Poster Presentation

P0154 - Serum Neurofilament light chain captures and predicts disability progression independent of relapses (PIRA) in multiple sclerosis (ID 809)

Abstract

Background

In relapsing MS, blood NfL has emerged as a promising biomarker of disease activity and worsening. The ability of serum NfL (sNfL) to detect relapse-independent disability progression is less well established.

Objectives

We investigated whether patients followed in the Swiss Multiple Sclerosis Cohort (SMSC) without any relapses during follow-up, had higher sNfL levels when experiencing confirmed disability progression independent of relapses (PIRA) as compared to stable patients. Secondly, we explored whether baseline (BL) sNfL could predict PIRA.

Methods

BL and 6- or 12-monthly follow-up sNfL were measured by Simoa NF-light® assay in 4608 samples from 806 relapse-free MS patients and 8865 serum samples from 4133 healthy controls (median age 45 yrs). Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalised additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. PIRA was defined as an EDSS increase of ≥1.5 steps if baseline EDSS 0, ≥1.0 if 1.0-5.5, or ≥0.5 if >5.5, confirmed after ≥6 months. We used mixed effects models to investigate the association between PIRA, clinical parameters, disease modifying treatment, and log(sNfL) as dependent variable at each sampling. The predictive value of BL sNfLz was investigated by uni- and multivariable Cox proportional hazards models.

Results

806 (4608 samples) of 1399 patients in the SMSC did not experience relapses during a median follow-up of 4.7 years (57.6%; BL: 715 RRMS, 43 SPMS, 48 PPMS; median age 42 yrs; samples/patient: 5; EDSS 2.0). PIRA occurred in 153/806 (19.0%). In a multivariable model, sNfL was positively associated with age (1.7%/year [95%CI 1.5;2.0], p<0.001) and EDSS at BL (7.6%/step, [5.8;9.6], p<0.001), whereas it was decreased when sampled during monoclonal antibody therapy (-10.8%, [-14.7;-6.6], p<0.001) or oral MS treatments (-10.4%, [-14.1;-6.5%], p<0.001) as compared to untreated timepoints. Importantly, patients experiencing PIRA had 11.6% higher sNfL levels, compared with stable patients (4.5;19.2, p=0.001). The hazard of future PIRA increased by 23.5% (8.3;40.8, p=0.002) per 1 standard deviation higher BL sNfLz. This finding was confirmed after adjusting for age, EDSS score and treatment at BL (27.8%, [11.5;46.5], p<0.001; sNfLz > 2: 2.5-fold risk [95%CI 1.7-3.9], p<0.001 for PIRA event vs. sNfLz < 2).

Conclusions

Our data support the value of sNfL to capture and predict neuro-axonal injury leading to disability progression independent from relapses.

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Biomarkers and Bioinformatics Poster Presentation

P0155 - Serum neurofilament light chain levels correlate with attack-related disability in neuromyelitis optica spectum disorder (ID 1291)

Abstract

Background

Pathogenic autoantibodies against aquaporin 4 (AQP4) in neuromyelitis optica spectrum disorder (NMOSD) cause central nervous system injury, with subsequent release of astroglial and neuronal proteins such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and Tau into the circulation. N-MOmentum is a randomized, placebo-controlled, double-masked trial of inebilizumab, a B-cell-depleting monoclonal antibody (NCT02200770).

Objectives

Investigate relationships of NfL, UCH-L1, Tau and serum (s)GFAP to disease activity and Expanded Disability Status Scale (EDSS) disability in N-MOmentum trial participants with either AQP4-immunoglobulin G (IgG) seropositive or seronegative NMOSD.

Methods

Serum biomarkers NfL, UCH-L1, Tau and sGFAP were measured using the single molecular array (SIMOA; Quanterix) in 1260 serial and attack-related samples from N-MOmentum participants (n=215) and healthy controls (HC; n=25).

Results

At baseline, biomarkers were elevated in subsets of patients with NMOSD (NfL, 16%; UCH-L1, 6%; Tau, 12%; sGFAP, 29%); NfL and UCH-L1 levels correlated with sGFAP (r=0.53 [p<0.001] and 0.18 [p=0.007]). Baseline elevations were significantly associated with increased attack risk (NfL, hazard ratio [HR] 2.5, p=0.01; UCH-L1, HR 2.8, p=0.039; Tau, HR 2.6, p=0.01; sGFAP, HR 3.03, p<0.001). After controlling for baseline sGFAP in Cox regressions, the other markers were not independently associated with attack risk (all HR <2; p>0.05). In the total cohort, a greater proportion of patients had an attack with placebo than inebilizumab (39% vs 12%). All biomarker levels increased after attacks and median-fold increases from baseline (95% confidence interval) trended higher with placebo than inebilizumab, reaching significance with sGFAP (NfL, 1.49 [0.93–3.37] vs 1.30 [0.84–2.14], p=0.4; UCH-L1, 6.70 [1.59–52.4] vs 1.85 [0.89–23], p=0.12; Tau, 2.19 [0.96–9.46] vs 1.09 [0.40–3.7], p=0.23; sGFAP, 20.2 [4.4–98] vs 1.11 [0.75–24.6], p=0.037). Following attacks, NfL correlated with EDSS score at attack assessments (R=0.55; p<0.001); other biomarkers did not correlate with EDSS score after controlling for NfL levels.

Conclusions

In NMOSD, serum NfL, UCH-L1 and Tau levels were higher than in HC; increased baseline sGFAP levels were associated with greater attack risk. Although sGFAP levels showed the greatest increase following attacks, NfL correlated with attack-related disability.

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Biomarkers and Bioinformatics Poster Presentation

P0156 - Serum neurofilament light levels correlate with reduced grey matter volume in advanced multiple sclerosis. (ID 770)

Speakers
Presentation Number
P0156
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Grey matter (GM) pathology is associated with physical and cognitive impairment in patients with multiple sclerosis (pwMS). Increased levels of serum Neurofilament light (sNfL), indicating neuro-axonal damage, have been described in MS and were related to the development of global brain atrophy. However, the relation of sNFL to MRI-based measures of distinct brain volumes, in particular the grey matter, is still poorly investigated.

Objectives

To investigate the association of sNfL with compartmental brain volumes in pwMS in a cross-sectional and longitudinal manner.

Methods

We included 109 pwMS (mean age = 38.1 years, standard deviation (SD) ±11.7 years, 63.3% female) and 17 sex- and age-matched non-inflammatory neurological controls (NC) (mean age = 39.2 years, SD± 9.8 years). The MS cohort consisted of 16 clinically isolated syndrome (CIS), 72 relapsing-remitting MS (RRMS) and 21 progressive MS (PMS) patients. sNfL levels were measured by an ultrasensitive Single Molecule Array (Simoa®). In MS, we assessed whole and compartmental normalized and lesion-filled brain volumes and T2-lesion loads based on 3T MRI data, using T2-FLAIR and T1-weighted 1mm isotropic structural scans, processed with SienaX (part of FSL, fsl.fmrib.ox.ac.uk).

Results

In the entire cohort sNfL levels correlated with age (r = 0.329, p < 0.001). sNfL was significantly elevated in RRMS (p = 0.019) and PMS (p < 0.010) compared to NC, as well as in PMS compared to CIS (p = 0.035). Similarly, we found decreased brain volumes in PMS vs. CIS and RRMS. This was evident for whole brain, white matter (WM), total GM and cortical GM (p ≤ 0.001). Likewise, WM lesion volume was elevated in PMS vs. CIS (p = 0.001) and RRMS (p = 0.022). In deep GM areas, including basal ganglia and thalamus, volumes were decreased in PMS vs. CIS (p = 0.001 and 0.012 respectively) and PMS vs. RRMS (p = 0.038 and 0.015 respectively).
Only in patients with PMS we found sNfL to be negatively correlated with volumes of the whole brain after correcting for age (r = –0.571, p = 0.008). This was mainly driven by the correlation with total GM (r = –0.615, p = 0.004) and cortical GM (r = –0.664, p = 0.001). Regarding deep grey matter, only in PMS we observed a negative correlation of sNfL with basal ganglia volume (r = –0.571, p = 0.011). There was no correlation of sNfL with thalamus volume in any subgroup.

Conclusions

Although sNfL is already increased in earlier phases of MS, our data indicates that its relation to brain tissue damage, in particular GM pathology, might only become apparent in more advanced progressive forms of the disease. Further analysis of longitudinal MRI and clinical data is currently ongoing to confirm and extend our results.

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Biomarkers and Bioinformatics Poster Presentation

P0157 - Serum neurofilament light-chain levels and long-term treatment outcomes in relapsing-remitting multiple sclerosis (RRMS) patients in the CombiRx trial (ID 798)

Speakers
Presentation Number
P0157
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light-chain (sNfL) is associated with disease activity and tissue damage, predicts long-term outcomes, and is reduced by disease-modifying therapies in RRMS patients.

Objectives

In a post hoc analysis, determine sNfL differences from baseline (BL) to 48 months and associations with long-term clinical outcomes in patients treated with intramuscular (IM) interferon (IFN) beta-1a, glatiramer acetate (GA), or both therapies (IFN+GA).

Methods

CombiRx was a placebo (PLB)-controlled double-blind phase 3 trial in treatment-naive RRMS patients randomized to IM IFN beta-1a 30 µg weekly+PLB, GA 20 mg/mL daily+PLB, or IFN+GA treatment for up to 7 years. Samples for biomarker analysis were collected at BL, 6, 12, 36, and 48 months from volunteers for a substudy offered in most sites. Relapses and Expanded Disability Status Scale (EDSS) scores were collected every 3 months. A Simoa Human Neurology 4-Plex A assay analysed sNfL levels. A linear mixed model compared sNfL values over time adjusted for BL EDSS, age, sex and body mass index (BMI). A Cox regression model with the same covariates analysed BL sNfL as a predictor of relapse.

Results

Samples were collected from 159 IFN, 172 GA, and 344 IFN+GA patients. BL characteristics were generally well balanced, including mean age, sex, mean BMI, mean time since symptom and diagnosis onset, and mean EDSS scores. Significant reductions relative to BL in sNfL levels were seen at 6, 12 and 36 months in the IFN, GA, and IFN+GA treatment groups. BL sNfL ≥16 pg/mL significantly predicted relapse within 90 days (hazard ratio [HR]: 2.25, P=0.0041), 180 days (HR: 1.67, P=0.0130) and 1 year from BL (HR: 1.40, P=0.0435), but not over the entire study duration (HR: 1.08, P=0.5596). In patients with BL sNfL ≥16 pg/mL and ≥1 BL gadolinium-enhancing (Gd+) lesion, a significantly higher percentage (16.8%) relapsed within 90 days than in patients with BL sNfL ≥16 pg/mL and no BL Gd+ lesions (9.2%), or BL sNfL <16 pg/mL with (7.3%) or without BL Gd+ lesions (6.7%) (P=0.0051).

Conclusions

Treatment with IFN, GA, and IFN+GA significantly reduced sNfL levels within 6 months and was maintained over 36 months. Results suggest that BL sNfL levels predict relapses within 1 year, and that the combination of lesion activity and sNfL is a stronger predictor of relapse than either one alone.

This analysis was funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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Biomarkers and Bioinformatics Poster Presentation

P0158 - Serum neurofilaments in Secondary Progressive Multiple Sclerosis: analysis from the MS-STAT trial (ID 1605)

Speakers
Presentation Number
P0158
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There is a clear need for biomarker development in progressive multiple sclerosis (PMS). Serum neurofilament light (sNFL), and to a lesser extent neurofilament heavy (sNFH), are leading candidates. Whilst sNFL in particular has been examined in relapsing remitting MS, data from PMS are limited and in contrast to immunosuppressive treatments, candidate neuroprotective treatments show a variable effect on these biomarkers [1]. We examine data from the original MS-STAT trial [2].

Objectives

To analyses serum neurofilament data from the MS-STAT trial, assessing cross-sectional and longitudinal sNFL and sNFH and their relationship with MRI and clinical variables.

Methods

Serum samples were acquired at months 0, 6, 12 and 24. sNFL and sNFH were quantified using Single Molecule Array (Simoa). Linear mixed models were used to assess for treatment effects between simvastatin and placebo, and regression, linear mixed and bivariate models to assess association with MRI and clinical variables.

Results

Median baseline sNFL was 14.6pg/ml (IQR 10.8-20.2) and sNFH 64.2pg/ml (23.9-119), rising to 16.0pg/ml (11.9-22.2) and 70.9pg/ml (26.5-123) by 24 months. Higher baseline sNFL was associated with greater subsequent brain atrophy. Similarly, higher sNFL was associated with higher T2 lesion volume (T2LV), and increases in sNFL were associated with increases in T2LV.

High baseline sNFL was associated with worse baseline EDSS (95% CI of coefficient: 0.120 to 0.633), 9-hole peg test (-0.009 to -0.002) and 25 foot walk (-0.515 to -0.019), and a greater deterioration in 25 foot walk from baseline to 2 years (-0.448 to -0.152). There was no evidence of an association between sNFH and these variables.

There was no evidence of a simvastatin treatment effect on either sNFL (95% CI -0.07 to 0.10, p=0.716) or sNFH (95% CI -0.17 to 0.22, p=0.827).

Conclusions

The mode of action of simvastatin in reducing brain atrophy remains to be elucidated, with actions upon vascular comorbidity and intermediate metabolites from cholesterol synthesis pathways as possible candidates [3]. Simvastatin is not immunosuppressive, and in common with other purportedly neuroprotective treatments, there is no evidence from this study that sNFL or sNFH can act as biomarkers of simvastatin treatment. The relationship between sNFL and T2LV supports the hypothesis that in MS, sNFL may act predominantly as a marker of neuroinflammation, even in this typical SPMS cohort.

1. Williams T et al (2020) Neurofilaments in progressive multiple sclerosis: a systematic review. J Neurol.

2. Chataway J et al (2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet

3. Palladino R et al (2020) Evaluating the Risk of Macrovascular Events and Mortality among People with Multiple Sclerosis in England. JAMA Neurol

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Biomarkers and Bioinformatics Poster Presentation

P0159 - Serum NfL predicts disability progression in MS in a six year longitudinal cohort study (ID 1196)

Speakers
Presentation Number
P0159
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Immunomodulatory therapies are effective in controlling disability progression in patients with multiple sclerosis (MS). Nonetheless, markers are needed to predict disease progression and transition into secondary progressive MS (SPMS) in order to guide individual treatment regimens.

Objectives

Evaluating the temporal evolution of neurofilament light chain (NfL) in patients with relapsing-remitting MS (RRMS) and its ability for forecasting EDSS progression and SPMS conversion within the prospective Neurofilament and long-term outcome in MS (NaloMS) cohort.

Methods

196 patients (median age 35.0 years (interquartile range (IQR) 27.2-43.1), 69.9% (n=137) female) with relapsing-remitting MS (RRMS) or clinically isolated syndrome were followed for median six years (IQR 4-8). Serum was collected at baseline and follow-up (FU); serum NfL (sNfL) levels were measured by single molecule array.

Results

During the study period, 34 of 196 patients (17%) suffered from relapse-free EDSS-progression (RFP) one year prior to FU and 27 of 196 patients (14%) converted to SPMS at FU. sNfL at Baseline was increased in patients with RFP, which remained significant after multivariate correction. Baseline sNfL levels ≥ 7.3 pg/ml were associated with increased probability of RFP in Kaplan-Meier analysis. In addition, sNfL levels at FU were increased in SPMS-converters and temporal NfL increases were more frequent in patients transitioning to SPMS than in non-converters.

Conclusions

sNfL levels at baseline predict disability progression at median six year follow-up in a prospective longitudinal cohort study. Moreover, sNfL levels are more frequently increased at follow-up compared to baseline in patients transitioning to SPMS. Therefore, temporal evolution of sNfL might thus be an ancillary tool facilitating timely SPMS diagnosis.

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Biomarkers and Bioinformatics Poster Presentation

P0160 - Serum NfL z-scores derived from a large healthy control group reflect different levels of treatment effect in a real-world setting (ID 916)

Abstract

Background

Serum neurofilament light chain (sNfL) levels reflect neuroaxonal damage and relate to disease activity in MS. sNfL may qualify as well as a biomarker of suboptimal treatment response to disease modifying therapies (DMT). Establishment of age-dependent reference ranges in healthy controls is a prerequisite for developing this biomarker for clinical use.

Objectives

To compare on-treatment sNfL levels with values from a healthy control cohort and to investigate the effect of DMTs on sNfL levels in patients from the Swiss MS Cohort Study.

Methods

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modeled in healthy controls using a generalized additive model for location scale and shape to reflect the deviation of a patient sNfL value from the mean value of same age healthy controls. Linear mixed models were used to investigate the associations between clinical characteristics, DMT and longitudinal sNfLz. Interaction terms and splines were used to model sNfLz and for comparison log(NfL), and their dynamics under treatment.

Results

sNfL was measured in 1368 patients with 7550 longitudinal samples (baseline: median age: 41.9 yrs; 5.4% CIS, 83.2% RRMS, 5.6% SPMS, 5.8% PPMS; median EDSS: 2.0; median follow-up: 4.6 yrs) and 4133 healthy controls with 8865 samples (median age: 44.8 yrs). In the multivariable model, sNfLz increased with EDSS (0.131/step, [95% CI 0.101;0.161]), recent (<120 days) relapse (0.739 [0.643;0.835]) decreased with age (-0.014/year [-0.02;-0.009]), and time on DMT (-0.040/year [-0.054;-0.027]); sNfLz were lower when sampled while on more effective DMT (oral versus platform injectables: -0.229 [-0.344;-0.144]; monoclonal antibodies (mAB) versus platform injectables: -0.349 [-0.475;-0.224]), (p<0.001 for all associations). sNfLz were inversely associated with the hierarchy in efficacy of mAB over orals and orals over platform therapies with regard to slope and extent of decrease (interaction between time under DMT and DMT class: p<0.001). sNfLz, but not log(NfL) showed normalization of sNfL levels by mAB to healthy control levels.

Conclusions

The dynamic change of sNfLz on DMT reflects closely their relative clinical efficacy and is more meaningful than log(sNfL) by excluding age as a confounding factor. Use of sNfLz based on a large normative database as an age-independent sNfL measure improves the accuracy of the sNfL signal and hence their clinical utility.

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Clinical Outcome Measures Poster Presentation

P0161 - Short-term evaluation of alemtuzumab to ocrelizumab switch in MS patients with disease activity after alemtuzumab: an Italian multicentric study. (ID 1603)

Speakers
Presentation Number
P0161
Presentation Topic
Clinical Outcome Measures

Abstract

Background

the management of MS patients (pts) who show disease activity after 2 alemtuzumab (ALM) courses represents an unsolved issue. No real-life data about the switch to ocrelizumab (OCR) have been reported yet.

Objectives

To describe efficacy and safety outcome of OCR patients switching from ALM due to persistence of disease activity after ALM

Methods

MS pts who switched from ALM to OCR from March 2019 to March 2020 were retro- and prospectively recruited from different Italian MS Centers. Clinical, immunological and neuroradiological data about ALM treatment period, ALM-OCR interval and OCR treatment period were collected.

Results

we recruited 23 MS pts [mean age: 35.7(SD±6.8); female, 40.1%; Relapsing Remitting, (RR): 75.8%, active Secondary progressive, (aSP): 24.2%; mean time interval (days) from II ALM course: 87.4(SD±108); cumulative number of relapses: 21; mean number of new T2 and Gd+ lesions: 4.1(SD±4.5) and 1.6(SD±3.1); median EDSS:3(range 1-7)]. The mean follow-up (FU) from OCR start was 7.9±7.4 months. Efficacy: 4 (17.4%) pts had a relapse after OCR start (1 pt relapsed between the first and the second OCR infusion and 3 pts after 3, 11 and 15 months from OCR start respectively), with complete recovery after steroid treatment. 4 (17.4%) pts showed radiological activity with no clinical correlates at 3 months (n=2), 4 months (n=1) and 9 months (n=1). EDSS was stable except for 1 aSP patient who showed 1-year disability progression. Safety: I) Infusion Associated Reactions (IARs) occurrence was significantly lower with respect to alemtuzumab courses (p<0.05); (ii) infections: mild upper airways (n=1), urinary infections (n=1), appendicectomy (n=1) and fever due to probable Sars-Cov2 infection (n=1). For 12 pts, data about immunophenotype were available. Of them, no pts showed T CD4+ cell count decrease <200 cell/mm3 at 3, 6-months and 1-year FU; complete B CD19+ cell depletion (<5 cell/mm3) was confirmed at 3, 6-months and 1-year FU. 10 (43.4%) pts developed hypogammaglobulinemia without developing associated infectious events. C) Autoimmunity: no alemtuzumab-related new complications occurred.

Conclusions

short-term FU seems to suggest that the switch to OCR in MS patients who showed disease activity after 2 ALM courses is characterized by a good safety and efficacy profile, although clinical and neuroradiological activity can be detected both in an early and in a later phase of treatment. Longer follow-up is warranted and recruitment is still ongoing.

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Biomarkers and Bioinformatics Poster Presentation

P0162 - Single cell RNA-seq of MS CSF cells reveals a bias toward expanded CD8 T cells (ID 1407)

Speakers
Presentation Number
P0162
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple Sclerosis (MS) is an immune mediated disease of the central nervous system (CNS). To better understand the role and mechanism of the immune system in MS, we performed single cell RNA-seq (scRNA-seq) on cerebrospinal fluid (CSF) cells of 14 untreated MS patients under the 10x Genomics Chromium Single Cell Immune Profiling system.

Objectives

To immunoprofile MS CSF cells and to identify specific cell types that may be relevant to MS pathogenesis or disease subtype.

Methods

Fourteen untreated MS CSF samples were obtained via lumbar puncture; 7 relapsing remitting MS (RRMS), 5 primary progressive MS (PPMS), and 2 secondary progressive MS (SPMS). Cells were isolated and processed according to 10x Genomics’ protocol. For each sample, 2 libraries were made; a 5’ gene expression library and a VDJ enriched library which targets the αβ chains of the T cell receptor (TCR). The combination of these libraries allows for the identification and analysis of clonally expanded T cells. 10x Genomics’ Cellranger pipeline was used for sequence analysis.

Results

Analyzing the top 15 expanded T cell clones for each sample, 11 of the 14 samples had more expanded CD8 T cell clones than expanded CD4 T cell clones. Of these 11 samples that have more CD8 expanded clones, 9 of the 11 samples actually have more total CD4 T cells than CD8 T cells in the CSF. In examining only highly expanded clones (10 cells or more), 9 of the 14 samples retained this CD8 T cell expansion bias. Our data suggests that expanded T cell clones in MS CSF are more likely to be of the CD8 subtype despite a total T cell ratio that favors CD4 T cells.

Conclusions

Immune clonal expansion suggests a targeted response that may be an integral part of the pathogenesis of MS. A bias of the T cell expansion toward CD8 cells may indicate a more cytotoxic environment in the MS CNS. More samples will be needed to determine if this CD8 bias correlates with a particular subtype of MS or if this is a general MS phenomenon.

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Biomarkers and Bioinformatics Poster Presentation

P0163 - Smartphone keystroke dynamics are sensitive to changes in disease activity and clinical disability measures in multiple sclerosis (ID 748)

Speakers
Presentation Number
P0163
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Typing behavior on a smartphone may be used as a biomarker in patients with multiple sclerosis (MS) by analyzing their keystroke dynamics (KD). The continuous acquisition of high sample rate data may provide unprecedented insights in short-term changes in important health outcomes in MS.

Objectives

To investigate the sensitivity of KD to clinically relevant change (i.e. responsiveness) in disease activity, fatigue, and clinical disability outcomes in patients with MS.

Methods

Patients with MS were recruited in this cohort study. Clinical outcomes were assessed at baseline and 3 months follow-up, including: MRI gadolinium-enhancing lesions (Gd-EL), patient-perceived fatigue, and clinical disability measures (Expanded Disability Status Scale, EDSS; Timed 25-foot Walk Test, TWT; Nine-Hole Peg Test, NHPT; Arm function in MS Questionnaire, AMSQ). Throughout the study, patients used the Neurokeys App which replaces the native keyboard with a smart-keyboard and unobtrusively collects time-stamped key press and release events in the real-world setting. Keystroke data of 14 days surrounding the clinical visits were aggregated for the analyses. The area under the receiver operating characteristics curve (AUROC) was calculated to assess responsiveness of KD in classifying anchor-based change within clinical outcomes. The minimally important change (MIC) was calculated as the mean change in KD in the lower +2 SD portion (to approximate minimal change) of patients with clinically relevant change for each clinical outcome. The MIC was compared to the smallest detectable change (SDC) to assess the capability of KD to distinguish important change from measurement error.

Results

102 patients with MS were included, of whom 94 completed follow-up. Responsiveness of KD were acceptable for change in number of MRI Gd-EL (highest AUROC = 0.73) and arm function based on the AMSQ score (highest AUROCs = 0.75). KD had excellent responsiveness to change in ambulatory function measured with TWT (highest AUROC = 0.84). EDSS and NHPT had lower AUC values than KD in classifying change in Gd-EL and AMSQ, respectively. For all keystroke features the MIC exceeded the SDC with differences ranging from 3.6 to 92.4%.

Conclusions

KD collected in patients with MS using the Neurokeys App demonstrated responsiveness to clinically relevant changes in gadolinium-enhancing lesions on MRI and clinical disability measures for arm and ambulatory function. Responsiveness of KD was higher than commonly used clinical measures in MS and sensitive enough to discriminate important change from measurement error.

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Biomarkers and Bioinformatics Poster Presentation

P0164 - Smoking is associated with increased plasma neurofilament light levels in multiple sclerosis (ID 1834)

Presentation Number
P0164
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Elevated levels of plasma neurofilament light chain (pNfL) is associated with increased disease activity, physical disability and reduced treatment response in persons with multiple sclerosis (MS). However, the association between environmental exposures such as cigarette smoking and pNfL levels is not clear.

Objectives

To investigate the association between cigarette smoking, as one of the most prominent environmental factor associated with MS disease activity, and pNfL-levels in MS.

Methods

This is a retrospective population-based cohort study. Blood samples from incident MS cases were collected at time of diagnosis (from 2001). Concentrations of pNfL were determined using antibodies from UmanDiagnostics and the high-sensitive Single Molecule Array (SimoaTM) NF-light® Advantage kit. We assessed the impact of self-reported cigarette smoking habits at time of sampling on age-stratified pNfL levels above 80th, 95th, and 99th of non-MS controls' percentiles (>C80, >C95, and >C99).

Results

pNfL levels were measured in 2881 MS cases with smoking history of which 320 (11.1%) were current regular smokers and 828 (28.7%) were past regular smokers (median years since quitting 6; IQR 1 to 14). Current smoking was associated with significantly increased odds ratios (OR) of having pNfL-levels >C80, >C95 and >C99 with OR ranging from 1.27 (95% CI: 0.96-1.68) to 1.70 (95% CI: 1.24-2.33) comparing current smokers to never smokers and 1.44 (95% CI: 1.06-1.94) to 1.6 (95% CI: 1.12-2.27) comparing current smokers to past smokers. The OR of having pNfL-levels >C80, >C95 and >C99 in past smokers who quitted 6 to 10 years ago, compared to current smokers, ranged from 0.6 (95% CI: 0.39-0.92) to 0.55 (95% CI: 0.30-0.95), and from 0.62 (95% CI: 0.43-0.89) to 0.53 (95% CI: 0.31-0.87) in those with >10 years since quitting smoking. Although decreased, the ORs were not significant among those quitting smoking 1 to 5 years before sampling (P>0.05).

Conclusions

Current regular smoking is associated with significantly increased risk of displaying high pNfL levels in MS patients, which argue for a negative effect on disease activity. In contrast, there was a beneficial effect of quitting smoking that increased with time since stopping. Our findings support the rational for life style counselling in MS.

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Clinical Outcome Measures Poster Presentation

P0165 - Social Matters: Social support is linked to mental health, quality of life, and motor function in multiple sclerosis (ID 1219)

Speakers
Presentation Number
P0165
Presentation Topic
Clinical Outcome Measures

Abstract

Background

We are social animals who naturally seek the companionship of others as an essential part of our physical and psychological well-being. Patients with multiple sclerosis (MS) who are dealing with a chronic and often debilitating disease are at higher risk for social isolation, which may be particularly detrimental to their health.

Objectives

We investigated associations of social support with mental health, cognition, and motor functioning in cross-sectional data from two independent cohorts of patients with MS. We further explored sex differences in these relationships, based on a bioevolutionary theoretical justification.

Methods

Social support was assessed in 185 recently diagnosed patients (RADIEMS cohort), and in an independent validation sample (MEM CONNECT cohort, n = 62). Patients also completed a comprehensive neurobehavioral evaluation including measures of mental health, fatigue, quality of life, cognition and motor function. Correlations tested links between social support and these variables, along with potential gender differences.

Results

In both samples, higher social support was associated with better mental health, quality of life, subjective cognitive function, and less fatigue. In the RADIEMS cohort, correlations showed positive associations between social support and motor functions. The most robust relationships were observed for gross motor functions (gait, grip strength), especially in women.

Conclusions

These findings highlight associations of social support to overall psychological health and motor functioning in persons with MS, underlining the potential opportunity of evaluating and promoting social engagement as a novel treatment strategy.

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Clinical Outcome Measures Poster Presentation

P0166 - Sociodemographic features and disability in African-American and Caucasian patients with Multiple Sclerosis (ID 1282)

Speakers
Presentation Number
P0166
Presentation Topic
Clinical Outcome Measures

Abstract

Background

A more severe disease course has been reported in African-American (AA) in comparison with Caucasian (CA) MS patients. Sociodemographic differences and limited access to treatment have been often used to explain the different disability profile in the two groups. To date, an objective assessment of disability in AA and potential differences with CA patients is still lacking.

Objectives

Here, we characterized sociodemographic, motor and neuropsychological features of AA and CA patients with multiple sclerosis.

Methods

Fifty-seven AA patients (43F, mean age 37.84 ± 10.54 yrs, mean disease duration 5.64 ± 5.74 yrs, median EDSS 2, EDSS range 0-6.5), 37 AA healthy controls (HC) (25F, mean age 35.97 ± 12.44 yrs), 50 CA patients (36F, mean age 39.02 ± 10.83 yrs, mean disease duration 5.90 ± 5.94 yrs, median EDSS 1.5, EDSS range 0-6) and 28 CA HC (17F, mean age 35.57 ± 11.77 yrs) were prospectively enrolled. In all subjects, an extensive neuropsychological and sensory-motor evaluation was performed. The sensory-motor evaluation included 9-hole peg test (9-HPT), grooved pegboard test (GPT), finger tapping test (FTT), 25-foot walk test (25-FWT), 2-minutes walk test (2-MWT), evaluation of segmental strength, grip strength, vibration sensitivity (VS) and standing balance (theta score from NIH toolbox). The neuropsychological evaluation included Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT), Brief Visuospatial Memory Test–Revised (BVMT), Stroop Color and Word Test (SCVT), Controlled Oral Word Association Test (COWAT) and a multitasking attention-memory test (MAMT). Each patient’s group was compared with a race-matched HC group via ANCOVA analysis, accounting for age, gender, years of education and socioeconomic status expressed as yearly income (9 categories with 1 = less than $5,000 and 9 = $100,000+). In the comparison of cognitive performance, years of education, premorbid intelligence estimated with the Wechsler Test of Adult Reading (WTAR) and depressive symptoms evaluated via Beck Inventory were also included as covariates of no interest.

Results

AA and CA patients did not differ in age, gender, disease duration, while they did differ in total years of education (p<0.001) and yearly income (p=0.001). When compared to their matched HC group, AA and CA patients showed similar deficits in information processing speed, ambulation, manual dexterity, sensitivity and balance (p ranging from 0.029 to <0.001). While CA showed an additional impairment of verbal memory (p=0.009), AA patients showed additional involvement of verbal fluency (p=0.005), multitasking capability (p=0.024), motor speed and coordination (p=0.048) and grip strenght (p=0.041).

Conclusions

Even when accounting for sociodemographic features, AA patients show more severe and widespread disability than CA patients with MS.

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Clinical Outcome Measures Poster Presentation

P0167 - Ten-Foot Tandem Walk: Detection of subtle gait changes and future fall risk in MS (ID 1534)

Speakers
Presentation Number
P0167
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Gait disturbance is common and often begins early in multiple sclerosis (MS). We have previously identified higher-challenge balance tasks as more sensitive than gait speed tasks (Timed 25 Foot Walk [T25FW], Two-Minute-Walk-Test [2MWT]) to patient-reported gait change and fall risk in a cohort of persons with early relapsing MS (<5 years diagnosed).

Objectives

To assess whether a clinically-feasible, quantifiable higher-challenge dynamic balance task is sensitive to subtle patient-reported gait changes and falls in persons with relapsing MS of varied disease duration and with normal gait speed as measured by the T25FW.

Methods

Persons with relapsing MS or clinically isolated syndrome (n=218, aged 18-65 years) with normal gait speed (T25FW <5.0s) reported gait disturbance (MS Walking Scale-12 [MSWS-12]) and recent falls/near-falls (within the past month); healthy controls (n=200) also reported recent falls/near-falls. Dynamic balance was assessed with the novel 10-Foot Tandem Walk (10FTW) task requiring patients to tandem walk on a 10-foot straight line with arms across their chest; number of quarters successfully completed across three trials was recorded (0-12). For comparison, patients also performed the 2MWT as a high-challenge gait speed task.

Results

Nearly half of patients (48.2%) reported at least mild walking difficulty despite normal T25FW, and MS patients reported twice as many falls as controls (11.5% vs. 5.5%). Among MS patients, logistic regression revealed that worse 10FTW (p=.006), but not 2MWT (p=.121), independently predicted falls. Percent of MS patients reporting falls across 10FTW quartiles was 22.4%, 11.7%, 9.5%, 2.5%. Supplemental analyses replicated findings when considering near-falls and when controlling for mood.

Conclusions

Many MS patients report gait disturbance despite normal walking speed (T25FW). Dynamic balance assessed with the clinically-feasible and quantifiable 10FTW was sensitive to subtle walking difficulties and fall risk in these patients. These findings replicate our previous work identifying balance tasks as more sensitive to gait disturbance and fall risk than speeded walking tasks. The 10FTW may hold promise as an clinical trial outcome measure, especially among patients with more mild disability.

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Clinical Outcome Measures Poster Presentation

P0168 - Test-retest reliability of the mini-BESTest in people with mild to moderate multiple sclerosis (ID 846)

Speakers
Presentation Number
P0168
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The mini-BESTest assesses several underlying physiological systems (anticipatory, reactive postural control, sensory orientation and dynamic gait) for balance control that may contribute to balance deficits in adults. There is a lack of studies exploring test-retest reliability of the mini-BESTest in large samples of people with multiple sclerosis (MS).

Objectives

To investigate test-retest reliability of the mini-BESTest total and section sum scores, and individual items, in people with mild to moderate overall MS disability.

Methods

Fifty-four people with mild to moderate overall MS-disability according to the Expanded Disability Status scale (EDSS) were included, 28 in the mild subgroup (EDSS 2.0–3.5) and 26 in the moderate subgroup (EDSS 4.0–5.5). Test-retest reliability of the mini-BESTest was evaluated by repeated measurements one week apart in a movement laboratory setting. The analysis was based on evaluation of test-retest reliability and measurement error.

Results

Test-retest reliability for the mini-BESTest total scores were considered good to excellent, with intraclass correlation coefficients of .88 for the whole sample and .83 in mild MS and .80 in moderate MS subgroups. Measurement errors were small with a standard error of measurement and smallest detectable change of 1.3 and 3.5, respectively, in mild MS and of 1.7 and 4.7 in moderate MS. The limits of agreement were -3.4 and 4.6. Test-retest reliability for the section scores were fair to good, or excellent; weighted kappa values ranged from .62 to .83. All items but one showed fair to good or excellent test-retest reliability, percentage agreement ranged from 61% to 100%.

Conclusions

The mini-BESTest demonstrated good to excellent test-retest reliability and small measurement errors and is recommended for use in people with mild to moderate MS in both research and clinical settings.

The mini-BESTest should be used in its entirety. The sections included in the test may be used to determine more precisely which of the underlying systems that are affected, even if the sensory orientation and reactive postural control sections should be interpreted cautiously.

Knowledge of limits of agreement and smallest detectable change contribute to interpretability of the mini-BESTest total score, which enhance the clinical usefulness for evaluation of balance control and, further, for designing of individually customized balance training with high precision and accuracy in people with MS.

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Biomarkers and Bioinformatics Poster Presentation

P0169 - The association between spontaneous MxA mRNA level and disease activity in multiple sclerosis (ID 1732)

Speakers
Presentation Number
P0169
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Myxovirus resistance protein A (MxA) is one of the proteins upregulated by interferon-beta. MxA mRNA level is often used in clinical practice to determine bioactivity of interferon-beta treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Lack of bioactivity is often due to the development of neutralizing antibodies against the drug. In 2010, we reported the association between spontaneous MxA mRNA level and clinical disease activity in multiple sclerosis (MS). Low levels of spontaneous MxA mRNA level were associated with contrast enhancing lesions (CELs) on baseline MRI, clinical relapses and a shorter time to first relapse. In the current study we assessed the long term data in the same cohort for the association between spontaneous MxA mRNA levels and clinical disease activity and disability.

Objectives

To investigate the association between spontaneous myxovirus resistance protein A (MxA) mRNA levels and disease activity in MS patients over a longer follow-up period.

Methods

Spontaneous MxA mRNA levels were determined in a previously described cohort of 116 patients diagnosed with a clinically isolated syndrome (CIS) or with a recent diagnosis of RRMS, and related to clinical scores (Expanded Disability Status Scale (EDSS), timed-25-foot walk (T25FW), 9-hole-peg test (9HPT)), and MS type over a long follow-up. MRI-imaging was performed at baseline and during follow-up to assess the development of new T2-lesions and CELs.

Results

116 patients where included in the analyses. 74 (63.8%) were female. At baseline, 67 patients (57.8%) were diagnosed with RRMS and 49 (42.2%) with a CIS. Median follow-up duration was 10.76 years (IQR 69.52-148.50 months). Median EDSS at follow-up was 3.0. Spontaneous MxA mRNA level was not associated with EDSS, T25FW and 9HPT, and MS subtype at follow-up. 89.7% of patients ever experienced MRI-activity during follow-up. Low spontaneous MxA mRNA levels were associated with the occurrence of more T2-lesions on MRI imaging during follow-up in patients with a small number of T2-lesions (<9 lesions) on baseline MRI (B=-1.595, p=0.029).

Conclusions

Baseline spontaneous MxA mRNA level is associated with the development of new T2-lesions on MRI during long-term follow-up and, if confirmed in other populations, has a potential value as a predictive biomarker for long-term inflammatory disease activity in MS.

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Clinical Outcome Measures Poster Presentation

P0170 - The GNDS is suitable for changes in walking performance in progressive multiple sclerosis   (ID 1696)

Presentation Number
P0170
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The Guy’s Neurological Disability scale (GNDS) and the Multiple Sclerosis Impact Scale (MSIS-29) are patient reported outcome measures (PROMs) which can serve as a proxy for measuring disability and impact in patients with diagnosed multiple sclerosis (pwMS). In times of increased interest for telemedicine such measures are important.

Objectives

The aim of this study was to investigate correlations between two multi-domain PROMs and often used clinical outcome measures.

Methods

248 MS patients were assessed using the GNDS, the physical part of the MSIS-29 (MSIS-phys), the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9-HPT) and the Timed 25-foot walk test (T25WT) at baseline (BSL) and follow-up (FU) with a mean of 6.4 years. Cross-sectional and longitudinal correlations were studied between the overall scores and specific subcategories of the PROMs and clinical outcome measures. Additionally, the relationship between clinically significant changes in the PROMs and clinical outcomes were studied. We defined a clinically significant change of three or more points on the GDNS, eight or more points on the MSIS-phys and one point or more on an EDSS score <5.5 and one-half point or more on an EDSS score ≥5.

Results

Strong cross-sectional correlations were found between the “legs” domain of the GNDS and the pyramidal functional system (p-FS) of the EDSS (Rbsl(247)=.55, p<0.001; RFU(238)=.77, p<0.001) and the T25WT (RBSL(247)=.56, p=0.000; RFU(233)=.77, p<0.001) especially in progressive patients (PPMSbsl R(34)=.76, p<0.001; PPMSFU R(26)=.86, p<0.001, SPMSBSL R(21)=.61, P=0.003; SPMSFUR(34)=.82, p<0.001). The MSIS-phys also showed strong correlations compared to the p-FS of the EDSS RBSL(162)=.59, p<0.001; RFU(236)=.70, p<0.001) and T25WT RBSL(162)=.61, p<0.001; RFU(231)=.61, p<0.001). Only good correlations were found between the MSIS-phys and T25WT in RRMS patients (RBSL(114)=.45, p<0.001; RFU(172)=.54, p<0.001).

Longitudinal correlations for the global GNDS/MSIS-phys and EDSS/MSFC were relatively poor except for changes on the leg domain of the GNDS in relation to changes on the T25WT (R(231)=.58, p<0.001), especially in PPMS patients (R(25)=.68, p<0.001). In the majority of cases a clinically significant deterioration on the EDSS also resulted in a clinically significant worsening of the GDNS and MSIS-phys.

Conclusions

The GNDS and MSIS-phys correlate well with clinical outcome measures for physical disability. The GNDS in particular, for the lower limb function in progressive patients. PROMs are easy to apply, less-time consuming and are a more cost-effective way of capturing patients’ disability.

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Biomarkers and Bioinformatics Poster Presentation

P0171 - The gut mycobiome in pediatric multiple sclerosis: establishing a bioinformatics pipeline (ID 876)

Speakers
Presentation Number
P0171
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Studies examining the role of the microbiota in multiple sclerosis (MS) often focus on the gut bacteria; few have considered a potential role of gut mycobiota. Methods for evaluating gut mycobiota are lacking and require systematic evaluation of sequencing protocols, reference databases, and bioinformatics pipelines to properly investigate possible gut mycobiome influences on MS.

Objectives

We set out to evaluate the performance of different sequencing conditions and analytical approaches for characterizing the gut mycobiome in a cohort of healthy individuals and cases with monophasic acquired demyelinating syndrome (mono ADS) or pediatric-onset MS.

Methods

We first assessed a mock-community control pool of known, staggered quantities of 19 defined fungal organisms. We then assessed 201 stool samples obtained from our cohort of 52 healthy individuals, 49 individuals with mono ADS, and 46 participants with pediatric-onset MS. The fungal internal transcribed spacer (ITS) 2 region was sequenced using the Illumina® MiSeq platform. Varying concentrations of PhiX Control v3 Library spike-in were tested to address low-complexity amplicon sequencing. Generated sequences were characterized by the UNITE database—a curated collection of eukaryotic ITS sequences—in conjunction with three distinct fungal sequence analysis pipelines: LotuS, mothur, and PIPITS.

Results

Taxa identified in our mock-community differed across sequencing conditions but were similar between technical replicates. LotuS correctly classified 7 taxa at species-level, 7 taxa at genus-level, whereas 5 remained unclassified. Mothur correctly identified 5 species-level taxa, 11 genus-level taxa, whereas 3 remained unclassified. Lastly, PIPITS correctly identified only 3 species-level taxa, 12 genus-level, while 4 remained unclassified. We successfully generated sequence data for 112 of 147 (76%) individuals (70 females; 42 males). The mean age at stool sample collection was 17.3 (SD 5.1) years. Of the tested sequencing conditions, a spike-in of 50% PhiX produced the highest-quality reads.

Conclusions

The LotuS pipeline best identified fungal taxa in our mock-community, with optimal resolution to species level. Sequencing read quality was optimal when 50% PhiX was used for sequencing ITS2 amplicon libraries of stool samples. Establishment of this validated sequencing pipeline, confirmed using a mock-community with known fungal identities, will aid characterization of gut mycobiomes for our cohort of individuals with/without pediatric-onset MS.

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Biomarkers and Bioinformatics Poster Presentation

P0172 - The prognostic value of lipid-specific IgM oligoclonal bands versus IgM index in patients with a clinical isolated syndrome: a comparative study. (ID 1114)

Speakers
Presentation Number
P0172
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The value of intrathecal IgM synthesis (ITMS) is increasingly recognized as a prognostic biomarker in patients with a clinically isolated syndrome (CIS). However, no comparative studies between different methods to assess ITMS have been described previously evaluating the prognosis of patients with CIS.

Objectives

To compare the predictive value of IgM Reibergram (IR) and the presence of lipid-specific IgM oligoclonal bands (LS-OCMB) in CSF to predict conversion to clinically defined multiple sclerosis (CDMS), and the onset of EDSS of 3, 6 and a secondary progressive MS (SPMS).

Methods

An observational single-center study with CIS patients with at least 2 years of follow-up attended at Hospital Universitario Ramón y Cajal was performed. Demographics, clinical, radiological and immunological variables were collected.

Results

196 patients were included, 131 (66.8%) women, with a median (range) age of 31 (12–63) years and mean (SD) follow-up of 13.2 (±7.0) years. Overall, positive LS-OCMB was observed in 52 (26.5%) patients and IR in 32/193 (16.6%), reaching a concordance of 59.4% between both. The risk of CDMS was significantly higher exclusively among LS-OCMB (adjusted HR 1.80 (95%CI 1.24-2.62), p=0.002), but not for IR. In addition, LS-OCMB predicted a higher risk of reaching an EDSS of 3 (OR 1.97, p=0.044), an EDSS of 6 (OR 3.82, p=0.001) and a SPMS (OR 2.67, p=0.013) among MS patients. No significant differences were observed with IR.

Conclusions

LS-OCMB are a more sensitive and reliable CSF biomarker to predict the natural history of CIS patients compare to semi-quantitative IR.

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Biomarkers and Bioinformatics Poster Presentation

P0173 - The serum levels of Interleukin 17 in patients with neuromyelitis optica spectrum disorder (ID 1286)

Speakers
Presentation Number
P0173
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neuromyelitis optica spectrum disorder is an inflammatory astrocytopathy disorder of the central nervous system (CNS) which the interaction between T cells and B cells is suggested for its development. Interleukin 17 (IL-17) is one of the pro-inflammatory cytokines that could affect T cells activity. But there is a limited data on the serum levels of IL-17 in NMOSD patients.

Objectives

In this study we aimed to compare the serum levels of IL-17 as a pro-inflammatory factor in NMOSD patients and healthy subjects.

Methods

A population-based case-control study was conducted on 56 NMOSD patients and 100 healthy controls. NMOSD patients were selected from NMOSD specialist clinic of Sina hospital, which is a referral center for NMOSD in Tehran, Iran. NMOSD diagnosis was based on the 2015 international consensus criteria and only patients with NMO-IgG seropositive status were included in the study. Age and sex matched controls were gathered from healthy population from all municipality zones of Tehran. Serum levels of participants were assessed by the enzyme-linked immunosorbent assay (ELISA) test. The difference between the serum levels of IL-17 in case and control groups were evaluated by independent samples T-test and univariate model adjusted for age, gender and body mass index (BMI). Data distribution was not normal, so IL-17 levels are reported as Ln.

This study was supported by the National Institute for Medical Research Development (NIMAD) [grant number 973227].

Results

89.3% of participants in case group and 93.0% in control group were women. The mean (SD) ages of subjects in case and control groups were 35.89 (9.39) and 37.40 (6.68) years old, respectively (P: 0.29). No significant differences was found regarding BMI between study groups (BMI in case group: 26.61 ± 5.15; in control group: 26.82 ± 5.45 Kg/m2 (P: 0.81)).

The mean (SD) levels of Ln serum IL-17 in NMOSD patients was 2.01 (1.18) pg/mL which was significantly higher than control group with the mean Ln serum levels of 1.11 (0.81) pg/mL (P <0.001). This difference was also significant in univariate model adjusted for age, gender and BMI (P <0.001).

Conclusions

This investigation suggested the possible role of IL-17 in NMOD development and also elevated serum level of IL-17 as a diagnostic criteria for NMOSD.

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Biomarkers and Bioinformatics Poster Presentation

P0174 - TNFα and IL-6 levels in Relapsing-Remitting Multiple Sclerosis Patients on Dimethylfumarate: a Biomarker Study (ID 97)

Speakers
Presentation Number
P0174
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background


Multiple sclerosis (MS) is an acquired, chronic demyelinating disease, affecting more than 2.3 million worldwide.
Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine produced by activated macrophages which in turn activate microglia.
Interleukin-6(IL-6) is a pro-inflammatory, anti-inflammatory myokine secreted by T cells, supporting B cell growth and inhibiting TNFα and regulatory T cells.
Tecfidera® (dimethyl fumarate: DMF) has been FDA-approved for treatment of RRMS since 2013. DMF decreases TNFα and IL-6 synthesis in activated microglia and astrocytes in vitro.

Objectives

A. To obtain TNFα and IL-6 levels in attack-free patients on DMF
B. To check correlations between TNFα, IL-6, EDSS, vitamin D levels, age, duration of disease, or number of MRI lesions

Methods

This was a 6-year retrospective study of patients seen by a single neurologist (WSB) Jan 1, 2014-Oct 31, 2019. Patients were diagnosed based on the 2010 McDonald MS criteria. Those with clinically isolated syndrome were included. Longitudinal data analysis was performed using generalized linear models.

Inclusion criteria:

1. Patients aged 18 or above either with a new or pre-existing diagnosis of MS or CIS

2. Patients with baseline laboratory data (TNFα and IL-6) every 3-4 months afterwards (at least three times), and MRI prior to starting DMF and afterwards (at least twice)

3. Patients who were naïve to MS medications or have been off treatment for at least 1 year prior to starting DMF

Exclusion criteria:

1. Those still on immunomodulatory agents at the time of the initial visit

2. Those non-compliant with either follow up visits, lab tests, MRIs or taking DMF

3. Patients with concurrent infectious or inflammatory/autoimmune conditions

4. Patients who relapsed during the study period

Results

84 patients were started on DMF either as de novo or second-line therapy. After exclusion criteria, 11 were included in the analysis. 10 were female and 1 was male. The average age was 46.9 years; the average age of onset 33.3. The average time from onset till diagnosis was 6.6 years. The average baseline EDSS score was 2.56. The average baseline number of T2-FLAIR lesions was 21.55 and 6.45 for T1 black holes. The median baseline number of T2-FLAIR lesions was 10 and 1 for T1 black holes. The average baseline vitamin D level was 25.84ng/ml.

There was a significant decrease in TNFα levels after initiating DMF in nearly all the cases. The decreasing TNFα levels separated into different groups based on the number of T2 lesions, age, and EDSS.

An insignificant trend towards a decrease in IL-6 levels was observed after initiating DMF in nearly all the cases. The decreasing IL-6 levels separated into different groups based on the number of T2 lesions, and age.

Conclusions

TNFα levels decreased significantly, whereas IL-6 showed only a decreasing trend after initiating DMF.

TNFα may be a promising serum biomarker in monitoring DMF therapy in MS.

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Biomarkers and Bioinformatics Poster Presentation

P0175 - Towards optimized monitoring of serum neurofilament light chain in MS (ID 1329)

Abstract

Background

Serum neurofilament light chain (sNfL) levels reflect only neuro-axonal injury that took place within 3-6 months prior to the date of sampling. Therefore, the frequency of assessment of sNfL levels for monitoring of disease activity warrants further investigation.

Objectives

To determine differences in accuracy of sNfL levels to detect radiological disease activity during the preceding 6 versus 12 months of follow-up.

Methods

This observational study included 148 patients with early relapsing-remitting multiple sclerosis (MS) from the SET cohort. Based on brain MRI performed at 0, 6 and 12 months, we assessed the ability of categorized sNfL measured at 12 months to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI performed in the previous 6 versus 12 months or contrast-enhancing lesion (e.g., active lesions).

Results

Together, 91% (95% CI=85-98%) of patients with ≥1 active lesion during the last 6 months and 84% (95% CI=77-92%) of patients with ≥1 active lesion during the last 12 months had sNfL≥30th percentile. Among the patients with sNfL<30th percentile, 14 (33.3%) developed ≥1 active lesion during the last 12 months, but only 6 (14.3%) developed ≥1 active lesion during the last 6 months. Among patients with sNfL<30th percentile, 6 (14.3%) developed ≥2 active lesions during the last 12 months, but only 2 (4.8%) developed ≥2 active lesions during the last 6 months.

Conclusions

Low levels of sNfL better identified MS patients with the absence of recent radiological disease activity during the previous 6 than the previous 12 months. In the future, assessment of sNfL at least every 6 months may substitute the need for annual brain MRI monitoring to exclude brain lesion activity in clinically stable patients with low sNfL levels.

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Clinical Outcome Measures Poster Presentation

P0176 - Treatment and care management, clinical outcomes and mobility impairment in people with or without MS aged ≥ 50 years: observational 6-year analysis (ID 832)

Speakers
Presentation Number
P0176
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Although multiple sclerosis (MS) is often described as a disease of young adults, a recent study conducted by the National Multiple Sclerosis Society showed that, in the US, people with MS have a median age of 52 years. Limited data are available in the older MS population.

Objectives

To characterize clinical outcomes, mobility impairment, treatment and care management patterns in people with MS ≥50 years of age (PwMS) compared with a cohort of adults ≥50 years of age without MS (AwoMS) from the general population.

Methods

Administrative US claims data from Truven Health MarketScan® Commercial and Medicare Databases 2011-2017 were analysed. PwMS included 3 claims with MS diagnoses (ICD9/10 340/G35) OR 1 MS diagnosis + 1 disease-modifying drug (DMD) within 1-year of each other, AND 1st diagnosis or DMD in 2012 as index; continuous enrollment 1-year pre-index (baseline), and ≥3 years follow-up; aged ≥50. AwoMS included those continuously enrolled from 2011 to minimum 2015, up to 2017, aged ≥50 and never diagnosed with MS, with July 1st 2012 used as index for baseline characteristics. A 1:1 matched cohort was created using propensity scores calculated from baseline covariates (age, sex, region, health plan and comorbidities). Multivariable models were used to compare infection and malignancy rates, treatment and care patterns including utilization of magnetic resonance imaging (MRI), skilled nursing facilities (SNF), and time to mobility aids (cane/walker or wheelchair use) between matched PwMS and AwoMS.

Results

Inclusion criteria were met by 10,746 PwMS and 3,521,326 AwoMS (10,746 matched to PwMS). Over the average 5-year follow-up, PwMS had a higher infection rate than AwoMS (0.738 vs. 0.247 per patient, respectively; rate ratio [RR]: 2.977 [with 95% confidence interval of [2.849-3.111]), a higher rate of MRI use (0.684 vs. 0.157 per patient, respectively; RR: 4.234 [4.016-4.464]), most being brain and spine MRIs, and a higher use of SNF (0.658 vs. 0.098 per patient, respectively; RR: 6.920 [6.487-7.385]). Having MS showed no significant association with the odds of developing a malignancy (odds ratio: 1.006 [0.940-1.076]). MS was associated with a shorter time to cane/walker or wheelchair use (hazard ratios: 2.374 [2.140-2.634] and 7.600 [6.516-8.863], respectively).

Conclusions

Compared with AwoMS, PwMS showed higher rates of infections, MRI utilization and SNF use, shorter time to cane/walker or wheelchair use, and similar rates of malignancies.

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Clinical Outcome Measures Poster Presentation

P0177 - Treatment Persistency for Patients in a Phase 2 Long-Term Extension Study of Ponesimod (ID 1700)

Speakers
Presentation Number
P0177
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple Sclerosis (MS) is a disorder of the central nervous system characterized by inflammation, demyelination, and degenerative changes. For chronic conditions requiring a potential lifetime of treatment, treatment discontinuation may result in significant clinical issues, including relapse risk and disease progression. There can be a number of factors contributing to treatment discontinuation, but several studies have demonstrated that adverse events and the lack of efficacy represented by continued disease progression are the leading causes. In MS, patient satisfaction with treatment is essential for sustained persistency and positive long-term health outcomes.

Objectives

Understanding the long-term safety and efficacy considerations of a potential treatment in a chronic disease such as MS is critical to both patients and providers. The aim of this analysis is to understand the frequency and reason leading to premature treatment discontinuation from the long-term extension for patients on the 20mg of ponesimod.

Methods

In the main phase 2 study (B201), a total of 464 subjects were randomized in a 1:1:1:1 ratio to receive ponesimod 10 mg (N=108), ponesimod 20 mg (N=116), ponesimod 40 mg (N=119), or placebo (N=121), resulting in a total of 462/464 (99.6%) treated subjects, of whom 393 completed the 24-week double-blind treatment period. Of the 393 subjects who completed treatment in the core study, subjects were eligible to be enrolled into of the extension study (B202) of three treatment phases (TP1, TP2, and TP3) maintaining the either the same dose or for placebo patients rerandomized to 10, 20 or 40mg (although the 40mg was discontinued after TP1).

Results

As of the 31 March 2019 (8.3 years after initiation), a total of 60.7% of subjects in the 20mg arm had maintained therapy on ponesimod over the course of the study and subsequent extensions. For those patients with premature discontinuations, reasons for discontinuation: 40.4% unknown subject decision, 28.1% tolerability/AE related, 17.5% efficacy related, and 14% other reasons.

Conclusions

Patient satisfaction with treatment is key to ensure adherence in a long-term chronic disease. The retention of over 60% of patients during an 8 year, phase 2 long term extension study suggests a high degree of patient satisfaction with the tolerability, safety and efficacy of ponesimod.

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Biosensors Poster Presentation

P0178 - Use of wearable biosensors to collect real-world patient activity data in two randomized phase 2 studies of elezanumab in multiple sclerosis (ID 987)

Speakers
Presentation Number
P0178
Presentation Topic
Biosensors

Abstract

Background

Clinical trials in acute and chronic neurologic conditions traditionally rely on functional assessments using clinical scales that can be insensitive to treatment response and capture a patient’s function at a single timepoint in a clinical setting. In order to assess the relative sensitivity of real-world activity levels for detection of disease progression and/or treatment response compared with in-clinic assessments, we are using wearable digital biosensors to passively collect activity data in 2 multiple sclerosis (MS) clinical trials.

Objectives

To assess patient biosensor compliance and the potential of real-world digital biosensor data to assess MS disease progression and/or treatment response

Methods

Two randomized, double-blind, placebo-controlled, 52-week Phase 2 clinical trials are currently evaluating the efficacy and safety of elezanumab in subjects with relapsing (RADIUS-R, NCT03737851) or progressive (RADIUS-P, NCT03737812) forms of MS. The primary efficacy assessment is performed in-clinic every 12 weeks. To generate real-world activity data, subjects wore MC10’s BioStamp nPoint® biosensors over 7-day intervals at Baseline and Weeks 24, 36, and 52. The sensors (chest, thigh and calf locations) monitor gait speed, step count and overall activity, including vital signs. Study sites were trained to apply, charge and reapply biosensors by MC10, and site staff trained subjects. Compliance was measured by the percentage of sensor wear days out of the instructed wear days.

Results

As of April 9, 2020, RADIUS-R had enrolled 208 subjects, RADIUS-P had enrolled 123 and 119,00 hours of actigraphy data were collected. Interim compliance rates for subjects completing each interval in RADIUS-R and RADIUS-P respectively were: Baseline (n=188, 101%; n=88, 94%), Week 24 (n=84, 99%; n=21, 86%), Week 36 (n=28, 104%; n=5, 103%), Week 52 (n=4, 79%; n=1, 114%). The average compliance rate across the studies and timepoints was 98%. All treatment-blinded actigraphy data were uploaded to the MC10 cloud for review. The objective at the completion of the studies is to determine differences between treatment groups in relation to clinical endpoints.

Conclusions

To our knowledge, these are the first randomized MS clinical trials to incorporate BioStamp biosensors to capture real-world activity. There was a high level of compliance to-date across study sites for the subjects that have completed one or more 7-day intervals, suggesting use is not overly burdensome.

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Clinical Outcome Measures Poster Presentation

P0179 - Using NIH Toolbox Standing Balance Test to quantify subtle balance impairment in patients with multiple sclerosis (ID 1648)

Speakers
Presentation Number
P0179
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Balance impairment is frequent in Multiple Sclerosis (MS). Attempts to measure balance deficits in clinical practice have mostly relied on EDSS, but its scarce capability to detect subtle deficits is an important limitation.

Objectives

To compare NIH Toolbox Standing Balance Test (SBT) with EDSS in detecting balance impairment in MS and to assess the contribution of the different Functional Systems (FS) involved in balance on SBT metrics.

Methods

128 consecutive MS patients and 36 age and sex-matched healthy controls (HCs) underwent NIH Toolbox SBT at the MS Center of the University of Genoa. Patients underwent clinical evaluation with EDSS FS recording and 3T brain MRI (Siemens Prisma). Theta scores (θ) were derived and corrected for age, sex, height and weight. T2 and T1 lesion volumes (LV) were obtained for the cerebellum and the total brain separately. A linear logistic regression model was performed to evaluate the relative contribution of cerebellar, sensory and brainstem impairment
on balance performance.

Results

92 (73.9%) MS patients were females, mean (SD) age was 41.2 (11.6) years; 108 (84.4%) patients had relapsing-remitting (RRMS) and 20 (15.6%) progressive MS (PMS). Mean disease duration was 10.6 (9.3) years, median (IQR) baseline EDSS was 2.5 (1-4). According to their FS, 73 (53.0%), 57 (44.5%) and 79 (61.7%) patients had no evidence of cerebellar, sensory and brainstem dysfunction respectively. On brain MRI, 95 (74.2%) patients exhibited cerebellar lesions [mean T2LV 0.31 (0.44) mL; mean T1LV 0.20 (0.31) mL]. Patients had significantly lower θ compared with HCs (-0.27vs0.91;p=0.003). RRMS had better performance than PMS patients (-0.05 vs -1.45;p=0.006). Patients with a cerebellar and brainstem FS=0 had higher θ than impaired patients (0.34vs-1.07;p&lt;0.0001 and 0.12vs-0.89;p=0.008 respectively). Patients without impairment in sensory and brainstem FS had worse performance than HCs (0.08vs0.91;p=0.046 and 0.12vs0.91;p=0.048, respectively). Each 1 point increase in cerebellar FS independently determined a -0.50 decrease in θ (95%CI:-0.91-0.09; p=0.017).  correlated with cerebellar T2LV and T1LV (Spearman r-0.29,p=0.001 and r=-0.28,p=0.001 respectively) but not with global T2LV and T1LV.

Conclusions

NIH Toolbox SBT is able to detect subtle balance impairment in MS patients, not detected by clinical examination. Clinical and radiological cerebellar involvement seem to be specifically related to NIH Toolbox SBT metric.

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Biomarkers and Bioinformatics Poster Presentation

P0180 - Utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in tracking treatment response in PPMS patients (ID 1447)

Speakers
Presentation Number
P0180
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There is growing evidence that serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are useful biomarkers in multiple sclerosis (MS). While these biomarkers have been studied in cohorts of MS patients including all disease subtypes (relapsing remitting, secondary progressive, and primary progressive [PP]), few studies have examined biomarker response to treatment in a cohort of exclusively PPMS patients.

Objectives

To assess how sNfL and sGFAP change over time in PPMS patients who transition from no medication to high potency medication.

Methods

Serum samples were collected from 25 patients biannually for 5 years. sNfL and sGFAP were measured using a sensitive single molecule array platform (Quanterix), and log-transformed to assume a normal distribution. Patients were split into two groups based on medication status: patients switched from no medication to a high-potency drug (n=5) versus patients never on medication for the study duration (n=14). Patients on platform drugs or high-potency drugs for the duration of the study were excluded. High-potency drugs include natalizumab, ocrelizumab, fingolimod, and dimethyl fumarate. Statistical analyses were performed in R.

Results

Linear models found sNfL positively associated with age (β=0.024, p=0.004), while higher sGFAP levels were seen in women (β=-0.737, p=0.037). Spaghetti plots examining change in sNfL and sGFAP over five years displayed no trend in either group. Paired Wilcoxon Tests comparing biomarker levels at first versus last available sample showed no significant difference for any group (‘No Drug’ NfL p=0.296, ‘High Potency’ NfL p=0.188; ‘No Drug’ GFAP p=0.583, ‘High Potency’ GFAP p=0.063).

Conclusions

Low levels of NfL are known to accumulate in blood of healthy individuals over time, so the association between sNfL and age is not surprising and has been previously reported. However, sGFAP showed a strong association with female sex; this may be related to a slightly higher average age at enrollment among women. Overall, the spaghetti plots showed little change in either group, with no statistically significant difference in any group over 5 years. This may indicate that these drugs do not affect biomarker level in PPMS. This is further supported by evidence that these immunosuppressive drugs are effective in preventing relapse and inflammatory activity, but may not help to prevent progression. These findings suggest that these biomarkers may have a limited role in judging treatment efficacy in PPMS patients who do not experience flares or new symptoms.

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Clinical Outcome Measures Poster Presentation

P0182 - Validation of the FeetMe® System versus GAITRite® to Assess Gait Characteristics in Patients with Multiple Sclerosis: Subpopulation analysis (ID 1275)

Abstract

Background

The complete and objective gait assessment in multiple sclerosis (MS) patients is an unmet need, with important biases in the usual way of assessing gait (neurological examination/EDSS). GAITRite® measures different visuospatial gait parameters; however, its use is limited to a few centres due to its high price, physical space and the need of trained personnel for use and interpretation.

Objectives

To determine the statistical agreement and precision of gait velocity in MS patients, measured by a shoe insole device with integrated motion and pressure sensors (FeetMe®) vs reference system (GAITRite®), in 25-Foot Walk Test (25FWT).

Methods

This was an observational, cross-sectional, prospective, single-centre study. Patients 18-55 years, with MS (McDonald-2010), EDSS 0–6.5 and relapse free ≥30 days were included. GAITRite®/FeetMe® devices used. Primary endpoint was gait velocity (cm/second) (velocity-1/velocity-2 formulas). Secondary endpoints: ambulation time (seconds), gait cadence (steps/min) and stride length (cm), among others. Results of the 25FWT-both devices patient group with valid data (25PG+VD) analysis are presented, corresponding to the subpopulation who met all the selection criteria and performed 25FWT with both devices, having valid and evaluable data, at least for velocity.

Results

127 patients included. At baseline, mean (SD) age was 40.7 (8.2) years, 67.7% women, 83.5% RRMS, EDSS 2.8 (1.9). Mean (SD) velocity-1 was 104.5 (31.6) for GAITRite®, 107.6 (30.3) FeetMe® with 0.88 intraclass coefficient correlation (ICC) and 0.89 Pearson correlation, while for velocity-2 were 104.5 (31.6) and 108.9 (31.0), respectively, with 0.90 ICC and 0.91 Pearson correlation. These results indicate a very strong agreement between devices on the same subjects. Mean (SD) ambulation time difference between devices was -0.01 (0.3). Cadence-1 and cadence-2 differences between devices were -0.3 (2.7) and -2.5 (2.7), respectively. Mean (SD) stride length difference was -2.6 (19.8). A stronger association was observed between EDSS and velocity, cadence and stride length, these parameters correlation decreased with higher EDSS scores. The analysis suggested that precision of FeetMe® device could be affected by level of disability of MS patients.

Conclusions

Agreement between devices was almost perfect (ICC≥0.8). FeetMe® assesses the gait of MS patients completely and objectively, with results correlated with significant clinical variables.

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Clinical Outcome Measures Poster Presentation

P0183 - Wearable technologies: where can we focus on next in Multiple Sclerosis? (ID 1126)

Speakers
Presentation Number
P0183
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Wearable technology refers to any sensor worn on the person, which as a result makes continuous and remote monitoring available to many people with chronic diseases, including multiple sclerosis (MS). Daily monitoring seems an ideal solution either as an outcome measure or as an adjunct to support rater-based monitoring in both clinical and research settings. There has been an increase in solutions that are available and we look to identify next generation wearables.

Objectives

To identify all validated wearable solutions for PwMS and identify areas of focus for wearable solutions in multiple sclerosis.

Methods

We completed a scoping review (using the PRISMA-ScR guidelines) to summarise the wearable solutions currently available in MS.

Our search strategy utilized subject heading searches: ‘Multiple Sclerosis’ and ‘wearable electronic devices’, as well as keywords ‘wearable technology’, and ‘electronic devices’. The literature search was conducted using MEDLINE (via PubMed) and Embase (via OVID) databases. This search included articles published from database inception to 30 May 2019. Additional searches looked at frequently published authors with different devices, as well as forward and backward citation tracking of included papers.

Results

We identified 35 validated unique solutions that measure gait, cognition, upper limb function, activity, mood and fatigue with most of these solutions being phone applications. Of these, 51% looked at lower limb function with activity levels being looked at by 37% of the total solutions. There was least focus on visual, and mood solutions at 3%, closely followed by quality of life and balance at 5%. Cognition and fatigue accounted for 14% of the total.

Conclusions

Looking forward, there is a change occurring from single measure solutions to multi-measure and multi-sensor solutions, such as the Floodlight Open app, which utilises multiple sensors within a smart-phone to remotely measure gait, cognition and upper limb function. Future research should consider costs and include implementation science as part of their research and design to ensure cost of delivery strategy is also accounted for.

As development in wearable technology in MS is still on-going, we can expect to see newer wearables focusing on other areas with technology advancements that allow for more upper body and cognitive measures. There is a dearth of validated solutions available for fatigue, mood, and pain.

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Clinical Trials Poster Presentation

P0184 - A novel approach to conducting Phase IV studies: The design of the global diroximel fumarate EXPERIENCE study initiative (ID 1313)

Speakers
Presentation Number
P0184
Presentation Topic
Clinical Trials

Abstract

Background

Diroximel fumarate (DRF) is an oral fumarate recently approved in the United States for relapsing forms of multiple sclerosis (MS). DRF demonstrated favorable gastrointestinal (GI) tolerability in clinical studies of MS patients (pts). Discontinuations due to GI adverse events (AEs) were low (0.7%) in an open-label 2-year study. In a randomized study versus dimethyl fumarate (DMF), fewer pts reported GI AEs (35%, 88/253 DRF vs 49%,123/251 DMF) and GI AEs leading to discontinuation (0.8% DRF vs. 4.8% DMF); GI AEs were less frequently reported as moderate/severe for DRF (23%, 20/88) vs DMF (40%, 49/123). It is important to characterize DRF persistence in a real-world setting and effectiveness across different patient types and geographies.

Objectives

To describe the novel design of the DRF EXPERIENCE (EXPloring diroximEl fumarate Real-world experIENCE) Study Initiative.

Methods

A Phase IV DRF study should collect data on meaningful real-world outcomes, including treatment persistence, real-world tolerability, and clinical effectiveness, including cognitive changes, to align with evolving treatment goals. As DRF was designed to reduce treatment burden, impact on quality of life should also be assessed. Country-specific nuances due to unique healthcare environments, ethnicity, and cultural considerations diminish the utility of a single-study design.

Results

The DRF EXPERIENCE Study Initiative uses a novel design comprising 4 individual studies, each conducted in different regions but anchored by a core protocol to characterize the early experience in pts initiating DRF per routine care. The core protocol defines a set of required assessments for each study, but also allows flexibility to include others that address country-specific research questions. The primary objective is to characterize persistence to DRF at 1 year. Core protocol assessments include relapse, disability, cognitive changes, and pt-reported Neuro-QoL. Each study will enroll ~200 pts; the pooled total sample size of ~800 will improve ability for subgroup analyses. Pts will be followed for 2 years and include those newly initiating a disease modifying therapy (DMT) or switching from previous DMTs (including prior DMF).

Conclusions

The DRF EXPERIENCE Study Initiative uses a novel design to characterize the improved GI tolerability profile and effectiveness of DRF in MS pts in the real-world and will be informative to providers and patients when considering MS treatment goals together with the burden of therapy.

Supported by: Biogen

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Clinical Trials Poster Presentation

P0185 - A phase II randomised controlled trial of a cognitive behavioral therapy intervention for depression in those newly diagnosed with MS (ID 1578)

Speakers
Presentation Number
P0185
Presentation Topic
Clinical Trials

Abstract

Background

Depression is a serious and co-morbid condition of MS. Up to 50% of individuals with MS experience clinically significant levels of depressive symptoms at any one time (Arnett et al., 2008). Depression and anxiety are especially high after diagnosis (Giordano et al., 2011; Kiropoulos et al., 2016) with 36% of individuals found to report high levels of depressive symptoms in the first years after diagnosis (Jensens et al., 2003). Cogntitive Behaviour Therapy (CBT) has shown to be effective in reducing symptoms of depression in those with MS (Kiropoulos et al., 2016) with the current study being the first RCT examining the effectiveness of a tailored cognitive behavioural therapy (CBT) intervention, compared to a supportive listening (SL) intervention, for depression in those who have been newly diagnosed with MS (within 5 years of having received a MS diagnosis).

Objectives

To assess efficacy of an early tailored CBT intervention, compared to SL, in producing significant and clinically meaningful reductions in: 1) depressive symptoms; 2) anxiety symptoms and 3) MS-related concerns (such as fatigue, sleep disturbance, pain impact). And to: 4) increase physical and mental health related quality of life, MS illness acceptance, social support, coping and resilience; and 5) to assess cost-effectiveness of providing the CBT intervention. An additional aim is to measure and examine changes in levels of cytokines before and after the interventions.

Methods

This is a two arm, parallel group, active comparator, assessor blinded RCT with the primary site being the Royal Melbourne Hospital. Recruitment is also being undertaken from three major MS clinics located in Melbourne, Victoria. 60 participants are being randomly allocated to a tailored CBT(n=30) or SL (n=30) intervention. 8 x 1 hour interventions will be delivered over 8 weeks by clinical psychologists for both treatment arms. Self-report and clinician data is and will be collected at pre, post and 3 mth follow up time points. Eligibility criteria includes mild to moderately depressed individuals newly diagnosed (within first 5 years of diagnosis) with MS. Exclusion criteria includes gross cognitive impairment; serious psychological disorder; delirium; undertaking psychological treatment for depression; unable to speak or read English.

Results

Preliminary results will be presented for the primary outcome which is the level of clinically significant change of 10 points or more on the BDI-2 at post therapy, secondary outcomes which are the level of depression at 3 mths and level of anxiety at post-assessment and tertiary outcomes which are the level of anxiety at 3 mths follow up, pain and fatigue impact, MS illness acceptance, sleep quality, coping, social support, resilience at post and 3 mth follow up.

Conclusions

Conclusions will be provided relating to the effectiveness of the CBT intervention in the treatment of depression in individuals newly diagnosed with MS.

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Clinical Trials Poster Presentation

P0186 - A Phase 1 study of BIIB091, a Bruton’s tyrosine kinase (BTK) inhibitor, in healthy adult participants: preliminary results (ID 390)

Abstract

Background

Bruton’s tyrosine kinase (BTK) is a key signalling node downstream of the B‑cell receptor (BCR) in B cells and Fc receptors (FcRs) in myeloid cells. Selective BTK inhibition may be beneficial for the treatment of MS by preventing B-cell and myeloid cell activation without immune cell depletion. BIIB091 is an orally active, selective, reversible (noncovalent), small molecule inhibitor of BTK in Phase 1 clinical development for the treatment of MS.

Objectives

Assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of BIIB091 in healthy adult participants.

Methods

This was a Phase I, randomized, double-blind, placebo-controlled, single ascending dose (SAD) and a multiple ascending dose (MAD) study in healthy adult participants (NCT03943056). Admitted participants were randomly assigned to BIIB091 or placebo (6:2). Participants received study drug orally at single dose levels of 50, 150, 300, 600, or 1200 mg in the fasted state during the SAD part. Participants completing 300 mg fasted dosing continued into a second period and received single dose 300 mg with a high fat meal. A separate group of participants enrolled in the MAD part and received doses of 50, 150, or 300 mg twice daily (BID) for 13 days, and a single dose on the morning of day 14. Safety (adverse events [AEs], vital signs, electrocardiograms [ECGs] and laboratory abnormalities), tolerability, and PK measures were assessed. The trial was ongoing as of February 2020. Preliminary results summarized here are based on a blinded data cut-off as of 20 Dec 2019, and include completed SAD cohorts, and 2 of 3 planned MAD cohorts.

Results

56 participants enrolled in the study (n=40 in SAD, n=16 MAD) and contributed to this analysis as of the data cut-off date. No deaths, serious AEs, severe AEs, cardiac related AEs, or AEs leading to study discontinuation were observed. All AEs were mild in severity. No clinically relevant changes in vital signs were reported as of the data cut-off date. BIIB091 PK was approximately dose linear, with median time to maximum plasma concentration ranging from approximately 0.8 to 1.4 hours after fasted dosing in SAD cohorts, with modest accumulation after multiple dosing. Food reduced Cmax variability and increased AUC.

Conclusions

BIIB091 was well tolerated at single doses up to 1200 mg. No dose limiting clinical AEs were identified in the MAD as of the data cut-off. Complete study results will be described in the poster. Preliminary safety and PK profile supports continued development of BIIB091 for the treatment of MS.

Supported by: Biogen

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Clinical Trials Poster Presentation

P0187 - A prospective randomized open-label blinded endpoint multicenter non-inferiority study of oral cladribine and rituximab in Multiple Sclerosis (NOR-MS) (ID 1194)

Abstract

Background

Both induction therapy, like oral cladribine, and B-cell depletion therapy, like rituximab, are highly effective disease modulatory treatments (DMTs) in relapsing multiple sclerosis (MS). The high economic costs of the registered DMTs may limit availability of treatment and strain health budgets worldwide.
Oral cladribine is a recently approved DMT in Europe, while rituximab is used off-label, especially in Norway and Sweden. Large observational studies indicate good tolerance and treatment effects in MS and studies from other diseases indicate a good safety profile. However, to our knowledge, no phase three studies have compared rituximab with any established highly effective DMT. Formal safety data is also lacking for rituximab treatment in MS.

Objectives

To perform a prospective randomized open-label blinded endpoint multicenter non-inferiority study. The primary objective is to test whether rituximab is non-inferior to oral cladribine for treatment of relapsing MS.

Methods

In total 264 MS patients with relapsing MS will be recruited from 11 Norwegian centers and followed for 96 weeks. Inclusion criteria are having a relapsing MS diagnosis, age 18-65 years, at least one clinical relapse or one new T2 lesion on MRI within the last year and willingness to use contraception during the study period. Exclusion criteria are contraindications to either treatment, previous use of either or a similar treatment, or treatment with fingolimod or natalizumab (due to risk of rebound activity) within the last six months. The study participants will be treated with either cladribine or rituximab according to current guidelines.

Results

The primary endpoint is difference in number of new or enlarging T2 lesions between the two groups from rebaseline at 12 weeks to the end of the study at 96 weeks. Furthermore, we will study clinical course, blood samples and MRI biomarkers to provide tools for personalized MS treatment. Finally, the health economic consequences of these treatment options will be evaluated. At the time of abstract submission, 55 patients have been included across three study sites. The Covid19 outbreak unfortunately resulted in a temporary halt in inclusion from March to May 2020, but the study has now been reopened. End of study is estimated to fall 2023.

Conclusions

This study will guide clinicians and patients in future treatment choices for MS. The results will provide valuable knowledge concerning treatment strategies and can potentially have a huge impact on the costs of future MS treatments.

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Clinical Trials Poster Presentation

P0188 - A Tablet-Based Cognitive Battery to Assess Cognitive Function in People with MS: Sensitivity to Change in A Randomized Controlled Trial (ID 270)

Speakers
Presentation Number
P0188
Presentation Topic
Clinical Trials

Abstract

Background

Cognitive impairment (CI) is one of the most debilitating manifestations of multiple sclerosis (MS), and digital tools provide promising approaches to overcoming barriers to access to cognitive remediation. Developing reliable, unsupervised tools is an unmet need.

Objectives

To determine the validity and efficacy of a novel digital tool to both query cognitive impairment in MS and capture sensitivity to change after cognitive remediation.

Methods

Fifty-three participants with MS (24 with CI and 29 without CI) and 24 non-MS participants were assessed with a tablet-based cognitive battery (Adaptive Cognitive Evaluation, ACE) and standard cognitive measures: Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). Associations between performance in ACE and SDMT/PASAT were explored, with group comparisons to assess if ACE modules can capture group-level differences. All 53 MS participants were then randomized to complete either a tablet-based, closed-loop digital therapeutic delivered through a video game-like interface (AKL-T03, N=27) or a control game (AKL-T09, N=26) at home for 25 minutes a day, 5 days a week, for 6 weeks. ACE assessment was repeated post-treatment. The primary outcome was performance on an attention task of ACE.

Results

Correlations between performance in SDMT/PASAT and ACE were observed (SDMT vs. ACE: R=-0.57, p<0.001; PASAT vs. ACE: R=-0.39, p=0.005). Compared to non-MS and non-CI MS participants, CI MS participants showed a slower reaction time (p=0.001) and a higher attention cost (p=0.001). Unlike the active control program, the AKL-T03 treatment program significantly improved attention task performance in MS by showing a reduced reaction time from pre- to post-treatment (p<0.001).

Conclusions

These results suggest that ACE, an adaptive, tablet-based cognitive battery, could provide reliable unsupervised cognitive assessment for people with MS. They also support our prior findings that AKL-T03 is an effective home-based cognitive remediation program for MS.

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Clinical Trials Poster Presentation

P0189 - AQP4-IgG seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder (ID 1288)

Abstract

Background

The N-MOmentum trial of inebilizumab included patients with aquaporin 4-IgG seropositive (AQP4+) or seronegative (AQP4−) neuromyelitis optica spectrum disorder (NMOSD).

Objectives

To report AQP4− participant outcomes in N-MOmentum. .......................................................

Methods

Medical histories and screening data for AQP4− patients were assessed independently by 3 clinical experts before enrollment. Majority decision confirmed diagnoses using the 2006 criteria. Myelin oligodendrocyte glycoprotein-IgG (MOG) serology and annualized attack rates (AARs) were tested post hoc. These observations do not account for bias in estimates of effects on the AAR caused by regression to the mean, introduced by inclusion criteria requiring attacks during the 1 to 2 years before study entry.

Results

Only 18/50 AQP4− patients (36%) were eligible for randomization; 17 were randomized, 4 to placebo (1 MOG+) and 13 to inebilizumab (6 MOG+). Reasons for not enrolling prospective AQP4− NMOSD participants were mainly related to lack of fulfillment of MRI findings required by the 2006 criteria.

Owing to limited patient numbers, we compared the on-study to the pre-study AAR for treated participants to assess treatment effects.

For AQP4− participants (n=17), 40 attacks occurred in 23 patient-years of pre-study follow-up with mean AAR (95% confidence interval) of 1.72 (1.23–2.33). For MOG+ participants (n=7), 16 attacks occurred in 8.3 patient-years of pre-study follow-up with an AAR of 1.93 (1.11–3.14). For double-seronegative participants (n=10), 24 attacks occurred in 15 patient-years of pre-study follow-up with an AAR of 1.60 (1.02–2.38).

After receiving inebilizumab, AARs declined in all groups by the end of the randomized controlled period: AQP4− participants (n=13), 0.09 (0.02–0.26), or 3 attacks in 34.2 patient-years; MOG+ participants (n=6), 0.08 (0.002–0.464), or 1 attack in 12 patient-years; double-seronegative participants (n=7), 0.09 (0.011–0.326), or 2 attacks in 22 patient-years.

The benefit was sustained with longer-term inebilizumab exposure. At 120 days into the open-label period (OLP), during which all participants received inebilizumab, the AAR in AQP4− participants (n=17) remained low (0.069 [0.014–0.202]). No attacks were seen in any AQP4−, MOG+ or double seronegative patient during the OLP.

Conclusions

The N-MOmentum trial provides clinically important insight on the difficulty of correctly diagnosing AQP4− NMOSD and suggests that inebilizumab may have a benefit on AAR in these patients.

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Clinical Trials Poster Presentation

P0190 - ASPIRE Study: Protocol for a double-blind RCT of aspirin for overheating during exercise in MS (ID 666)

Speakers
Presentation Number
P0190
Presentation Topic
Clinical Trials

Abstract

Background

Background Exercise holds many benefits for persons with multiple sclerosis (MS), yet many MS patients are heat sensitive and therefore avoid exercise due to overheating and exhaustion that result. The exercise literature in MS to date is likely subject to bias by predominant representation of patients who are not heat sensitive and may not be a representative sample. Finding ways to facilitate comfortable engagement in exercise for persons with MS is a key priority. Our pilot trial of aspirin as a cooling pretreatment for exercise in MS showed favorable results: after aspirin, participants who experience overheating during exercise were able to exercise longer and the amount of body temperature increase they experienced was reduced by 56%.

Objectives

Objective Conduct a large-scale double-blind randomized controlled trial of aspirin (acetylsalicylic acid, ASA) pretreatment as a convenient and inexpensive method to prevent overheating and improve exercise performance in persons with MS, compared to placebo and acetaminophen.

Methods

Methods Participants are seen for three separate sessions (separated by at least one week) for a laboratory maximal exercise test. At each session, body temperature is measured tympanically before oral administration of a standard adult dose (650 mg) of aspirin, acetaminophen (APAP), or placebo. Participants then perform a maximal ramp test on a cycle ergometer. Primary outcomes are (a) time to exhaustion (TTE, i.e., time spent cycling to peak exertion) and (b) body temperature change. Secondary outcomes include patient reported outcomes including pain, fatigue, and mood. Cross-over analyses will include tests for effects of treatment, period, treatment–period interaction (carryover effect) and sequence.

Results

Results Enrollment in the ASPIRE trial was begun in February 2019. Adherence and acceptability of the treatment are high. To date, 35 participants have been enrolled; of these, 16 have completed all 3 study visits. There have been 6 drop-outs and 7 non-serious adverse events. Heterogeneity of sample is notable, with 26% men, 9% Black, 6% Hispanic/Latinx. Study data will not be unblinded until completion of all participants (target N=60).

Conclusions

Conclusions Exercise is highly beneficial for persons with MS, but only if they do it. Positive findings from this trial would yield an effective, inexpensive, readily available, unobtrusive treatment to allow many more persons with MS access to the benefits of exercise via a cooling mechanism. Thus far, enrollment and adherence in the ASPIRE trial, as well as diversity of our sample suggest good acceptibiliity of aspirin as a treatment, and favorable generalizability of trial results.

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Clinical Trials Poster Presentation

P0191 - Autologous Stem Cell Transplantation versus Alemtuzumab or Ocrelizumab in Relapsing Remitting Multiple Sclerosis (StarMS) (ID 359)

Speakers
Presentation Number
P0191
Presentation Topic
Clinical Trials

Abstract

Background

In recent years, autologous haematopoietic stem cell transplantation (aHSCT) has been increasingly used to treat patients with highly-active relapsing remitting multiple sclerosis (RRMS) who failed disease modifying therapies (DMTs). Observational and limited clinical trial data suggest that aHSCT reduces relapse rates, improves disability and enhances quality of life to a greater degree than most DMTs. There is now a need to compare aHSCT with the two most efficacious DMTs: Alemtuzumab and Ocrelizumab.

Objectives

StarMS aims to determine whether aHSCT has superior clinical efficacy to Alemtuzumab and Ocrelizumab with an acceptable safety profile. Mechanistic studies will assess immune re-constitution which will enhance understanding of the biological mechanisms of these treatments. Other sub-studies will assess their effect on cognitive recovery, neurofilament light and retinal nerve fibre layer measurements as markers of neuronal damage, and the safety of re-vaccination post-aHSCT.

Methods

This National Institute for Health Research (NIHR) funded parallel-group rater-blinded RCT will randomise 198 patients (1:1) to aHSCT versus DMT (Alemtuzumab or Ocrelizumab) from 19 centres across the UK. The primary endpoint, no evidence of disease activity (NEDA) rate, will be assessed throughout the 2-year follow-up period.

Results

Results are expected to be available in approximately 4 years’ time. Results will be published in peer-reviewed academic journals, presented at relevant conferences, and disseminated via patient groups as applicable.

Conclusions

The StarMS trial has the potential to provide definitive data on the comparative efficacy of aHSCT vs highly efficacious DMTs, help improve patient outcomes, and impact national and international guidelines.

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Clinical Trials Poster Presentation

P0192 - Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients (ID 1601)

Speakers
Presentation Number
P0192
Presentation Topic
Clinical Trials

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody with a monthly 20 mg s.c. dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in the Phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials.

Objectives

To evaluate the benefit-risk profile of ofatumumab treatment in patients with early RMS in the Phase 3 ASCLEPIOS I/II trials.

Methods

Key efficacy and safety outcomes were assessed in the subgroup of 615 newly diagnosed (within 3 years before screening), treatment-naïve (no prior disease-modifying therapy [DMT] use) patients who received ofatumumab or teriflunomide as a first-line therapy in ASCLEPIOS I/II trials (32.7% of the total 1882 patients).

Results

Baseline characteristics of the newly diagnosed, treatment-naïve subgroup were typical of early MS patients (median age and MS duration since diagnosis (years) were 36 and 0.35, respectively). Compared to patients on teriflunomide, ofatumumab reduced ARR by 50.3% (0.09 vs 0.18; p<0.001), 3mCDW risk by 38% (10.1% vs 12.8%; p=0.065), 6mCDW risk by 46% (5.9% vs 10.4%; p=0.044), gadolinium-enhancing T1 lesions/scan by 95.4% (0.02 vs 0.39: p<0.001), and new/enlarging T2 lesions/year by 82.0% (0.86 vs 4.78, p<0.001). Treatment-emergent adverse events (AEs) occurred in 84.7% ofatumumab vs 86.0% teriflunomide-treated patients; serious AEs were reported in 7.0% and 5.3%, respectively. No cases of malignancies were reported in this newly diagnosed subgroup, randomized to either drug. Infection rates were comparable between ofatumumab (56.1%) and teriflunomide (56.5%); serious infections rates were 1.9% and 0.7%, respectively, and no opportunistic infections were reported. Systemic injection reactions were only imbalanced between ofatumumab and teriflunomide (with placebo injections) at the first injection given at the study site, and 99.8% of injection reactions were mild-to-moderate in this subgroup; after the 4th injection, >70% RMS patients self-injected at home. Compliance of all patients with ofatumumab was high (98.8%).

Conclusions

Ofatumumab is the first high efficacy DMT that can be self-administered at home, as demonstrated in Phase 3 ASCLEPIOS I/II trials. Ofatumumab showed superior efficacy vs teriflunomide in newly diagnosed, treatment-naïve patients with low absolute relapse rates, very low MRI lesion activity and prolonged time to disability worsening, consistent with the overall study population.

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Clinical Trials Poster Presentation

P0193 - BEST-MS: A standardized and prospective study comparing the efficacy of natalizumab versus fingolimod in active relapsing multiple sclerosis (ID 237)

Abstract

Background

Therapeutic options are growing for active RRMS patients, however, few prospective studies are available to compare the efficacy of those treatments. Best Escalation Strategy in MS (BEST MS) started in France in 2013 when natalizumab (NTZ) and fingolimod (FTY) were the two most employed second-line therapies in active RRMS.

Objectives

To compare the efficacy between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting multiple sclerosis (RRMS).

Methods

BEST-MS is a French prospective multicentric study.

Patients with active RRMS (defined as at least 1 relapse in the last 12 months on a well-conducted 1st line treatment with at least 9 T2 hyperintensities on MRI, OR at least 2 relapses in the last 12 months with evidence of active disease on MRI for naïve patients) were enrolled to be treated either with NTZ or FTY. Treatments choice was at the discretion of the physician.

Relapses, EDSS and brain MRI were collected at baseline and at 12 months.

The main outcome measure was the proportion of patients reaching No Evidence of Disease Activity (NEDA) at 12 months, defined as the absence of relapses, absence of new T2 lesions, absence of new gadolinium enhancing lesions and a stable EDSS score.

Results

230 patients were included (age: 38.2 yrs, F/M: 3.1, FTY: 117, NTZ: 113). There was no statistical difference between groups regarding baseline characteristics.

Treatment drop out rate was higher in FTY group (22% vs 12%, p<0.0001) and most of thoses cases were related to a lack of efficacy.

At M12, 43% of patients treated with NTZ reached NEDA versus 27% in the FTY group (p=0.04)

NTZ indicated a better efficacy regarding new T2 lesions (0.7 vs 1.4, p=0.01) and gadolinium enhancing lesions (0.03 vs 0.5, p<0.0001).

Relapse rate (ARR) was lower in NTZ group (0.2 vs 0.27, p = 0.04), even if most relapses occurred during the first 4 months of treatment in both groups.

Conclusions

NTZ showed higher efficacy than FTY on MRI in active RRMS patients. ARR was also lower in favor of NTZ, but most relapses occurred early. However, the rate of drop out was higher for patients treated with FTY.

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Clinical Trials Poster Presentation

P0194 - Cardiac Safety of Ponesimod in Relapsing Multiple Sclerosis in the Randomized, Active-Controlled, Double-Blind, Parallel-Group Phase 3 OPTIMUM Study (ID 565)

Abstract

Background

Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator. Activation of these receptors on cardiomyocytes during treatment initiation cause transient effects on heart rate (HR) and antrioventicular (AV) conduction. The OPTIMUM phase 3 study assessed efficacy, safety, and tolerability of PON and teriflunomide (TER) in relapsing multiple sclerosis.

Objectives

We report on the cardiac safety profile of ponesimod versus teriflunomide in the phase 3 OPTIMUM study (NCT02425644).

Methods

Patients (18-55 years) were randomized 1:1 to PON (20 mg) or TER (14 mg) for 108 weeks. For PON, a gradual 14-day up-titration starting with 2 mg was implemented to address 1st-dose cardiac effects. Cardiac safety was assessed by blood pressure (BP) and 12-lead ECG measurements. Cardiac treatment-emergent adverse events (TEAEs), major adverse cardiovascular (CV) events (MACE; defined as CV death, non-fatal myocardial infarction [MI], and non-fatal stroke), and TEAEs of special interest (AESIs) are reported.

Results

Of 1131 patients who received treatment (PON: n=565, TER: n=566), baseline mean HR was 70.6 bpm (PON), 70.3 bpm (TER), range 45-126 bmp. Cardiac TEAEs leading to treatment discontinuation occurred in 1 (0.2%) patient on PON (cardiomyopathy) and 2 (0.4%) patients on TER (1 atrial fibrillation, 1 coronary artery insufficiency). No MACE were reported on PON; 3 MACE occurred on TER. HR and rhythm AESIs were reported in 29 (5.1%) PON patients vs. 24 (4.2%) TER patients. Incidence of HR and rhythm AESIs on Day 1 in the PON group (2 mg) was 2.1%, and included bradycardia (HR<50bpm) in 0.7% and 1st degree AV block in 0.5%; vs. 0.4% in TER. Max mean reduction in HR from pre- to post-dose on Day 1 was observed at 2h post-dose for PON at -8.7bpm compared with -1.7bpm for TER. On Day 1, 3 patients on PON had post-dose asymptomatic HR≤40bpm, all had pre-treatment HR<55bpm. On Day 1, new ECG findings of sinus bradycardia was 20.0% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0% (all asymptomatic) in patients who were not at-risk. The up-titration was not associated with clinically significant bradyarrhythmia events; none were serious or leading to discontinuation of treatment, no 2nd degree or higher AV blocks were reported.

Conclusions

In the 2-year OPTIMUM study, PON treatment was not associated with an increased risk for major CV events such as MI, stroke, or CV death compared to TER. The up-titration regimen successfully mitigates 1st-dose effects and supports removing the requirement for 1st-dose cardiac monitoring in patients without risk factors of symptomatic bradycardia.

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Clinical Trials Poster Presentation

P0195 - Characteristics of Therapeutic Sequences of Patients Enrolled in the PRO-MSACTIVE Study Evaluating Ocrelizumab in Active Relapsing Multiple Sclerosis (ID 727)

Speakers
Presentation Number
P0195
Presentation Topic
Clinical Trials

Abstract

Background

At any time in multiple sclerosis (MS) management, a disease-modifying therapy (DMT) stop, restart or change can occur. In PRO-MSACTIVE (NCT03589105), an open-label, single-arm, phase IV study designed to evaluate the efficacy, safety and impact of ocrelizumab on patient reported outcomes in patients with active relapsing MS (RMS), every patient’s treatment history was gathered.

Objectives

To describe the therapeutic management of French patients with active RMS (relapsing-remitting [RRMS] and secondary progressive [SPMS]), as reported at baseline, prior to the first ocrelizumab infusion (IV OCR).

Methods

PRO-MSACTIVE is being conducted in France (46 active centers) in patients with active RMS, ≥18 years old, naïve or pretreated with DMT. Washout periods between the last DMT taken by the patient and baseline IV OCR were pre-specified. For each patient, all previous DMTs were collected during the screening period, ≤4 weeks prior to baseline.

Results

Treatment history was documented for the 422 enrolled patients: 376 RRMS and 46 SPMS. Most (74.9%) had at least one previous DMT prior to the first IV OCR: 73.9% for RRMS and 82.6% for SPMS patients. The longest therapeutic sequence includes 8 DMTs prior to the first IV OCR. The most frequent previous DMTs were β interferons and assimilated products (IFN-AP) (51.4% all patients, 49.2% RRMS, 69.6% SPMS); selective oral immunosuppressants (30.8% all patients, 30.6% RRMS, 32.6% SPMS; mainly fingolimod); and teriflunomide (24.2% all patients, 24.5% RRMS, 21.7% SPMS). IFN-AP ranked first among the older DMTs (46.5% all patients, 45.0% RRMS, 58.7% SPMS). Mean time (standard deviation, SD) from the oldest DMT to the first IV OCR was 6.55 yrs (5.44) for RRMS patients, and 14.20 yrs (8.46) for SPMS patients. The most recent DMTs prior to IV OCR were fingolimod (22.8% all patients, 23.7% RRMS, 15.2% SPMS); dimethyl fumarate (14.7% all patients, 15.7% RRMS, 6.5% SPMS); teriflunomide (14.5% all patients, 14.6% RRMS, 13.0% SPMS); IFN-AP (14.0% all patients, 14.1% RRMS, 13.0% SPMS); and natalizumab (4.3% all patients, 4.5% RRMS, 2.2% SPMS). Mean time (SD) from the most recent DMT to the first IV OCR was 2.65 yrs (2.12) for RRMS patients and 3.01 yrs (2.85) for SPMS patients.

Conclusions

Treatment history with DMTs prior to the first IV OCR is well characterized in the PRO-MSACTIVE study. These data permit a better understanding of the therapeutic strategies in RMS patients in current medical practice.

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Clinical Trials Poster Presentation

P0196 - Cladribine to halt deterioration in people with advanced multiple sclerosis (ChariotMS) (ID 585)

Abstract

Background

Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.

Objectives

Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.

Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T2 lesion burden, (iv) hypo-intense lesions on T1 weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.

Methods

Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.

Results

Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.

Conclusions

ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.

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Clinical Trials Poster Presentation

P0197 - Clinical relapse rates in relapsing MS patients treated with the BTK inhibitor evobrutinib: results of an open-label extension to a Phase II study (ID 1127)

Speakers
Presentation Number
P0197
Presentation Topic
Clinical Trials

Abstract

Background

Evobrutinib (EVO) is a highly selective Bruton’s tyrosine kinase inhibitor (BTKI) with a dual mode of action targeting both B cells and myeloid cells, which are known to play a key role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Clinical efficacy of EVO in relapsing MS was shown in a Phase II randomized controlled trial (RCT; NCT02975349) with a significant reduction of T1 Gd-enhancing lesions compared to placebo at Week 24 (the primary endpoint of the study) and continued efficacy through Week 48.

Objectives

To report the long-term efficacy of EVO measured as the annualized relapse rate [ARR]), cumulative probability of and time to qualified relapse (QR, change in neurological symptoms or expanded disability status scale score increase attributed to MS lasting ≥24 hours preceded by a stable or improving neurological status ≥30 days).

Methods

In the 48-week double-blind period (DBP), patients received EVO 25mg once daily (QD), 75mg QD, 75mg BID or placebo (PBO) for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except PBO patients who were switched to EVO 25mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75mg QD (for a median of ≈48 weeks) before switching to 75mg BID. Long-term efficacy of EVO was assessed at up to 60 weeks of OLE.

Results

Of 213 patients randomized to EVO or PBO, 164 (77%) entered the OLE; of these 148 (90%) completed 108 weeks of treatment. For patients initially receiving PBO or EVO 25mg QD, 75mg QD or 75mg BID in the DBP, ARR (95% CI) was 0.37 (0.21, 0.59), 0.52 (0.33, 0.78), 0.25 (0.12, 0.44) and 0.11 (0.04, 0.25), respectively, at Week 48, and 0.31 (0.21, 0.45), 0.37 (0.25, 0.52), 0.18 (0.10, 0.29) and 0.12 (0.06, 0.22) at Week 108. The cumulative probability of QR in these groups was 0.26 (0.14, 0.38), 0.24 (0.12, 0.36), 0.15 (0.05, 0.25) and 0.08 (0.00, 0.16) at Week 48, and 0.39 (0.25, 0.53), 0.34 (0.20, 0.48), 0.25 (0.12, 0.38) and 0.20 (0.08, 0.31) at Week 96, respectively. The estimated time from randomization by which 20% of patients had a qualified relapse was almost three times longer for patients initiated in the DBP with EVO 75mg BID (827 days [327, not evaluable]) than for patients initiated in the DBP with PBO (281 days [99, 407]) and longer than for patients initiated in the DBP with EVO 25mg QD (166 days [61, 606]) and 75mg QD (530 days [244, 838]). EVO was generally well tolerated, with the safety profile maintained during the 60-week OLE.

Conclusions

With EVO 75mg BID, the efficacy (ARR, 0.11) at Week 48 was maintained at 108 weeks. Probability of and time to QR highlighted that, despite switching to EVO 75mg QD/BID in OLE, patients initiated in the DBP on EVO 25mg QD, 75mg QD or PBO did not achieve the same level of efficacy of those initiated in the DBP on 75mg BID. The maximum efficacy observed at the 75mg BID dose correlated with optimal BTK occupancy achieved with BID dosing.

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Clinical Trials Poster Presentation

P0198 - Comparative effectiveness of different DMT strategies in new onset RRMS; First results of the CombatMS trial (ID 1812)

Speakers
Presentation Number
P0198
Presentation Topic
Clinical Trials

Abstract

Background

Increasing evidence suggest that early initiation of highly effective disease modulatory therapies (DMTs) reduce disability progression in relapsing-remitting MS (RRMS), but few studies strive to identify the most successful DMT strategy for new onset RRMS by also including drug survival. The CombatMS study is a Swedish nationwide observational drug trial involving all Sweden´s University Clinics (NCT03193866).

Objectives

To compare effectiveness of different DMT strategies for early RRMS, defined as treatment start latest two years after symptom onset.

Methods

The CombatMS population comprises 3500 RRMS patients starting a first DMT or doing a first DMT switch between Jan 1st 2011 to Oct 31st 2018, who from study start (June 2017) undergo an annual structured follow up with EDSS, patient reported outcomes and imaging. For this study we selected patients aged 18 to 50 years starting a first DMT within two years from symptom onset with a previously registered EDSS score 12 months before or 2 months after treatment start. We restricted the analysis to the four most frequent DMT choices in this category: interferons (INF), natalizumab (NTZ), dimethyl fumarate (DMF) and rituximab (RTX), resulting in total study population of 954 patients. We used an ever-treated approach, disregarding if the patient later switched or stopped therapy. Two-year disability progression was determined by comparing the baseline EDSS score to the EDSS score closest to two years, while relapse rate and drug survival were measured for a two-year follow-up period from treatment start.

Results

The proportion of patients experiencing disability progression was 7.3 % (NTZ), 7.6 % (RTX), 12.4 % (DMF) and 19.2 % (INF). After adjusting for baseline differences in age, sex, region of residence, baseline EDSS, relapse rate before DMT start, and follow-up time, only the difference between RTX and INF remained significant. Two-year drug survival ranged from 38.3 % (INF) to 92.4 % (RTX), with these two extremes being significantly different from all other DMTs. Annualized relapse rates varied from 0.04 (RTX) to 0.27 (INF), with significant difference between all other DMTs and INF and between RTX and DMF.

Conclusions

We observe relatively large differences in two-year outcomes across the studied DMTs, where the most striking findings are that patients initiating INF perform worse and those starting RTX better in most comparisons. Longer observation times will be needed to inform on risk-benefit with different DMT choices beyond two years.

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Clinical Trials Poster Presentation

P0199 - Declining to participate in a randomised controlled trial of a cognitive occupation-based program for people with multiple sclerosis. (ID 827)

Speakers
Presentation Number
P0199
Presentation Topic
Clinical Trials

Abstract

Background

The enhancement of recruitment strategies has become an important objective for many clinical trials and though research has investigated a variety of research design manipulations in this respect, there is a dearth of research on the perspectives of those who decline participate. Such exploration is also important to consider given that those who decline is often not accounted for in terms of accurately representing the population under investigation. Though this ‘flaw’ is inherent in all research that studies human participants, enhanced efforts to diminish decline and increase recruitment is not only important for statistical purposes, but also for strengthening the validity of conclusions regarding implementation in ‘real-world’ scenarios.

Objectives

To explore individuals’ decisions to decline participation in research trialling a Cognitive Occupation-Based program for people with MS (COB-MS) thus, informing feasibility assessment of the trial; and to extend research on recruitment to randomised controlled trials, more generally.

Methods

Seven semi-structured telephone interviews were conducted with willing participants who had previously declined to participate in COB-MS. Data were examined through thematic analysis, via an iterative, recursive process; characterised by continual re-reading of the data, data coding and thematic identification (e.g. development of categories/themes and hierarchical ordering). Thematic analysis facilitated the exploration of potentially important factors that required consideration in an under-researched topic. Subsequently, findings were presented to the public and patient involvement (PPI) panel for consultation regarding the implications of these findings.

Results

Results are presented and discussed in light of extant theory and research. Preliminary results suggest that reasons for declining may include misinterpretation of the participant information sheet, feelings regarding appropriateness of their candidacy for COB-MS, inability to commit to the COB-MS program and particular issues regarding the design of the study and/or program. Including perspectives of PPI panel added valuable insights that supported fuller interpretation and ensured ‘trustworthiness’ to the data.

Conclusions

Though reasons for declining to participate can be many and diverse, some could be avoided through further consideration and ‘amendment’ during future trial development. Development of program-specific Patient & Public Involvement panels may be particularly useful in this context. Despite the numbers who declined to participate, the COB-MS trial was well received by those who did not participate, who expressed finding the program to be acceptable and accessible.

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Clinical Trials Poster Presentation

P0200 - Diroximel Fumarate in Patients With Relapsing-Remitting Multiple Sclerosis: Interim Safety and Efficacy Results From the Phase 3 EVOLVE-MS-1 Study (ID 435)

Speakers
Presentation Number
P0200
Presentation Topic
Clinical Trials

Abstract

Background

Diroximel fumarate (DRF) is a novel oral fumarate for relapsing forms of multiple sclerosis (MS). DRF is converted to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). Oral administration of DRF 462mg and DMF 240mg produce bioequivalent MMF exposure and are therefore expected to exhibit comparable efficacy and safety profiles. DRF has an improved gastrointestinal (GI) tolerability profile compared to DMF.

Objectives

To report interim safety, tolerability, and efficacy outcomes in DRF-treated patients from EVOLVE-MS-1 and to assess GI tolerability in a subgroup of patients who received DMF prior to DRF.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week study assessing DRF safety, tolerability, and efficacy in adults with relapsing-remitting MS. Patients entered the study either as newly enrolled in the DRF clinical development program or after completing EVOLVE-MS-2 (NCT03093324), a randomized, blinded, phase 3 study in which patients received DRF or DMF over 5 weeks.

Results

As of 2 July 2019, 1051 patients were enrolled, 458 of whom had completed EVOLVE-MS-2. Median DRF exposure was 1.5 (range 0.0-1.9) years. Overall, 44.2% of patients completed the study and 17.3% discontinued treatment; 6.3% discontinued due to AEs and 0.7% due to GI AEs. AEs occurred in 82.1% (863/1051) of patients; 90% (779/863) were mild or moderate in severity. Incidence of GI AEs was 28.4% (299/1051) in the overall population, 21.7% (51/235) in patients with prior DRF treatment, and 21.5% (48/223) in patients with prior DMF treatment. Patients who had experienced GI AEs in EVOLVE-MS-2 (DRF to DRF, 33.6% [79/235]; DMF to DRF, 44.8% [100/223]) had low rates of recurrence (3.4% [8/235] and 3.6% [8/223] for those previously treated with DRF and DMF, respectively) and/or onset of new GI AEs (19.6% [46/235] and 20.6% [46/223], respectively) in EVOLVE-MS-1, regardless of prior treatment group. In the overall population (n=1051), annualized relapse rate was 0.14, and 86.1% of patients were relapse-free. Outcomes in patients who were newly diagnosed or most recently switched from interferon or glatiramer acetate will be presented.

Conclusions

Safety and efficacy results from the ongoing EVOLVE-MS-1 study were consistent with previous findings of DRF and the known benefit-risk profile for DMF. In patients who switched from DMF to DRF, no worsening of tolerability was observed.

Supported by: Biogen

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Clinical Trials Poster Presentation

P0201 - Disability improvement in relapsing-remitting multiple sclerosis patients receiving cladribine tablets, evaluated by expanded disability status scale (ID 416)

Speakers
Presentation Number
P0201
Presentation Topic
Clinical Trials

Abstract

Background

In CLARITY, treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates and slowed disability progression versus placebo in RRMS patients. A key question is to evaluate whether and for how long cladribine tablets can improve EDSS scores.

Objectives

To evaluate post hoc long-term prevalence of disability improvement assessed by Expanded Disability Status Scale (EDSS) score in relapsing-remitting multiple sclerosis (RRMS) patients treated with cladribine tablets enrolled into CLARITY Extension.

Methods

Patients enrolled into CLARITY Extension were included and pooled by early (CT3.5 in CLARITY then CT3.5 or placebo in CLARITY Extension; n = 284), versus delayed (placebo in CLARITY then CT3.5 in CLARITY Extension; n = 244) treatment. Disability improvement was defined as a decrease in EDSS from baseline of ≥ 1 point for baseline EDSS < 5.5, or ≥ 0.5 points for baseline EDSS ≥ 5.5, confirmed at 6 months. Improvement was considered lost when EDSS returned to ≥ baseline (regression of improvement confirmed at 6 months). Prevalence of improved EDSS was estimated by a new statistical approach, accounting for not only the onset of improvement but also the duration. Prevalence was estimated as the difference between the Kaplan-Meier (KM) estimators for the probability of having an improvement before time t and the probability of returning to baseline before time t. P values were estimated using a bootstrap technique on the area under the modified KM curve.

Results

The prevalence of disability improvement (KM estimate) for the early versus delayed treatment groups at 2-years post-CLARITY baseline was 15.6% (95% confidence interval [CI]: 11.9–19.3) versus 9.3% (95% CI: 6.1–12.4), respectively and at 5-years was 12.7% (95% CI: 8.8–16.6) versus 8.6% (95% CI: 4.8–12.4), respectively (early versus delayed treatment group: P = 0.048 for 5-years difference).

Conclusions

Patients receiving early treatment with cladribine tablets had a greater prevalence of disability improvement over 5 years versus those with delayed treatment.

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Clinical Trials Poster Presentation

P0202 - Durable efficacy of cladribine tablets: cumulative relapse incidence over 5 years in CLARITY and CLARITY Extension (ID 960)

Speakers
Presentation Number
P0202
Presentation Topic
Clinical Trials

Abstract

Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

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Clinical Trials Poster Presentation

P0203 - Effect of teriflunomide on MRI lesion activity across age groups in patients with relapsing multiple sclerosis from the TEMSO study (ID 870)

Speakers
Presentation Number
P0203
Presentation Topic
Clinical Trials

Abstract

Background

Teriflunomide is a once-daily oral immunomodulator approved for treating relapsing multiple sclerosis (RMS) and relapsing-remitting MS, depending on the local label. Efficacy and safety of teriflunomide were established in the phase 2 (NCT01487096) and phase 3 trials of patients with RMS (TEMSO [NCT00134563], TOWER [NCT00751881], TENERE [NCT00883337]) and clinically isolated syndrome (TOPIC [NCT00622700]). In post hoc analysis of TEMSO patients stratified by age, structural image evaluation using normalization of atrophy (SIENA) revealed teriflunomide 14 mg significantly reduced the percentage of brain volume change in patients aged >25 to ≤35 years (48%; P=0.0217) and >45 to ≤55 years (35%; P=0.0092) versus placebo over 2 years.

Objectives

To analyze the effect of teriflunomide treatment on MRI lesion activity in TEMSO study patients with RMS stratified by age.

Methods

In TEMSO, patients were randomized 1:1:1 to receive either placebo or teriflunomide 7 mg or 14 mg for ≤108 weeks (Year 2). Through Year 2, MRI lesion activity (unique combined active lesions [UCAL], contrast-enhancing T1 weighted lesions [CEL], and T2 weighted [T2w] lesions) and safety were assessed in the SIENA analysis subgroup; patients were stratified by age at baseline: ≥18 to ≤25 years (n=97 [10%]); >25 to ≤35 years (n=283 [29%]); >35 to ≤45 years (n=388 [40%]); and >45 to ≤55 years (n=201 [21%]). P values between treatment groups were determined for MRI lesions using a Poisson model.

Results

Of 1086 patients in the TEMSO core study, 969 (89%) had scans appropriate for SIENA analysis. Compared with placebo, teriflunomide 14 mg significantly reduced the number of UCAL (0.31–1.44 vs 0.92–6.11 lesions; P≤0.0013) and CEL (0.10–0.46 vs 0.54–3.42 lesions; P≤0.0001) per scan across all age groups. In all age groups except the >45 to ≤55 years group, teriflunomide 14 mg significantly reduced the number of T2w lesions (0.50–0.93 vs 1.07–2.80 lesions; P≤0.001) per scan versus placebo. Similar effects on MRI lesion activity were seen with teriflunomide 7 mg versus placebo. Incidence of adverse events (AEs) generally increased with age, with no deaths reported through Year 2.

Conclusions

Over 2 years in TEMSO RMS patients, teriflunomide reduced the number of new MRI lesions versus placebo across age groups. Significant treatment effects were seen with teriflunomide 14 mg across all age groups for UCAL and CEL. Age-related increases in AEs were observed through Year 2.

STUDY SUPPORT: Sanofi.

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Clinical Trials Poster Presentation

P0204 - Effect on disability measures and MSFC in patients with relapsing multiple sclerosis from the phase 3 ponesimod versus teriflunomide optimum study (ID 1667)

Abstract

Background

OPTIMUM was a multicenter, double-blind, active-comparator phase 3 superiority trial that assessed efficacy, safety, and tolerability of ponesimod 20 mg (PON) vs teriflunomide 14 mg (TER) in patients with relapsing multiple sclerosis (RMS). The primary endpoint of annualized relapse rate was met demonstrating PON’s superiority vs TER.

Objectives

To assess treatment effect on disability progression using time to worsening of timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test [PASAT-3] , Expanded Disability Status Scale (EDSS) and composites of these endpoints.

Methods

OPTIMUM enrolled patients with RMS (EDSS:0-5.5), randomized (1:1) to daily PON or TER for 108 weeks. Change in MS functional composite (MSFC) Z-score (mean of T25FW, 9HPT, PASAT-3 Z-scores), and SDMT from baseline to Week 108 was assessed using Mixed-Effect Model Repeated Measures. Analyses of time to first confirmed (12-week) disability event were conducted post-hoc; disability was defined as 4-point worsening in SDMT, 20% worsening in T25FW or 9HPT, in addition to EDSS (as defined for the secondary endpoint).

Results

Of 1133 patients (PON=567, TER=566), 86.9% completed study. Changes from baseline in overall MSFC Z‑score: 0.02 PON vs −0.039 TER (mean difference, 0.059; p=0.047); for the 3 individual components of MSFC Z-score, mean differences (p-values) were: T25FW, 0.20 sec (p=0.37); 9HPT, –0.93 sec (p<0.0001); PASAT-3, 0.55 number correct (p=0.16). The PON vs TER worsening events up to EOS were, respectively: confirmed 20% worsening in T25FW, 9.2% vs 13.1% (hazard ratio [HR]:0.70; p=0.045); 4-point worsening in SDMT, 22.1% vs 26.4% (HR:0.82; p=0.12)], composite EDSS/SDMT, 26.3% vs 32.7% (HR:0.80; p=0.045)]; composite EDSS/9HPT/T25FW, 18.2% vs 24.0% (HR:0.76; p=0.035); numerical differences in favour of PON in time to confirmed worsening in 9HPT and SDMT assessed individually were not statistically significant.

Conclusions

Measures of worsening of impairment and disability in this exploratory analysis indicated benefits for PON vs TER. Composite endpoints provide more power to statistical assessments owing to greater number of events analyzed, making them particularly useful in RMS trials.

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Clinical Trials Poster Presentation

P0205 - Effects of Diroximel Fumarate on Brain Volume Change and Disability Progression in Adults With Relapsing-Remitting Multiple Sclerosis From EVOLVE-MS-1 (ID 434)

Speakers
Presentation Number
P0205
Presentation Topic
Clinical Trials

Abstract

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved in the United States for relapsing forms of multiple sclerosis (MS). DRF undergoes pre-systemic hydrolysis to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of MMF and are expected to have similar efficacy and safety profiles. In DMF-treated patients, annual rates of brain volume loss over 6 years ranged from -0.19 to -0.37, approaching rates observed in healthy adults (-0.1% to -0.3%).

Objectives

To report percent brain volume change (PBVC) and impact on disability in patients from EVOLVE-MS-1 who have received DRF treatment for up to 2 years.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, phase 3 study to assess the long-term safety, tolerability, and efficacy of DRF 462 mg over 96 weeks in adults with relapsing-remitting MS. Normalized brain volume was assessed at baseline and used to calculate PBVC at Weeks 48 and 96. Confirmed Disability progression (CDP) was measured using the Expanded Disability Status Scale (≥1.5-, ≥1.0-, or ≥0.5-point increase from a baseline score of 0, 1.0-5.5, or 6.0, respectively), with changes sustained for 12 weeks. Estimated proportion of patients with CDP was calculated by the Kaplan-Meier method. No evidence of disease activity (NEDA)-3 was defined as no relapses, no 12-week CDP, and no new/enlarging T2 or new gadolinium-enhancing lesions. This post hoc analysis was conducted in a subgroup of patients who had brain volume scan measurements at baseline, Week 48, and Week 96. The Week 48 and Week 96 visits occurred within an analysis window of ±12 weeks.

Results

As of 2 July 2019, a total of 1051 patients were enrolled in EVOLVE-MS-1 and 365 patients were included in this analysis. Median (range) exposure was 96 (75-100) weeks. Mean (SD) PBVC was -0.36 (0.60) from baseline to Week 48 and -0.35 (0.55) from Week 48 to Week 96. Estimated proportion of patients who were free of CDP was 94.3% at Week 48 and 90.7% at Week 96. The proportion of patients with NEDA-3 at Week 48 and Week 96 was 44.7% (163/365) and 25.2% (91/361), respectively.

Conclusions

Interim findings from the ongoing EVOLVE-MS-1 study demonstrate that yearly PBVC in DRF-treated patients approached the rate observed in healthy adults and was consistent with previous studies of DMF. Most patients remained free of CDP at 2 years.

Supported by: Biogen

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Clinical Trials Poster Presentation

P0206 - Effects of nanocatalysis on CNS bioenergetic markers in patients treated with CNM-Au8: Interim results from two Phase 2 31Phosphorous imaging studies (ID 1741)

Presentation Number
P0206
Presentation Topic
Clinical Trials

Abstract

Background

Multiple sclerosis (MS) and Parkinson’s Disease (PD) patients display marked bioenergetic deficits in the CNS. 31Phosphorous magnetic resonance spectroscopy (31P-MRS) is a non-invasive, quantitative imaging technique for monitoring bioenergetic metabolites, as well as phospholipid and myelin precursors. CNM-Au8 is a suspension of clean-surfaced, faceted, gold nanocrystals that catalyze NAD and ATP production and reduce oxidative stress, resulting in remyelination and neuroprotection. Two Phase 2 CNS imaging trials, REPAIR-MS and -PD, were initiated to determine the effects of orally delivered CNM-Au8 on 31P-MRS brain metabolites. An interim analysis of data from completers of these ongoing trials is presented.

Objectives

The objective of this study is to determine the effect of CNM-Au8 treatment on 31P brain bioenergetic metabolites in MS and PD patients.

Methods

7 Tesla 31P-MRS was conducted at baseline (BL) and after 12-16 weeks of CNM-Au8 treatment (30 mg/day, p.o.). A full volume coil was used to collect whole brain spectra in ~600 voxels with a spatial resolution of 2 cm3. Automated analyses of the integrated area of each 31P peak by voxel was normalized to phosphocreatine area and then averaged across voxels for each patient at BL and end of study (EOS). Linear regression determined r2 values for the percentage change from BL for each metabolite versus BL values.

Results

Results for 4 MS and 6 PD completers were analyzed. Percent change from BL at the EOS visit was highly correlated to BL levels for key bioenergetic markers. Patients with nicotinamide adenine dinucleotide (NAD) levels less than the BL mean significantly increased whole-brain NAD levels at the EOS visit, while patients with BL NAD levels greater than the mean normalized levels to the BL mean. Importantly, this relationship was observed for total NAD levels (r2 = 0.6384; p = 0.0056), β-ATP (r2 = 0.8723; p < 0.0001), and several other 31P metabolites, indicating a homeostatic effect of CNM-Au8 on brain bioenergetics. In the 4 MS patients, there were marked correlations for NAD (r2 = 0.9241; p = 0.039), β-ATP (r2 = 0.968; p=0.016), and several other 31P metabolites.

Conclusions

These preliminary results provide the first clinical evidence demonstrating the catalytic effects of CNM-Au8 on key bioenergetic metabolites in MS and PD brains. Full analyses will be conducted once the trials are completed. The brain metabolic homeostasis observed with CNM-Au8 treatment may be neuroprotective, a hypothesis currently being explored in the ongoing VISIONARY-MS study.

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Clinical Trials Poster Presentation

P0207 - Effects of Nurse Practitioner Care compared to Community Neurologist Care on Depression and Anxiety Levels in People with MS: a randomized trial (ID 311)

Speakers
Presentation Number
P0207
Presentation Topic
Clinical Trials

Abstract

Background

Canada has one of the highest rates of MS in the world. As treatments for people with MS (PwMS) become more comprehensive, it is challenging for general community neurologists to optimally provide care with the pressures of busy office practices in a public health care system. Specialized nurse practitioners (NPs) provide advanced skills to those with complex medical conditions such as PwMS, with potential to enhance care for PwMS.

Objectives

Our objective was to evaluate the effect of NP-led care for PwMS on depression and anxiety (Hospital Anxiety and Depression Scale, HADS) compared to ‘usual care’ (community neurologist and MS specialized RN nursing).

Methods

PwMS followed by community neurologists were randomized to NP-led (NP) or usual care (CN) for 6 months. Primary outcome was the change in the anxiety and depression sub-scales of the HADS at 3 months. Higher scores indicate greater severity. Secondary outcomes included HADS-A and HADS-D at 6 months, quality of life as measured by the EQ5D (3, 6 months), fatigue as measured by the MSIF (3, 6 months), and the Consultant Satisfaction Survey (3, 6 months).

Results

We recruited 248 subjects; 226 completed the trial (NP arm n=118, CN arm n=108). There were no baseline differences between groups. Study subjects were highly educated (72%), working full-time (42%), living independently (69%), with mean age of 47 (SD 11.02) and mean duration since MS diagnosis of 12.45 years (SD 8.73). Most had relapsing remitting MS (85%), with mean EDSS of 2.54 (SD 2.07). The mean change in HADS-D at 3 months was: -0.41 (SD 2.81) NP group vs 1.11 (2.98) CN, p=0.001; and for HADS-A, -0.32 (2.73) NP vs 0.42 (2.82) CN, p=0.059, similar at 6 months. There were trends, but no significant changes in MSIF and EQ5D from baseline in either arm at 3 and 6 months. There was no difference in patient satisfaction with the NP-led care compared to usual care (63.83 (5.63) for NP group vs. 62.82 (5.45) for usual care, p=0.194).

Conclusions

NP-led care improved depression (at 3 and 6 months) and anxiety levels (at 6 months) in PwMS; there was no difference in patient satisfaction with care between NP and community neurologist. Further research with longer follow-up is needed to explore how NPs could enrich and supplement the care provided for PwMS in a Canadian public healthcare system.

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Clinical Trials Poster Presentation

P0208 - Effects of Wahls Elimination and Swank Dietary Patterns on Multiple Sclerosis Related Fatigue, Quality of Life, Processing Speed and Waking Distance (ID 482)

Speakers
Presentation Number
P0208
Presentation Topic
Clinical Trials

Abstract

Background

The Wahls Elimination (Wahls) and Swank dietary patterns are popular in the multiple sclerosis (MS) community but there is limited randomized clinical trial data on both.

Objectives

To assess and compare the impact of both diets on fatigue (primary endpoint) and other secondary endpoints within and between diet groups. Main hypothesis: Wahls diet group would experience a greater mean reduction in fatigue as measured by the Fatigue Severity Scale (FSS) than Swank diet group.

Methods

Parallel group, randomized, principal investigator (PI) and assessor-blinded. Measures included the FSS (primary endpoint), and secondary endpoints: Modified Fatigue Impact Scale (MFIS), MSQoL54 physical health and mental health subscales (QoL-PH; QoL-MH), Symbol Digit Modalities Test-Oral (SMDT-O), and 6 Minute Walk Test (6MWT[feet walked]) in adult relapsing-remitting MS patients with moderate fatigue (FSS ≥4). Study was 36 weeks with 4 in-person visits and 3 12-week periods. A 12-week observation period was followed by randomization (visit 2 [V2]), along with training on assigned diet and 5 telephone support calls by a registered dietitian. During the final period (visit 3 [V3] to visit 4 [V4]), there were no scheduled calls. Differences between V2 and V3, and V2 and V4 were analyzed using general linear mixed models to assess changes within and between groups over time using demographic and clinical control variables.

Results

There was no difference in baseline demographic or clinical characteristics between diet groups, with 77 participants completing V3 and 72 completing V4. Both groups had similar clinically significant improvements in FSS mean scores at V3 and V4 (Wahls, -0.7, -1.3; Swank, -0.9, -1.0; MFIS (Wahls, -14, -19; Swank, -10, -11), and QoL-PH (Wahls, 13, 13; Swank, 10, 13; all p<0.01). Improvements were observed for QoL-MH (Wahls, 11, 14, both p<0.01; Swank, 4, p=0.14, 6, p=0.03), SMDT-O (Wahls, 0.9, p=0.27, 2.3, p=0.01; Swank, 2.9, 2.6, both p <0.01), and 6MWT at V4 only (Wahls, 120, p<0.01; Swank, 33, p=0.13). Better outcomes were observed for the Wahls diet group: MFIS at V4 (-8.6, p=0.02), QoL-MH (V3, 7.5; V4, 8.1, p=0.05), and 6MWT at V4 (87.1, p=0.08).

Conclusions

Wahls and Swank diets groups showed clinically significant mean reductions in fatigue scores. The Wahls diet was associated with better outcomes for QoL-MH/MFIS, with suggested improvement on three other measures. Longer studies including brain imaging are warranted to establish effects for both diets on brain structure.

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Clinical Trials Poster Presentation

P0209 - Efficacy and safety of ofatumumab versus placebo in relapsing multiple sclerosis patients in Japan and Russia: Results from the Phase 2 APOLITOS study (ID 1656)

Speakers
Presentation Number
P0209
Presentation Topic
Clinical Trials

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide with a favorable safety profile in the Phase 3 ASCLEPIOS I/II trials in relapsing multiple sclerosis (RMS) patients (Global, Ex-Japan). APOLITOS was designed to support ofatumumab registration for RMS treatment in Japan in conjunction with ASCLEPIOS.

Objectives

To evaluate the efficacy and safety of ofatumumab versus placebo in RMS patients and assess consistency of effect in Japanese and non-Japanese patients.

Methods

APOLITOS was a 24-week, double-blind, placebo-controlled study followed by an open-label extension up to week 48. Patients aged 18–55 years with confirmed MS diagnosis (2010 revised McDonald criteria), prior evidence of disease activity (≥1 relapse in the last 2 years AND MRI activity in the last year), and an EDSS score of 0–5.5 were randomized (2:1) to subcutaneous ofatumumab 20 mg or matching placebo (initial doses: Days 1, 7, 14, week 4; subsequent doses: every 4 weeks). Randomization was stratified by region (Japan or ex-Japan) and baseline gadolinium-enhancing (Gd+) T1 lesions (0 or ≥1). The primary endpoint was a reduction in cumulative number of Gd+ T1 lesions across weeks 12, 16, 20, and 24. Secondary outcomes included consistency in reduction of Gd+ T1 lesions across regions, annualized relapse rate (ARR), and safety.

Results

In total, 64 patients were randomized (32 each from Japan and Russia; by treatment: ofatumumab, N=43; placebo, N=21), and 59 completed the double-blind phase. The majority of patients had high baseline disease activity ([mean] 1.5 relapses in the last year, 1.2 Gd+ T1 lesions) and 69% received prior disease-modifying therapies. At week 24, ofatumumab significantly reduced Gd+ T1 lesions versus placebo by 93.6% (p<0.001); the results were consistently in favor of ofatumumab across regions. Ofatumumab reduced the ARR versus placebo by 58.0% (p=0.119). Adverse events occurred in 69.8% of patients with ofatumumab and 81.0% with placebo; injection-related reactions were the most common (20.9% and 19.0%, respectively). One ofatumumab-treated patient was diagnosed with serious chronic inflammatory demyelinating polyradiculoneuropathy after completing the study. No deaths, opportunistic infections, or malignancies occurred during the study.

Conclusions

Ofatumumab demonstrated superior efficacy versus placebo in a RMS population with recent disease activity in Japanese and non-Japanese patients. No new safety signals were observed and the results were consistent with the Phase 3 ASCLEPIOS I/II trials.

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Clinical Trials Poster Presentation

P0210 - Elezanumab in patients with different disease courses of multiple sclerosis: study design and baseline analysis from two phase 2 studies (ID 404)

Speakers
Presentation Number
P0210
Presentation Topic
Clinical Trials

Abstract

Background

Background: Multiple sclerosis (MS) treatment involves disease-modifying therapies (DMTs) and symptom management. There is an unmet need for MS treatments that reverse demyelination and neuronal damage. Elezanumab (formerly ABT-555) is a monoclonal antibody that neutralizes repulsive guidance molecule A (RGMa), a neurite outgrowth inhibitor thought to be involved in MS.

Objectives

Objective: Present the study design and baseline data from 2 studies investigating elezanumab efficacy and safety in patients with progressive MS (PMS) and relapsing MS (RMS).

Methods

Methods: RADIUS-R (NCT03737851) and RADIUS-P (NCT03737812) are 2 ongoing, 52-week, proof-of-concept, RAndomized, Double-blind, placebo-controlled, multIple-dose phase 2 stUdies investigating efficacy and safety of elezanumab added to Standard of care in patients with RMS and PMS, respectively. RADIUS-R includes patients with relapsing-remitting MS (RRMS; no relapse 6 months before screening), or active secondary-progressive MS (SPMS; relapse 6 to 24 months before screening). RADIUS-P includes patients with primary-progressive MS (PPMS) or non-active SPMS (no relapses 24 months before screening). Patients in both studies were randomized 1:1:1 to receive 1 of 2 doses of elezanumab or placebo intravenously every 4 weeks through week 48. The primary endpoint for both studies is mean overall response score (ORS; based on Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-hole Peg Test [9HPT]-dominant and nondominant) at week 52.

Results

Results: Overall, 208 patients enrolled in RADIUS-R and 123 in RADIUS-P. In RADIUS-R, 199 (96%) patients were diagnosed with RRMS, while 9 (4%) were diagnosed with SPMS. In RADIUS-P, 59 (48%) patients were diagnosed with PPMS, and 63 (52%) were diagnosed with SPMS. Baseline mean (SD) age was 45.7 (8.4) years (RADIUS-R) and 52.6 (7.0) years (RADIUS-P). Overall, 66% of RADIUS-R and 48% of RADIUS-P patients were women. Mean (SD) ORS components for RADIUS-R were: T25FW, 7.3 (4.0); 9HPT-dominant, 28.0 (22.5); and 9HPT-nondominant, 30.0 (23.5); EDSS (median [range]), 3.5 (1.0, 6.5). ORS components for RADIUS-P were: T25FW, 12.5 (11.2); 9HPT-dominant, 31.4 (27.6); and 9HPT-nondominant, 38.1 (37.3); EDSS, 6.0 (2.0, 7.0). Most patients used concomitant DMTs (RADIUS-R, 75%; RADIUS-P, 69%), most commonly ocrelizumab (RADIUS-R, 45%; RADIUS-P, 59%).

Conclusions

Conclusion: RADIUS-R and RADIUS-P are ongoing phase 2 studies investigating safety and efficacy of elezanumab as a remyelination agent.

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Clinical Trials Poster Presentation

P0211 - Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis (ID 1225)

Abstract

Background

Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.

Objectives

To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.

Methods

We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).

Results

To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).

Conclusions

Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

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Clinical Trials Poster Presentation

P0212 - Ginseng as a possible candidate for fatigue management in neuromyelitis optica spectrum disorder: a double-blind randomized clinical trial (ID 1629)

Abstract

Background

Fatigue is one of the most common complaints of patients with neuromyelitis optica spectrum disorder (NMOSD). From 50 up to 71.4% of NMOSD patients reported fatigue in their daily life. Fatigue can decrease patients’ quality of life, quality of sleep and it can increase the severity of their pain.

Objectives

Ginseng has shown positive effects on decreasing fatigue in multiple sclerosis patients. Due to similar manifestations between the two diseases, this study was designed to evaluate the same effects on NMOSD.

Methods

This study was a double-blind randomized clinical trial designed and performed in Sina hospital, Tehran, Iran in 2018-2019. A total number of 58 patients were enrolled and underwent treatment with 250-mg ginseng or placebo twice daily for 3 months. Severity of fatigue was measured using the valid and reliable Farsi version of fatigue severity scale (FSS) questionnaire at the time of admission and after completing the study. Questionnaires were filled by patients and the scores were calculated and evaluated by a trained senior neurology resident.

Results

All 58 participants completed the study. Mean age was 36.84 ± 9.37, and 89.7% of patients were female. There was no difference between the study and control group regarding age, EDSS, duration of disease or types of medications used for NMOSD treatment. After administering Ginseng/placebo for 3 months there were no major side effects reported. The FSS was decreased significantly in the study group (40.21 ± 13.51 to 28.97 ± 14.18) comparing to placebo group (35.03 ± 13.51 to 38.79 ± 12.27) after treatment (p-value: <0.001).

Conclusions

This study demonstrates positive results from ginseng on relieving fatigue in NMOSD patients. No major side effects were observed after 3 months of follow-up. More studies are needed to further evaluate ginsengs’ effects and mechanisms of effects on fatigue in NMOSD.

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Clinical Trials Poster Presentation

P0213 - Immune cell profiles and clinical and safety outcomes with fingolimod in the 12 month FLUENT study of patients with relapsing multiple sclerosis (ID 1750)

Speakers
Presentation Number
P0213
Presentation Topic
Clinical Trials

Abstract

Background

FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.

Objectives

To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).

Methods

In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.

Results

165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.

Conclusions

These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.

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Clinical Trials Poster Presentation

P0214 - Improved GI tolerability with diroximel fumarate Is associated with clinically meaningful benefits on QoL compared to dimethyl fumarate in EVOLVE-MS-2 (ID 703)

Speakers
Presentation Number
P0214
Presentation Topic
Clinical Trials

Abstract

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF demonstrated improved gastrointestinal (GI) tolerability vs DMF, with significantly fewer days with a score of ≥2 on the patient-assessed Individual Gastrointestinal Symptom and Impact Scale (IGISIS).

Objectives

To determine whether an IGISIS score ≥2 is an appropriate threshold for comparing GI tolerability and detecting clinically meaningful quality of life (QoL) improvements in EVOLVE-MS-2.

Methods

EVOLVE-MS-2 (NCT03093324) was a 5-week, randomized study comparing GI tolerability of DRF vs DMF in patients with relapsing-remitting MS. Patients self-assessed severity of 5 key GI symptoms by completing IGISIS and Global GISIS (GGISIS) questionnaires. GGISIS assessed interference of GI symptoms on daily activities and missed work. The association between worst IGISIS score ≥2 and measures of treatment burden (worst interference with daily activities, missed work due to GI symptoms, and use of concomitant symptomatic medication to treat GI AEs) by treatment group was assessed using risk ratios (RR; DRF/DMF).

Results

Overall, 253 patients received DRF and 251 received DMF. Fewer DRF-treated patients reported any IGISIS score ≥2 (DRF, 43.1% [109/253]; DMF, 51.4% [128/249]). IGISIS score ≥2 detected moderate/severe GI AEs of IGISIS with 90% sensitivity and 59% specificity. Among patients reporting GI symptoms as “Quite a Bit” or “Extremely” interfering with daily activities (n=47) or missing ≥ 1 hour work due to GI symptoms (n=46) using GGISIS, 89.4% and 91.3% reported a worst IGISIS score ≥2, respectively. In patients with worst IGISIS score ≥2, DRF was associated with lower likelihood of GI symptoms interfering with daily activities “Quite a bit” or “Extremely” (RR 0.88; 95% CI 0.51–1.53), leading to missed work (RR 0.88; 95% CI 0.51–1.53), and resulting in concomitant symptomatic medication use for GI AEs (RR 0.57; 95% CI 0.32–1.00).

Conclusions

Fewer patients reported IGISIS score ≥2 with DRF vs DMF, and an IGISIS score ≥2 was sensitive for identifying moderate/severe GI AEs and clinically meaningful GI symptoms that could impact QoL from a patient perspective.

Supported by: Biogen

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Clinical Trials Poster Presentation

P0215 - Long-term efficacy and safety of ponesimod: Results from randomized phase II core and extension studies in relapsing‑remitting multiple sclerosis (ID 470)

Speakers
Presentation Number
P0215
Presentation Topic
Clinical Trials

Abstract

Background

Ponesimod, an orally active, selective sphingosine 1-phosphate receptor-1 (S1P) modulator, showed benefits in clinical and MRI outcomes in a double-blind, placebo controlled, phase 2b Core Study (NCT01006265). Patients rolled-over into an ongoing Extension Study (NCT01093326).

Objectives

Evaluate the long-term efficacy and safety of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods

A total of 435 patients with RRMS received ≥1 dose of ponesimod (10, 20, or 40-mg/day) during the Core and/or Extension Study. The 40 and 10-mg doses were subsequently discontinued during Treatment Period 1 (TP1) and TP2 of the Extension Study. All patients received 10 or 20-mg during TP2, followed by open-label 20-mg in TP3. Key efficacy parameters: annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), and MRI outcomes. Safety parameters: frequencies of adverse events (AEs) and serious AEs (SAEs). Results of combined analyses of Core and Extension studies are presented.

Results

As of 31 March 2019, 214 patients were still on ponesimod treatment; median exposure in 20-mg group was 8.02 years; Cumulative exposure across all doses was 2372.47 patients-years. In 20-mg group, ARR (95% CI) for confirmed relapses was 0.154 (0.111‒0.214); 64.1% patients remained free of confirmed relapse; Kaplan-Meier estimate of 6- month CDA at Week 432 was 20.4% (13.7‒29.7); Mean number of T1 gadolinium enhancing lesions per patient per scan was 0.448 (0.305‒0.657); Mean number of new or enlarging T2 lesions per year was 0.718 (0.523‒0.985). In ponesimod-treated patients, the most common treatment-emergent AEs were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%). Most SAEs were reported in a single patient, no SAE was reported at an incidence of >1%.

Conclusions

Long-term treatment with ponesimod 20 mg showed consistently low levels of disease activity across relevant clinical and MRI outcomes in patients with RRMS. No new safety signals were identified.

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Clinical Trials Poster Presentation

P0216 - Long-term reduction of relapse rate and 48-week confirmed disability progression after 6.5 years of ocrelizumab treatment in patients with RMS (ID 844)

Speakers
Presentation Number
P0216
Presentation Topic
Clinical Trials

Abstract

Background

The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week controlled double-blind period (DBP) of the Phase III OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.

Objectives

To assess the efficacy of switching from interferon (IFN) β-1a or maintaining OCR therapy on disease activity and confirmed disability progression (CDP) after 4.5 years of follow-up, in the open-label extension (OLE) of OPERA I and OPERA II.

Methods

In the DBP of OPERA I and OPERA II, patients were randomized to receive OCR or IFN β-1a. Patients completing the DBP either continued OCR (OCR-OCR) or switched from IFN β-1a to OCR (IFN-OCR) when entering the OLE period. Adjusted annualized relapse rate (ARR), time to onset of 48-week CDP (CDP48) and time to 48-week confirmed Expanded Disability Status Scale score ≥6.0 (time to require a walking aid) were analyzed up to Week 336.

Results

Overall, 79.2% of patients who entered the OLE period completed OLE Year 4.5. Adjusted ARR decreased year-on-year from the pre-switch year to OLE Year 4.5 in IFN-OCR switchers (pre-switch, 0.20; OLE Year 4.5, 0.06) and was maintained at low levels in OCR-OCR continuers (pre-switch, 0.12; OLE Year 4.5, 0.04). The rates of CDP48 were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (4.1% vs 8.5%; p<0.001) and at OLE Year 4.5 (16.0% vs 20.3%; p=0.05). The rates of patients requiring a walking aid were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (0.8% vs 3.1%; p=0.001) and at OLE Year 4.5 (5.1% vs 8.3%; p=0.024). Over the DBP and OLE periods, the risk of CDP48 was 28% lower (HR [95%CI]: 0.72 [0.56–0.93]; p=0.01) and the risk of requiring a walking aid was 46% lower (HR [95%CI]: 0.54 [0.35–0.83];p=0.004) in OCR-OCR continuers vs IFN-OCR switchers. The safety profile in the OLE was generally consistent with the DBP.

Conclusions

Switching from IFN β-1a to ocrelizumab at the start of the OLE period was associated with a rapid and robust reduction in ARR that was maintained through the 4.5-year follow-up of the OLE period. Compared with patients switching to ocrelizumab at the OLE, patients initiating ocrelizumab 2 years earlier accrued significant benefits on CDP48 and time to require a walking aid that were maintained vs the switch group through the 4.5 years of the OLE period.

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Clinical Trials Poster Presentation

P0217 - Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1−3 trials (ID 991)

Abstract

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).

Objectives

To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.

Methods

Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.

Results

In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.

Conclusions

In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.

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Clinical Trials Poster Presentation

P0218 - Long-term safety, compliance, and effectiveness of ofatumumab in patients with relapsing multiple sclerosis: ALITHIOS Phase 3b study (ID 1580)

Speakers
Presentation Number
P0218
Presentation Topic
Clinical Trials

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide along with a favorable safety profile in the Phase 3 ASCLEPIOS trials in relapsing multiple sclerosis (RMS) patients. Assessment of the long-term use of subcutaneous (s.c.) ofatumumab 20 mg is important to further understand its benefit-risk profile.

Objectives

To present the design of the ALITHIOS extension study of ofatumumab and evaluate treatment compliance, including treatment discontinuations, in patients transitioning to the ALITHIOS study.

Methods

ALITHIOS is an ongoing Phase 3b, open-label, umbrella extension study which has enrolled eligible patients (approximately 1700 patients) completing the Phase 3 ASCLEPIOS I/II, Phase 2 APOLITOS and APLIOS trials from >300 sites worldwide. ALITHIOS consists of three parts: screening, loading, and open-label treatment. Ofatumumab 20 mg is administered at the site on Day 1 (patients from ASCLEPIOS have a blinded loading part with two additional ofatumumab/matching placebo s.c. injections on Days 7 and 14; no blinding is required for those from the APOLITOS and APLIOS studies) followed by open-label treatment every 4 weeks from Week 4 for up to 5 years. The primary endpoint is the proportion of patients with adverse events (AEs); abnormal laboratory, vital signs or electrocardiogram results; and the proportion of patients meeting predefined criteria of suicidal behavior as per the Columbia Suicide Severity Rating Scale. Secondary endpoints include relapse rate, disability (worsening and improvement), and magnetic resonance imaging outcomes. Patient-reported outcomes was included as an exploratory endpoint. The proportion of eligible patients who accepted transition to ALITHIOS from the Phase 2/3 trials and treatment compliance (defined as exposure to study drug [days]/duration of on-treatment period [days]×100%) are recorded.

Results

As of May 2020, 1692 patients from 37 countries and 294 sites were screened, and 1671 (98.8%) were enrolled into ALITHIOS; 1615 patients are ongoing and 56 (3.3%) patients discontinued. The most common reasons for discontinuation were patient/guardian decision (0.9%), AEs (0.5%), and physician decision (0.2%). The study is expected to complete in 2025. Study design details and compliance data will be presented at the congress.

Conclusions

The ALITHIOS study is designed to allow patients who participated in prior ofatumumab studies to continue with the treatment, and to further assess the benefit-risk profile of ofatumumab in RMS and tolerability in long-term use.

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Clinical Trials Poster Presentation

P0219 - Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs (ID 974)

Speakers
Presentation Number
P0219
Presentation Topic
Clinical Trials

Abstract

Background

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The Phase IIIb CASTING study (NCT02861014) of ocrelizumab evaluated the efficacy/safety in patients with RRMS who had a prior suboptimal response to one or two DMTs (primary endpoint: 2-year no evidence of disease activity [NEDA] rate).

Objectives

To evaluate CASTING 2-year NEDA outcomes by inclusion criteria, baseline characteristics and prior DMT.

Methods

Patients (Expanded Disability Status Scale [EDSS] score ≤4.0; discontinued prior DMT of ≥6 months’ duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint of NEDA (with prespecified MRI re-baselining at Week 8) was defined as absence of: protocol-defined relapses, 24-week confirmed disability progression, T1‑weighted contrast-enhancing and new/enlarging T2-weighted lesions over 2 years.

Results

A total of 680 patients were evaluated (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; pretreated with one or two DMTs, including orals and injectables, n=411 [60.4%]/n=269 [39.6%]; enrolled due to activity of: MRI only, n=167 [24.6%]; relapse only, n=238 [35.0%]; MRI and relapse, n=275 [40.4%]). After 2 years, 74.8% (n/N=492/658) of patients had NEDA (with MRI re-baselined at Week 8). The NEDA rate was highest among patients enrolled due to MRI activity alone (80.6%) versus enrollment for relapse (75.1%) or relapse with MRI (70.5%). NEDA rates across disease-related subgroups were highest in the subgroups of baseline EDSS score <2.5 (77.2%), ≤1 relapse prior to enrollment (78.2%) and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%) versus the counterpart subgroups of EDSS score ≥2.5 (70.8%), >1 relapse prior to enrollment (66.3%) and the event leading to enrollment occurring <6 months prior to entry (71.0%). The NEDA rate did not vary by baseline age (≤40 years, 74.7%; >40 years, 75.0%). NEDA rates were higher in patients receiving one prior DMT (77.6%) versus two prior DMTs (70.3%) and remained generally high when stratified by the last prior DMT received before enrollment: interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Conclusions

The NEDA rate was high overall and across a wide range of disease-related and demographic subgroups, regardless of prior treatment background.

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Clinical Trials Poster Presentation

P0220 - Ocrelizumab Phase IIIb efficacy: 1-year NEDA rates (with MRI re-baselining) from the ENSEMBLE study in early-stage relapsing-remitting MS patients (ID 849)

Abstract

Background

Early treatment of multiple sclerosis (MS) has been shown to provide significant long-term benefits in terms of Expanded Disability Status Scale (EDSS) score versus delayed treatment (patients switching from placebo to active treatment). ENSEMBLE (NCT03085810) is a Phase IIIb study evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting multiple sclerosis (RRMS). Assessments of effectiveness in ENSEMBLE include composite endpoint measures, e.g. the proportion of patients with no evidence of disease activity (NEDA).

Objectives

To report ENSEMBLE 1-year interim NEDA rates.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; EDSS score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients received OCR 600 mg every 24 weeks (first dose 2×300 mg separated by 14 days) throughout the 192-week (4-year) treatment period (max 8 doses). Clinical assessments will be conducted every 24 weeks. NEDA is defined as absence of: protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1-weighted contrast-enhancing (CEL) and new/enlarging T2-weighted (T2w) lesions. The effects of OCR are not immediate. MRI measures were re-baselined at Week 8 (prespecified) so that the calculation of NEDA would reflect a more accurate treatment effect.

Results

A total of 678 patients (female, 64.6%) were enrolled (74.6% of patients based on the presence of reasons of both MS relapse and MRI activity) and analyzed. Baseline demographics and disease characteristics reflected a population with early-stage disease (mean [SD]: age, 32.4 [9.1] years; baseline EDSS, 1.71 [0.95]; time since RRMS diagnosis, 0.36 [0.40] years; time since MS symptom onset, 1.10 [0.84] years). At Week 48 most patients (84.8% [n/N=545/643]) reached NEDA. Most patients were free of PDR (98.1%), 24W-CDP (94.1%), CEL (94.2%; re-baselined) and new/enlarging T2w (95.2%; re-baselined) lesions. NEDA calculated without MRI re-baselining was achieved by 62.1% of patients (n/N=404/651). Safety results were consistent with prior studies.

Conclusions

In ENSEMBLE, the Year 1 NEDA rate with MRI re-baselining was high (84.8%) in patients with early-stage disease. No new safety signals were observed.

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Clinical Trials Poster Presentation

P0221 - Ocrelizumab treatment in patients with RRMS who had a suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results (ID 1216)

Presentation Number
P0221
Presentation Topic
Clinical Trials

Abstract

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

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Clinical Trials Poster Presentation

P0222 - OLIKOS study design: exploring maintained ofatumumab efficacy in relapsing MS patients who transition from intravenous anti-CD20 therapy (ID 1757)

Speakers
Presentation Number
P0222
Presentation Topic
Clinical Trials

Abstract

Background

Depletion of B cells in patients with relapsing multiple sclerosis (RMS) using anti-CD20 monoclonal antibodies (mAbs) reduces annualized relapse rates and inflammatory lesion activity on magnetic resonance imaging, and delays time to confirmed disability worsening. Anti-CD20 mAbs ocrelizumab and rituximab are administered by intravenous infusion in clinic; ofatumumab is administered subcutaneously with a pre-filled syringe or autoinjector (AI) pen, facilitating self-administration. No outcome data exist relating to transition of patients treated with ocrelizumab or rituximab to ofatumumab.

Objectives

OLIKOS is a 12 month, prospective, single-arm, multicenter phase 3b study that will explore maintained efficacy of ofatumumab in patients with RMS who transition from intravenous anti-CD20 mAb therapy.

Methods

About 100 adults with RMS will be enrolled at 10-20 centers in the USA. Eligible patients will have been previously treated with 2-5 consecutive courses of intravenous ocrelizumab or rituximab (other anti-CD20 mAbs are excluded), with last dose 4-9 months before OLIKOS baseline. Other inclusion criteria are Expanded Disability Status Scale score 5.5 or lower at screening and CD19 B cells depleted to below 1% at baseline. Patients with suboptimal response to anti-CD20 therapy in the previous 6 months (relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new/enlarging T2 lesions, clinical worsening), or who discontinued anti-CD20 therapy because of severe infusion-related reactions or recurrent infections, or with progressive disease, will be excluded. All participants will receive subcutaneous ofatumumab 20 mg administered by AI pen on Days 1, 7 and 14, then monthly in Months 1-12. The primary endpoint will be no change or a reduction in Gd+ lesion count at Month 12. Secondary endpoints will be participant retention and changes in immune biomarkers, treatment satisfaction, safety and tolerability at Months 6 and 12. There will be a 6 month interim analysis.

Results

The detailed study design will be presented. OLIKOS will complement the ofatumumab phase 3 program in RMS by generating maintained efficacy, retention and satisfaction data based on monthly subcutaneous drug delivery with the AI pen in patients previously treated with ocrelizumab or rituximab.

Conclusions

OLIKOS will provide important data on the maintained efficacy of ofatumumab in patients with RMS transitioning from intravenous anti-CD20 therapies.

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Clinical Trials Poster Presentation

P0223 - “Personalized extended interval dosing of natalizumab in relapsing remitting multiple sclerosis – a prospective multicenter trial in The Netherlands" (ID 1418)

Speakers
Presentation Number
P0223
Presentation Topic
Clinical Trials

Abstract

Background

Natalizumab is an effective disease-modifying therapy for relapsing remitting multiple sclerosis (RRMS). However, natalizumab trough concentrations remain high in a treatment regimen of 4-weekly infusions in 85% of patients. Previous studies showed that patients on extended interval dosing (EID) of natalizumab had comparable disease activity to standard interval dosing (SID) and a decreased risk of progressive multifocal leukoencephalopathy.

Objectives

To validate the maintenance of efficacy, measured by radiological disease activity, of personalized EID of natalizumab based on natalizumab trough concentrations. Feasibility of further extending intervals up to trough concentration of 5 μg/ml will be studied in a subgroup.

Methods

In this national multicenter prospective study (ClinicalTrials.gov Identifier: NCT04225312), 300 patients diagnosed with RRMS that received ≥ 6 consecutive natalizumab infusions will be included. Patients will be included in the main personalized EID group (aimed trough concentration 10 μg/ml), the low EID group (trough 5 μg/ml) or the SID group. Follow-up is two years with an extension phase of two years with annual MRI brain scans and 6 monthly scans for patients in the low EID group. Questionnaires will be filled in yearly by all participants.

Results

Inclusion of patients started in February 2020. Participants will be included in 22 centers in The Netherlands. So far, 69 patients were included, of whom 19 in the main EID group, showing natalizumab trough concentrations at baseline of 18.5 μg/ml (IQR 9.2 to 30.0). Current treatment intervals are 4 weeks (n=5), 5 weeks (n=5), 6 weeks (n=8) or 7 weeks (n=1). In the low EID group (n=37), natalizumab trough concentrations at baseline were 15.0 μg/ml (IQR 10.3 to 21.8). Current treatment intervals are 4 weeks (n=2), 5 weeks (n=8), 6 weeks (n=17) or 7 weeks (n=10). In the SID group (n=13), natalizumab trough concentrations at baseline were 18.0 μg/ml (IQR 14.5 to 26.0). Wearing-off symptoms were present in 33.9% of participants at baseline. No signs of radiological or clinical disease activity were present during follow-up so far.

Conclusions

Personalized extended interval dosing of natalizumab based on trough concentrations has the potential to become a safe, standardized treatment for RRMS patients using natalizumab. Final results of this study are expected in January 2024.

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Clinical Trials Poster Presentation

P0224 - Pharmacokinetic-Pharmacodynamic Models of Lymphocyte Count and Heart Rate Following Ponesimod Dosing in a Phase 2 Study in Multiple Sclerosis Patients (ID 582)

Abstract

Background

Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator in development for the treatment of relapsing multiple sclerosis. A population PK (PopPK) model was previously developed from data of healthy volunteers (HV) and MS patients. Pharmacokinetic-pharmacodynamic (PK-PD) models describing the effect of PON on lymphocyte count (LC) and heart rate (HR) were also available based on data from HV.

Objectives

To evaluate previously developed PopPK and PK-PD models to characterize the effect of PON on LC and HR in patients with MS from a phase 2 study.

Methods

Patients randomized (1:1:1:1) in the multicenter, double-blind, B201 study (NCT01006265) received PON 10, 20, and 40 mg QD (up-titrated every 7 days from 10 mg) or placebo for 24 weeks. PON plasma concentrations, LC, and HR measurements (2508, 3938, and 10336 measurements, respectively) were obtained from 461 patients (107, 114, 119, 121 patients in 10, 20, 40 mg PON, or placebo, respectively). Models were fit to the observations using nonlinear mixed-effects models, using NONMEM 7.3.0 (ICON plc).

Results

PON PK were well described by the available open 2-compartment linear PopPK model. The PK-LC model was characterized by parameters (maximal effect and concentration inhibiting 50% LC of 0.86∙109 L-1 and 43.4 ng/mL, respectively) in agreement with those previously obtained in HV. The model estimated a mean reduction of LC at steady state (CV%) of 50.20% (19.2%), 66.61% (12.2%), and 72.36% (12.6%) for 10, 20, and 40 mg doses, respectively. LC are predicted to return to baseline by 1 week after the end of dosing. No clinically relevant covariates were identified for this model, indicating that covariate-based dose adjustments are not warranted. The maximal effect parameter of the PK-HR model was found to be lower in MS patients (24.7% decrease) compared to HV (44.9%) to accommodate a lower incidence of bradycardia (HR<50bpm). After 2 weeks of treatment with 10 mg, the model indicated full tolerance development. Further increasing the PON dose did not have additional effects on HR. Baseline HR was identified as a significant covariate indicating increased bradycardia in case of low baseline HR. The PK-HR model supported first-dose HR monitoring in patients with baseline HR<55 bpm given PON.

Conclusions

The previously developed PopPK, PK-LC, and PK-HR PON models were able to describe the observed data and corresponding variability in patients with MS, consistently with previous knowledge from HV.

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Clinical Trials Poster Presentation

P0225 - Phase 3 Study Results Assessing the Efficacy and Safety of ADS-5102 (Amantadine) Extended Release Capsules in MS Patients with Walking Impairment (ID 1919)

Speakers
Presentation Number
P0225
Presentation Topic
Clinical Trials

Abstract

Background

ADS-5102, FDA-approved as Gocovri, to treat dyskinesia in Parkinson’s disease, has a unique PK profile, such that once daily bedtime dosing provides higher amantadine concentrations from morning throughout the day and lower at night. Based on results from a 60-subject, 4-week, Phase-2 study, INROADS was designed to confirm benefit of ADS-5102 on walking in MS patients.

Objectives

To evaluate the efficacy and safety of ADS-5102 (amantadine) extended release capsules in patients with multiple sclerosis with walking impairment.

Methods

INROADS comprised a 4-week placebo run-in, followed by a 12-week double-blind period. Five hundred ninety-four MS patients with walking impairment from the US or Canada enrolled, and 560 were randomized, 1:1:1, to 274 mg ADS-5102 (n=185), 137 mg ADS-5102 (n=187), or placebo (n=186). The primary endpoint was the proportion of responders (≥20% improvement from baseline measured in ft/sec) in timed 25-foot walk [T25FW] at Week 16, comparing 274 mg ADS-5012 versus placebo. Subjects who did not have a Week 16 assessment were counted as non-responders. Additional outcomes included timed up and go test, 2-minute walk test, and MS walking scale-12. Prespecified subgroups, including prior dalfampridine use, were analyzed.

Results

Baseline characteristics were similar across treatment arms, with mean time since diagnosis 15.9 years, median EDSS 6.0, and mean T25FW 12.4 seconds; 52.5% reported prior dalfampridine use. At Week 16, 274 mg ADS-5102 demonstrated a statistically significantly greater response rate, 21.1% (P=.01) than placebo (11.3%); the response rate for 137 mg ADS-5102 was 17.6% (P=.08). For subjects who completed the study, the response rates were 28.3% (P< .001) for 274 mg, and 19.6% (P=.049) for 137 mg, vs. 11.9% for placebo. Response rates were consistent for subjects with (20.0%, 15.9%, vs. 11.0%) and without (22.5%, 19.2%, vs. 11.6%) prior dalfampridine use. The most commonly reported (>5%) adverse events (AEs) were peripheral edema, dry mouth, fall, constipation, UTI, and insomnia; AEs led to study drug discontinuation for 20.5% (274 mg), 6.4% (137 mg) and 3.8% (placebo) of subjects.

Conclusions

INROADS met its primary objective of showing clinically meaningful benefit in MS walking speed for 274 mg ADS-5102. A dose-response was seen for both efficacy and tolerability. AEs were consistent with the known safety profile of amantadine. Results suggest a role for ADS-5102 to improve walking in patients with MS, particularly those who have tried and discontinued dalfampridine.

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Clinical Trials Poster Presentation

P0226 - Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis (ID 1635)

Speakers
Presentation Number
P0226
Presentation Topic
Clinical Trials

Abstract

Background

Epstein-Barr virus (EBV) is a necessary risk factor for the development of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J et al. Mult Scler 2012]. Early experience with autologous EBV-specific T-cell adoptive immunotherapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018].

Objectives

This Phase I study evaluated the safety and potential efficacy of off-the-shelf, allogeneic EBV-targeted T-cell therapy (ATA188) in adults with progressive forms of MS (NCT03283826).

Methods

In part 1, four cohorts received escalating doses of ATA188 to determine the recommended part 2 dose (RP2D). Patients (pts) were followed for 1-year and given the option to participate in a 4-year open label extension (OLE) at the RP2D (cohort 3 dose). In addition to safety, sustained disability improvement (SDI) was assessed, defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at ≥2 consecutive time points [Pender MP et al. EAN 2020; LB130]. Other measures evaluated include Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole brain volume (via magnetic resonance imaging [MRI]). As of August 2020, we expect 12-month (m) data for all 4 cohorts, which marks the end of the dose finding portion of this study, will be available for presentation.

Results

As of April 2020, 25 pts had received ≥1 dose of ATA188. No grade >3 events, dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion reactions were observed. Two treatment-emergent serious adverse events were reported: muscle spasticity (grade 2; not treatment related) and MS relapse (grade 3; possibly treatment related). Efficacy endpoints were assessed in cohorts 1–4 (n=24) at 6m and in cohorts 1–3 (n=17) at 12m. Six pts met SDI criteria at 6m and 5 pts met it at 12m, which was driven by EDSS in all but 2 pts at both 6 and 12m. At both timepoints, a higher proportion of pts showed SDI with increasing dose. In cohorts 1–3, all pts with SDI at 6m maintained it through 12m. Pts with SDI (vs those without) tended to have greater improvements in FSS, MSWS-12, and MSIS-29 (physical) scores, as well as less reduction in whole brain volume on MRI, from baseline to 12m. As of June 2020, OLE data from the 15m timepoint were available for 4 pts; 3 had SDI at 6m and 12m which was maintained at 15m.

Conclusions

Preliminary data indicate ATA188 is well tolerated. A higher proportion of pts showed sustained disability improvement (SDI) with increasing dose. Pts who achieved SDI at any timepoint maintained it at all future timepoints and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 12m. Based on these data, part 2 of the study (randomized placebo-controlled portion) has been initiated using the cohort 3 dose.

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Clinical Trials Poster Presentation

P0227 - Phase I, multicenter, two-part study of ATA188, an open-label, dose-escalation and double-blind, placebo-controlled dose-expansion study (ID 1691)

Speakers
Presentation Number
P0227
Presentation Topic
Clinical Trials

Abstract

Background

Infection with Epstein-Barr virus (EBV) is a necessary risk factor for the development of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J, et al. Mult Scler 2012]. ATA188 – an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy – is being evaluated in a two-part Phase I, multicenter study in adults with progressive forms of MS (PMS; NCT03283826). Part 1 of the study (open-label, single-arm sequential dose escalation) indicates ATA188 is well tolerated, with a higher proportion of patients (pts) showing sustained disability improvement with increasing dose [Pender MP et al. EAN 2020]. These data need to be confirmed in a well-designed randomized, double-blind, placebo-controlled study (DBPCS).

Objectives

Part 2 is a DBPCS designed to further characterize ATA188 safety/tolerability, product kinetics, as well as to assess the impact of treatment on clinical endpoints and biological markers of MS compared to placebo.

Methods

This trial will utilize an adaptive study design. Potential adaptations include considerations in dose, sample size, and endpoints.

Results

In this DBPCS, 36 pts will be randomized to receive ATA188 or placebo; up to 36 additional pts (72 total) may be added if needed. Based on part 1 results, the first 18 pts in part 2 will be randomized to receive ATA188 Cohort 3 dose (2.0x107cells) or placebo. Different doses of ATA188 may be explored in additional pts. In year 1, pts will receive two treatment cycles, ATA188 or placebo. In year 2, pts in the placebo arm will cross over to receive two cycles of ATA188; pts in the ATA188 arm will receive one cycle of ATA188 followed by one cycle of placebo. Pts completing year 2 will be eligible for a 3-year open-label extension, receiving ATA188 once a year.

Eligible pts are those with a current diagnosis of PMS (primary or secondary), EBV seropositivity, age 18–55 years, and an expanded disability status scale (EDSS) score of 3.0–6.5 at screening. Key exclusion criteria include evidence of clinical relapse or radiological activity within the 2 years prior to screening. Pts in part 1 are not eligible for part 2.

Endpoints include: incidence of adverse events; change from baseline in cerebrospinal fluid (CSF) immunoglobulin G index; change from baseline in clinical disability per EDSS, Timed 25-Foot Walk, and/or 9HPT; ambulatory activity monitoring; cervical spinal cord volume and whole brain volume on magnetic resonance imaging (MRI); the number of gadolinium-enhancing and new or enlarging T2 lesions on brain MRI scans. Exploratory endpoints include assessment of potential biomarkers such as oligoclonal bands in CSF, persistence of ATA188, and cytokine profiling in blood and CSF compartments.

Conclusions

Part 2, the randomized, placebo-controlled portion of this phase 1 study, is now enrolling pts with the objective of evaluating the safety/tolerability, product kinetics and biological and clinical effect of ATA188 on PMS.

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Clinical Trials Poster Presentation

P0228 - Post-treatment recovery of lymphocyte subsets in healthy volunteers treated with ozanimod (ID 861)

Speakers
Presentation Number
P0228
Presentation Topic
Clinical Trials

Abstract

Background

Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of MS (RMS). Ozanimod blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the central nervous system. In healthy volunteers (HV) and patients with RMS, ozanimod induces differential reductions in lymphocyte subset counts.

Objectives

To evaluate the recovery of lymphocyte subsets to pre-treatment levels following discontinuation of ozanimod in HV.

Methods

In a phase 1, randomized, double-blind, placebo-controlled study (NCT03694119) in HV (25–55 y), oral ozanimod 1.84 mg/d (2 x the approved dose, n=27) was administered for 28 days, which included a 10-day dose escalation (0.23 mg/d x 4 d, 0.46 mg/d x 3 d, and 0.92 mg/d x 3 d). Lymphocyte subset counts were evaluated at baseline and at 7±2 and 75±10 days after cessation of ozanimod. Lymphocyte subsets were measured using an epigenetic platform and are summarized descriptively as mean (standard deviation [SD]) percentage change from baseline.

Results

At 7±2 days after cessation of ozanimod, total lymphocyte counts were reduced by 52.4% (23.0) from baseline and CD3+ T cells were reduced by 49.7% (20.1). Within the T-cell population, CD4+ (−56.1% [22.5]), CD8+ (−39.3% [24.5]), regulatory T cells (−31.6% [30.3]), and Th17 cells (−36.5% [27.2]) were reduced from baseline. Total B cells (−56.3% [25.3]) and memory B cells (−46.6% [16.5]) were also reduced. At 75±10 days after cessation of ozanimod, total lymphocytes and all subsets had recovered to near baseline values, although at different rates. Total lymphocytes (−18.3% [26.1]) had less recovery than CD3+ (−4.8% [28.0]), CD4+ (−14.5% [27.5]), and CD8+ (−11.0% [26.0]) T cells. Th17 cells (3.8% [33.5]) recovered faster than regulatory T cells (−15.4% [28.8]). Total B cells (−18.6% [25.1]) and memory B cells (−18.9% [24.7]) had recovered less than T cells.

Conclusions

Ozanimod induced differential declines in T and B cell subsets in HV. By the final assessment at 65‒85 days after cessation of ozanimod, all cell populations evaluated showed gradual and variable rates of recovery to near baseline levels, indicative of a return of circulating lymphocytes toward pre-treatment levels.

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Clinical Trials Poster Presentation

P0229 - Quiescent MRI activity in neuromyelitis optica spectrum disorder: results from the N-MOmentum randomized placebo-controlled trial (ID 1292)

Abstract

Background

Magnetic resonance imaging (MRI) findings in patients with neuromyelitis optica spectrum disorder (NMOSD) have not previously been studied with data from a prospective, randomized controlled study. During N-MOmentum, longitudinal MRIs were performed systematically.

Objectives

To characterize MRI findings in patients with NMOSD in the N-MOmentum study of inebilizumab. .....................

Methods

MRIs of the spinal cord, optic nerve and brain were performed at baseline, within 8 days of an NMOSD attack and at the end of the randomized controlled period (RCP; month 6.5). MRIs were read centrally by two independent, blinded-to-treatment neuroradiologists for new gadolinium-enhancing (Gd)-T1 enhancement events. Attacks were adjudicated by an expert committee.

Results

Complete MRI data were available for 192 (83%) of 230 participants, 42 of whom had an adjudicated attack (22 myelitis, 14 optic neuritis, 6 multi-domain). The remaining 38 patients did not have valid post-baseline MRI scans available for analysis. Inter-rater agreement between the two neuroradiologists for gadolinium-enhancing lesions was 98% for brain, 95% for spinal cord and 90% for optic nerve.

At the time of acute adjudicated NMOSD attacks, new Gd-T1 MRI enhancement corresponding to the affected clinical domain was present in 19/22 myelitis attacks (86%) and 11/14 optic neuritis attacks (79%). At the time of acute optic neuritis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 4/14 spinal cord MRIs (29%) and 1/14 brain MRIs (7%). At the time of acute myelitis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 6/22 optic nerve MRIs (27%) and 3/22 brain MRIs (14%).

In the 150 participants without an adjudicated attack, new Gd-T1 MRI enhancements compared with baseline readings were observed in the brain, spinal cord and optic nerve in 3%, 18% and 51% of patients at the end of the RCP, respectively.

Conclusions

At the time of attack, MRI enhancements were highly correlated to the clinical presentations. However, asymptomatic Gd-T1 enhancements were detected outside the symptomatic attack domain in about one-third of cases. Furthermore, subclinical Gd-T1 enhancements were observed in many patients who did not experience clinically overt attacks. Subclinical blood–brain barrier breakdown, particularly in the optic nerve, may be a frequent phenomenon in patients with active NMOSD.

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Clinical Trials Poster Presentation

P0230 - Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS (ID 971)

Abstract

Background

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

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Clinical Trials Poster Presentation

P0231 - Reduced grey matter atrophy in patients with relapsing multiple sclerosis treated with cladribine tablets (ID 951)

Speakers
Presentation Number
P0231
Presentation Topic
Clinical Trials

Abstract

Background

It is increasingly understood that grey matter (GM) atrophy is associated with disability progression and cognitive decline in patients with multiple sclerosis (MS). Previously, we demonstrated that treatment with cladribine tablets 3.5 mg/kg bodyweight (CT3.5; cumulative dose over 2 years) in the CLARITY study (NCT00213135) decreased brain atrophy compared with placebo, which was closely associated with a lower risk of disability progression [De Stefano et al. MSJ 2018].

Objectives

Post hoc evaluation of GM and white matter (WM) volume changes in patients with relapsing MS randomized to CT3.5 or placebo in the CLARITY study.

Methods

Images from pre-gadolinium T1-weighted magnetic resonance imaging scans of patients randomized to CT3.5 or placebo for 2 years in CLARITY were evaluated using SIENA-XL software. Images from 0–6 months (CT3.5, n=267; placebo, n=265) were analyzed independently of images from 6–24 months (CT3.5, n=184; placebo, n=186) to account for the potential effects of pseudoatrophy. Annualized mean changes in percentage of GM volume (PGMV) or WM volume (PWMV) between CT3.5 and placebo for 0–6 and 6–24 months were compared using a variance model.

Results

CT3.5 reduced GM and WM volume vs placebo in the first 6 months, consistent with pseudoatrophy [PGMV change: CT3.5 -0.53 vs placebo -0.25 (p=0.045); PWMV change: CT3.5 -0.49 vs placebo -0.34 (p=0.137)]. Brain volume loss from 6–24 months was reduced in patients randomized to CT3.5 with the difference between CT3.5 and placebo significant for GM [PGMV change: CT3.5 -0.90 vs placebo -1.27 (p=0.026); PWMV change: CT3.5-0.32 vs placebo -0.40 (p=0.52)].

Conclusions

Volume loss reduction in WM and, particularly, in GM was noted from 6-24 months in CT3.5-treated patients vs placebo, after a period of pseudoatrophy (0-6 months). Such findings suggest that CT3.5 significantly reduces brain atrophy predominantly in the GM, an effect that may contribute to lower risk of disability progression.

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Clinical Trials Poster Presentation

P0232 - Safety and efficacy of dimethyl fumarate in patients with primary progressive multiple sclerosis: A double-blind, randomized phase 2 trial (ID 1651)

Presentation Number
P0232
Presentation Topic
Clinical Trials

Abstract

Background

Dimethyl fumarate (DMF) has been shown to have immunomodulatory and neuroprotective properties that may inhibit disease progression in patients with progressive multiple sclerosis (MS). Increased levels of neurofilament light chain (NFL) in blood or cerebrospinal fluid (CSF) indicates neuroaxonal damage, and concentrations significantly decrease upon treatment with DMF in relapsing-remitting MS.

Objectives

To evaluate the efficacy and safety of DMF therapy in primary progressive MS (PPMS) in a randomized placebo-controlled phase 2 trial with change in NFL in CSF as primary outcome.

Methods

The study was conducted at Copenhagen University Hospital Rigshospitalet, Denmark. Participants with PPMS were randomly assigned 1:1 to treatment with 240 mg DMF twice daily or placebo for 48 weeks. Primary endpoint was change in NFL in CSF from screening to week 48. Secondary endpoints were change in CSF concentrations of myelin basic protein (MBP), B-cell maturation antigen, chitinase-3-like-1, soluble CD27, soluble CD14, IgG-index, and albumin quotient; change in fractional anisotropy of normal-appearing white matter, magnetization transfer ratio of lesions, mean thalamic volume, difference in number of new or enlarged T2 lesions, and percentage brain volume change; and change in expanded disability status scale, timed 25-foot walk test, 9-hole peg test, and symbol digit modalities test. ClinialTrials.gov: NCT02959658.

Results

54 patients were randomized from December 2016 to January 2018 to placebo (n=27) or DMF treatment (n=27). Mean age was 55 years (SD 6·1), mean disease duration was 14 years (SD 9·4), median EDSS was 4·0 (range 2·0 – 6·5) and mean concentration of NFL in CSF was 844 ng/L (SD 631 ng/L). Twenty-six participants (96%) in the dimethyl fumarate group and 24 participants (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (99 ng/l; 95% CI -292 – 491 ng/l) but we did observe a decrease in CSF concentrations of MBP in patients treated with DMF compared with placebo. Common infections were more frequent in the DMF group. Serious adverse events were comparable between groups.

Conclusions

DMF treatment for 48 weeks did not reduce CSF concentrations of NFL in patients with PPMS but might reduce demyelination as assessed by the CSF concentration of MBP.

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Clinical Trials Poster Presentation

P0233 - Safety and tolerability of conversion to siponimod in patients with relapsing multiple sclerosis: interim results of the EXCHANGE study (ID 1134)

Speakers
Presentation Number
P0233
Presentation Topic
Clinical Trials

Abstract

Background

In the USA, siponimod is approved in adults for the treatment of relapsing multiple sclerosis (RMS), including active secondary progressive MS (SPMS). Understanding washout requirements when converting from other disease-modifying treatments (DMTs) to siponimod is important in clinical practice and should be assessed prospectively.

Objectives

To report results from an interim analysis of EXCHANGE (NCT03623243), a prospective, 6 month, multicenter, open-label, single-arm study evaluating safety and tolerability of overlapping effects when converting to siponimod from other DMTs.

Methods

Patients aged 18-65 years with advancing RMS, Expanded Disability Status Scale (EDSS) score of >2.0 to 6.5, and on continuous oral/injectable DMTs for ≥3 months at time of consent were included in the analysis. Patients were immediately converted to siponimod, except those previously on teriflunomide who required 11-14 days’ washout (with cholestyramine or activated charcoal). During days 1-6, siponimod was titrated from 0.25 mg to 2 mg. Primary endpoint was incidence of drug-related adverse events (AEs). About 100 patients are being enrolled in a parallel, novel virtual cohort, with telemedicine tools.

Results

112 patients (1 in the virtual arm; 70.5% female) from 42 centers in the USA were enrolled, completed screening and were eligible for safety analysis (33.9% ongoing; 20.5% discontinued; 45.5% completed). At screening, 74.1% (n=83) of patients had relapsing-remitting MS, 21.4% (n=24) had SPMS, 3.6% (n=4) had primary progressive MS and 0.9% (n=1) had a single demyelinating event; 42.0% (n=47) had ≥1 relapse in the prior 12 months. At baseline, median age was 45.5 years, median time since MS diagnosis was 11.2 years and median EDSS score was 3.5. In the safety analysis set, ≥1 drug-related AE was reported in 34.8% of patients (n=39) (95% confidence interval [CI]: 26.2-44.5); 4.5% (n=5) had ≥1 serious AE and 5.4% (n=6) had ≥1 AE leading to drug discontinuation. In the subgroup of patients who had completed or discontinued from the study (n=74), 40.5% (n=30) (95% CI: 29.5-52.6) had ≥1 drug-related AE. Change from baseline in heart rate to 6 hours post first dose and AEs by prior DMT will be presented.

Conclusions

Conversion from oral/injectable DMTs to siponimod without washout had a good safety and tolerability profile with no unexpected findings. Subsequent analyses will include data on conversion to siponimod from infusible (natalizumab/ocrelizumab) DMTs.

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Clinical Trials Poster Presentation

P0234 - Safety experience with extended exposure to ofatumumab in patients with relapsing multiple sclerosis from Phase 2 and 3 clinical trials (ID 1638)

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide in Phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials. Long-term data to assess the safety and benefit-risk profile of ofatumumab 20 mg per month is required.

Objectives

To report the overall safety data of all patients treated with subcutaneous (s.c.) ofatumumab 20 mg for RMS, including patients who continued treatment and those who were newly switched in the ongoing open-label Phase 3b ALITHIOS study.

Methods

The overall safety population was divided into 2 groups 1) Continuous: Patients randomized to ofatumumab in the core Phase 2 APLIOS (12 weeks) or Phase 3 ASCLEPIOS I/II (up to 30 months) trials and continued in ALITHIOS, or completed core study and continued with the safety follow-up, and 2) Newly-switched: Patients randomized to teriflunomide in ASCLEPIOS I/II and switched to ofatumumab in ALITHIOS. All adverse events (AEs), serious AEs (SAEs) and deaths up to and including the safety cut-off of 100 days after last administration of ofatumumab are included in this safety analysis until 30 November 2019.

Results

A total of 1873 patients (continuous: 1230; newly-switched: 643) were exposed to ofatumumab ([median duration] continuous: 21.0 months; newly-switched: 4.4 months) for 2118.6 patient-years (continuous: 1903 patient-years; newly-switched: 215.6 patient-years). 71.4% of patients (continuous: 82%; newly-switched: 51%) experienced at least one AE; most were mild-to-moderate. AEs led to ofatumumab discontinuation in 3.0% of patients. SAEs were observed in 6.2% of patients. Incidence of infections was 38.5% (continuous: 49.3%, newly-switched: 18.0%). Serious infections occurred in 1.8% of patients. Incidence of injection-related reactions (IRRs) was 23.7% (continuous: 24.9%; newly-switched: 21.3%); most IRRs were non-serious, grade 1 or 2 and none led to ofatumumab discontinuation. Hepatitis B reactivation, progressive multifocal leukoencephalopathy or deaths have not been reported. No cases of opportunistic infections have been identified. Incidence of malignancies was 0.3% (with confounding) and no new cases have been reported in either continuous or newly-switched patients as of the data cut-off time.

Conclusions

No new safety signals were identified in this extended analysis. The safety profile of ofatumumab in RMS patients remains consistent with data reported in the core studies, including the ASCLEPIOS I/II trials.

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Clinical Trials Poster Presentation

P0235 - Safety of the Bruton’s tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis during an open-label extension to a phase II study (ID 1687)

Speakers
Presentation Number
P0235
Presentation Topic
Clinical Trials

Abstract

Background

In a Phase II randomized study (NCT02975349) in patients with relapsing MS, evobrutinib (EVO) 75 mg twice-daily (BID) reduced total T1 Gd+ lesions (primary endpoint) and annualized relapse rate (ARR) over 24 weeks versus placebo, with efficacy maintained through Week 108. EVO was generally well tolerated.

Objectives

To describe the safety profile of EVO in the long-term treatment of MS by reporting detailed safety data from the study’s open-label extension (OLE) over 60 weeks.

Methods

In the 48-week double-blind period (DBP), patients received EVO 25 mg once-daily (QD) or 75 mg QD, 75 mg BID, or placebo for the first 24 weeks. All arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to EVO 25 mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75 mg QD (for a median of ~48 weeks) before switching to 75 mg BID. Safety was assessed throughout the OLE by the nature, severity, and occurrence of treatment emergent adverse events (TEAEs) by NCI-CTCAE v4.03 criteria, as well as vital signs, ECGs, and clinical laboratory safety parameters.

Results

Of 213 patients who received EVO during the double-blind period, 164 (77%) entered the OLE (safety analysis population) and 148 (90%) completed 60 weeks of treatment. Overall, 107 (65.2%) patients had a treatment emergent adverse event (TEAE), the majority of which were mild (47.6%) or moderate (36.0%), and none led to death. TEAEs were balanced across previous DBP treatment groups; the most frequent TEAEs over the OLE period, including the dose-switch, were nasopharyngitis (7.9%, Grade 2 or less), increased lipase (7.9%, Grade 3 or less), upper respiratory tract infection (6.1%, Grade 2 or less), and urinary tract infection (4.9%, Grade 2 or less); analysis of TEAEs by exposure-adjusted incidence rate showed no evidence of an increase after patients switched to 75 mg BID. Thirteen patients (7.9%) reported a serious TEAE, most frequently related to infections (6 patients, not treatment-related). Five patients (3.0%) had a TEAE during the OLE that led to treatment withdrawal, of which 3 were considered related to treatment (nausea, increased lipase, and increased lipase and amylase). The incidence of overall infections in the OLE was similar to that observed in the DBP. Transient elevated liver aminotransferases reported in the 48-week DBP were not observed in the OLE after prolonged treatment or after the switch to 75 mg BID. No adverse ECG findings were noted across all evobrutinib groups. There was also no apparent effect of EVO dose received in the DBP on safety parameters in the OLE.

Conclusions

In a 60 week OLE period of a Phase II study, the safety of EVO was similar to that seen in the DBP. Overall, long-term EVO treatment was generally well tolerated in patients with relapsing MS.

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Clinical Trials Poster Presentation

P0236 - Serum immunoglobulin levels and infection risk in the Phase 3 trials of ofatumumab in relapsing multiple sclerosis (ID 1566)

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy vs teriflunomide with a favorable safety profile in relapsing MS (RMS) patients in the Phase 3 ASCLEPIOS I/II trials. Reductions in serum immunoglobulin (Ig) M and IgG levels are associated with anti-CD20 therapies.

Objectives

To assess the effect of ofatumumab on serum Ig levels and evaluate potential association between a decrease in IgM/IgG levels and risk of infections.

Methods

Patients were randomized to receive subcutaneous ofatumumab 20 mg (initial doses: Days 1, 7, and 14; subsequent doses: every 4 weeks from Week (W) 4 onwards) or oral teriflunomide 14 mg once-daily for up to 30 months (m, mean follow-up duration: 18m). Serum IgM/IgG levels were monitored at baseline (BL), W4, W12, and every 12 weeks thereafter (ofatumumab, n=946; teriflunomide, n=936). Proportion of patients with IgM/IgG levels below the lower limit of normal (<LLN [g/L]: IgM, 0.4; IgG, 7.0), and association of IgM/IgG levels with incidence of infections that occurred up to 1m prior and 1m after any decrease in IgM/IgG levels (<LLN vs ≥LLN) were analyzed. Infections in conjunction with IgM/IgG <LLN and lymphopenia and/or neutropenia on the same visit were also analyzed.

Results

Mean IgM/IgG levels were well within reference ranges over time. Over all post-BL visits, a higher proportion of patients on ofatumumab had IgM<LLN (17.7% vs 6.6%), whilst a lower proportion had IgG<LLN (14.2% vs 22.9%) vs patients on teriflunomide. At W96, a similar trend was observed (IgM<LLN: 11.1% vs 1.9%; IgG<LLN: 2.7% vs 6.0%). Proportion of patients on ofatumumab who experienced ≥1 infection within 1m prior and until 1m after IgM<LLN was 31.1% (52/167; 2 serious) vs 51.5% (400/777) with IgM≥LLN (18 serious). Similarly, 27.6% (37/134) reported infections during a drop in IgG<LLN (3 serious) vs 50.6% (410/810) with IgG≥LLN (21 serious). The most common infection was nasopharyngitis. Overall, 1/11 patients with concurrent IgM<LLN and lymphopenia and/or neutropenia, and 7/20 patients with concurrent IgG<LLN and lymphopenia and/or neutropenia reported infections; none were serious.

Conclusions

Reduction in serum IgM levels was observed over time, but for the majority of patients, Ig levels remained above the lower limit of normal. No decrease in IgG levels was reported within the observation period (mean follow-up: 18m). There was no apparent association between decreased Ig levels and infections in conjunction with lymphopenia and/or neutropenia in ofatumumab-treated RMS patients.

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Clinical Trials Poster Presentation

P0237 - Sustained reduction in 48-week confirmed disability progression in patients with PPMS treated with ocrelizumab in the ORATORIO OLE: 7-year follow-up (ID 109)

Speakers
Presentation Number
P0237
Presentation Topic
Clinical Trials

Abstract

Background

The efficacy and safety of ocrelizumab (OCR) in primary progressive multiple sclerosis were demonstrated vs placebo (PBO) in the Phase III ORATORIO study (NCT01194570).

Objectives

To assess the efficacy of switching to or maintaining OCR therapy on 48-week confirmed disability progression (CDP), in the open-label extension (OLE) of ORATORIO, over 7 years (360 weeks).

Methods

In the double-blind period (DBP), patients were randomized to OCR or PBO and followed for ≥120 weeks until a prespecified number of CDP events occurred. At DBP completion, patients remained on blinded treatment until the trial outcome was determined (extended controlled period; ECP). At OLE start, patients continued OCR (OCR-OCR) or switched from PBO to OCR (PBO-OCR). Time to 48-week CDP-EDSS (Expanded Disability Status Scale [EDSS] score increase from baseline [BL] of ≥1 point if BL EDSS ≤5.5 or ≥0.5 points if BL EDSS >5.5), time to 48-week CDP on the 9-Hole Peg Test (CDP-9HPT; ≥20% increase from BL in timed 9HPT) and time to 48-week confirmed EDSS≥7 (wheelchair requirement) are presented up to Week 360.

Results

Overall, 72% of patients entered the OLE. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 48-week CDP-EDSS in the PBO-OCR and OCR-OCR groups was 44.4% vs 30.5% (Δ=13.9%; p<0.001), respectively; at Week 360 the corresponding proportions were 65.7% vs 54.2% (Δ=11.6%; p=0.006). At Week 168, the proportion of patients with 48-week CDP-9HPT in the PBO-OCR and OCR-OCR groups was 27.9% vs 15.8% (Δ=12.1%; p<0.001); at Week 360 the corresponding proportions were 41.6% vs 31.1% (Δ=10.6%; p=0.014), respectively. At Week 168 the proportion of patients with 48-week confirmed EDSS≥7 in the PBO-OCR and OCR-OCR groups was 9.1% vs 4.8% (Δ=4.3%; p=0.054), respectively; at Week 360 the proportions were 21.7% vs 12.3% (Δ=9.4%; p=0.009). During the DBP+ECP+OLE, compared with the PBO-OCR group, continuous OCR treatment reduced the risk of CDP-EDSS by 31% (HR [95% CI]: 0.69 [0.56–0.86]; p<0.001), CDP-9HPT by 34% (HR [95% CI]: 0.66 [0.50–0.87]; p=0.003) and 48-week confirmed EDSS≥7 by 44% (HR [95% CI]: 0.56 [0.37–0.85]; p=0.006). Timed 25-Foot Walk, composite CDP and 24-week CDP will also be presented. The OLE safety profile was consistent with the DBP.

Conclusions

After 7 years, 48-week CDP outcomes favoured those on earlier and continuous OCR treatment. Patients initiating OCR 3–5 years earlier had a significantly reduced risk of requiring a wheelchair vs those switching from PBO.

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Clinical Trials Poster Presentation

P0238 - Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years (ID 1471)

Abstract

Background

In the EXPAND Core part, in the subgroup of patients with active secondary progressive multiple sclerosis (aSPMS: presence of relapses in the 2 years prior to screening and/or ≥1 T1 gadolinium-enhancing (Gd+) lesion at baseline), siponimod reduced the risk of 3-/6-month confirmed disability progression on Expanded Disability Status Scale (3m/6mCDP) by 31% and 37%, respectively, and the risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) by 27% versus placebo.

Objectives

To assess the long-term efficacy and safety of siponimod in patients with aSPMS in the Core and Extension parts of the EXPAND study.

Methods

In patients with aSPMS who had received ≥1 dose of randomized treatment during Core part, and who entered the Extension (36 month extension data cut-off [6 April 2019]; total study duration ≤5 years), time to 3m/6mCDP, 6mCCW, and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in the Core and Extension) and Switch (placebo in the Core and switched to open-label siponimod in the Core/Extension) groups.

Results

Of the 1651 patients randomized in the EXPAND Core part, 779 were with aSPMS (Continuous group: N=516; Switch group: N=263), of which 582 entered the Extension. The risk of 6mCDP was reduced by 29% (0.71 [0.57‒0.90]; p=0.0044) for the Continuous versus Switch group, corresponding to an about 70% delay in time to 6mCDP across the 25th–40th percentile). Median time to 6mCDP was 48 months for the Switch group and was not reached for the Continuous group. The risk of 6mCCW for the Continuous versus Switch group was reduced by 33% (0.67 [0.53‒0.86]); p=0.0018), corresponding to an about 70% delay in time to 6mCCW across the 25th–30th percentile, median time to 6mCCW (55.5 months) was reached only for the Switch group. In patients without active disease, a nonsignificant trend for reduced risk of disability progression and cognitive worsening was observed for the Continuous vs Switch groups. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with (0.08 vs 0.12; p=0.0023) or without active disease (0.03 vs 0.08; p<0.0001).

Conclusions

In EXPAND, long-term data analyses in the Continuous versus Switch groups showed that siponimod treatment effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained for up to 5 years, and highlight the value of early treatment initiation.

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Clinical Trials Poster Presentation

P0239 - Temelimab for prevention of neurodegeneration: preclinical safety profile and design of the ProTEct-MS (temelimab following rituximab in RMS) study (ID 1803)

Abstract

Background

Background: The envelope protein of the human endogenous retrovirus type W (HERV-W ENV) is expressed in chronic active MS lesions. Preclinical models have shown that HERV-W ENV activates microglia, prevents maturation of oligodendrocyte precursor cells, and leads to neuronal death. Following the effects of a B-cell depleting, anti-inflammatory therapy, rituximab (RTX), with temelimab (TML), a humanized, IgG4-κ monoclonal antibody against HERV-W ENV represents a novel therapeutic approach against neurodegenerative features of MS.

Objectives

Objective: To present safety preclinical results on the interaction of RTX and TML, and the trial design of the ProTEct-MS study.

Methods

Design/Methods: Interactions between RTX and TML were studied in vitro in high density-peripheral blood mononuclear cells (PBMCs) and ex-vivo in a whole blood loop system from fresh human blood.

ProTEct-MS is a randomized, double-blind, placebo controlled, parallel group study. Enrolment commenced in 2020/6 and will be completed in 2020/12. Patients with RMS (2017 McDonald criteria) (N=40) being previously treated for ³12 months with RTX are randomized (1:1:1:1) to monthly iv TML (18, 36 or 54mg/kg) and placebo for 48 weeks.

Eligibility criteria: age 18-55 yrs, Expanded Disability Status Scale (EDSS) of 2.5-5.5 at screening; clinical worsening in ³1 neurological domain as assessed by EDSS, 6MWT or T25FW, or cognitive functioning as assessed by SDMT over the last year.

Primary objective: assessment of safety and tolerability of TML

Secondary outcome measures: MRI: change of brain atrophy, lesion volume and magnetization transfer ratio

Results

Results: Co-administration of TML with RTX was overall comparable to vehicle for all blood parameters assessed including cytokine levels of all five donors tested in both in vitro and ex-vivo assays. Co-administration of TML with RTX did not affect the functionality profile of either compound. By September 2020, 25% of patients are expected to be randomized, providing baseline clinical and MRI characteristics.

Conclusions

Conclusions: Preclinical safety experiments of the drug combination showed no evidence against the use of TML following RTX in humans. ProTEct-MS study patients represent a RMS cohort with progression in absence of relapse activity (PIRA,) i.e. whose present clinical condition is stable under RTX therapy, enabling TML's effects on attenuating mechanisms of progression to be measured without interference by acute inflammatory activity.

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Clinical Trials Poster Presentation

P0240 - Therapeutic Decisions in MS Care: An International Study comparing Clinical Judgement vs. Information from Artificial Intelligence-Based Models (ID 752)

Abstract

Background

The rapidly evolving therapeutic landscape of multiple sclerosis (MS) can make treatment decisions challenging. Novel tools using artificial intelligence (AI) can provide estimations of MS disease progression, which may aid MS therapeutic decisions. However, whether neurologists are willing to utilize information provided by AI-based models when making therapeutic decisions is unknown.

Objectives

To assess whether neurologists rely on clinical judgment (CJ) or quantitative/ qualitative estimations of disease progression provided by hypothetical AI-based models (assuming these models can reliably identify patients at high vs. low risk of disease progression) in simulated MS case scenarios.

Methods

Overall, 231 neurologists with expertise in MS from 20 countries were randomized to receive qualitative (high/low) or quantitative (85-90% vs. 15-20%) information regarding the likelihood of disease progression. Participants were presented with simulated MS case scenarios, and initially made 7 treatment decisions based on the clinical information using CJ. After randomization, participants made 10 treatment decisions using CJ and estimations of disease progression provided by AI models. We evaluated concordance and discordance of therapeutic decisions based on CJ and AI. The primary outcome was the proportion of “optimal” treatment decisions defined as treatment escalation when there was evidence of disease progression or continuing the same treatment when clinically stable. Mixed models were used to determine the effect of randomization group, case risk level, and CJ/AI. Clinicaltrials.gov #NCT04035720

Results

Of 300 neurologists invited to participate, 231 (77.0%) completed the study. Study participants had a mean age (SD) of 44 (±10) years. Of 2310 responses, 1702 (73.7%) were classified as optimal. Optimal decisions were more common for the high-risk vs. low-risk CJ group (84.5% vs 57.6%; p<0.001). There were no differences in the estimated odds of optimal responses between the quantitative vs. qualitative groups (OR 1.09; 95%CI 0.86, 1.39) after adjustment for pre-intervention responses. The estimated odds of optimal decisions for the high-risk vs low-risk CJ group was 2.96 (95%CI: 2.47, 3.56 ) after adjusting for group, pre-intervention responses, and AI-based estimations. For low-risk CJ cases, additional input by AI-based estimations was associated with a lower likelihood of optimal responses; being worse for high-risk vs. low-risk AI estimations (OR 0.235; 95%CI: 0.16, 0.340) adjusting for covariables.

Conclusions

Neurologists were more likely to make optimal treatment choices for high-risk simulated scenarios. The addition of hypothetical information provided by AI-based models- did not improve treatment decisions for low-risk cases. These results provide a framework for understanding therapeutic decision-making in MS neurologists, who are more reliant on their own CJ over AI-based tools.

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Clinical Trials Poster Presentation

P0241 - Top-line Results of EMPhASIS, a Phase 2 Clinical Trial of Vidofludimus Calcium (IMU-838) in Relapsing-Remitting Multiple Sclerosis (ID 1409)

Speakers
Presentation Number
P0241
Presentation Topic
Clinical Trials

Abstract

Background

Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for disease-modifying treatment of relapsing-remitting multiple sclerosis (RRMS). Vidofludimus calcium (IMU-838) is a selective and potent second-generation DHODH oral immunomodulator being developed for the treatment of several immune-mediated diseases including MS and COVID-19. The inhibition of the DHODH enzyme leads to metabolic stress in stimulated lymphocytes with subsequent reduction of pro-inflammatory cytokines and induction of apoptosis. Due to IMU-838’s pharmacological selectivity and lack of relevant off-target effects on kinases, increased rates of typical antiproliferative effects (neutropenia, alopecia and gastrointestinal disturbances) have not been observed in clinical trials. The serum half-life of approximately 30 hours allows quick on- and off-dosing.

Objectives

To report top­line efficacy, safety, and tolerability of IMU-838 in the relapsing MS EMPhASIS trial (NCT03846219), the first trial of IMU-838 in MS.

Methods

EMPhASIS is a phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of two once-daily oral doses of IMU-838 (30 and 45 mg/day) in patients with RRMS. Inclusion criteria are age 18-55 years, active RRMS defined by the evidence of clinical and radiological disease activity, and Expanded Disability Status Scale (EDSS) 0-4. The primary endpoint is the cumulative number of combined unique active MRI lesions over 24 weeks. Secondary endpoints include efficacy, safety and tolerability parameters. The study also includes a subsequent optional, open-label treatment period to evaluate long-term safety and tolerability.

Results

210 subjects (65% women) were enrolled in 36 centers across four European countries. The mean age at baseline was 36.8 years (SD 8.8). 198 subjects (94%) completed the 24-week main treatment period, with the last follow-up visit in April 2020. Database lock will be in July 2020 and top-line data will be available shortly thereafter. Primary outcome and several secondary outcomes (including safety data) will be presented.

Conclusions

IMU-838 is an orally available, next-generation selective immunomodulator with a potentially more favorable profile than first-generation DHODH inhibitors. Top-line results of IMU-838 on primary and several secondary endpoints in patients with RRMS in the EMPhASIS trial will be presented.

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Clinical Trials Poster Presentation

P0242 - Treating minority patients with multiple sclerosis: development of the CHIMES trial (ID 1212)

Speakers
Presentation Number
P0242
Presentation Topic
Clinical Trials

Abstract

Background

Minority patients with multiple sclerosis (MS), including those of African ancestry (AA) and Hispanic and Latino ethnicity (HA), have greater disease severity and faster progression than Whites. Minorities are vastly underrepresented in clinical trials, owing to poor access and cultural, economic and other participation barriers. Ocrelizumab (OCR), an anti-CD20 therapy targeting B cells, reduced the rates of disease activity and progression in patients with relapsing MS (RMS) and primary progressive MS in pivotal studies; however, minority participation was <10%.

Objectives

To investigate the efficacy and safety of OCR in AA and HA patients with RMS (2017 McDonald criteria) who meet the US prescribing information criteria in a single-arm Phase IV clinical study designed exclusively to meet the needs of these specific demographic groups.

Methods

An industry-sponsored collaborative approach rooted in minority needs and known knowledge gaps was used.

Results

Key differences between CHIMES (NCT04377555) and other MS trials are as follows:

1. CHIMES was developed in collaboration with patients with MS, patient advocacy groups and investigators.

2. Inclusion criteria allow for ≈150–200 participants with specific, well-controlled, pre-existing comorbidities and baseline creatinine levels within race-specific limits; these factors may disproportionately limit minority patient qualification in other trials.

3. OCR was chosen because of the indications that AA patients with MS may have greater B-cell–mediated pathology, such as a higher CSF IgG index.

4. Written materials will be available in English and Spanish and will be reviewed by a minority patient panel to ensure that they are easy to understand.

5. To enable early results, the primary endpoint is disease activity, defined by the proportion of patients free of protocol-defined events (clinical relapses, CDP or MRI activity) at the end of year 1.

6. All patients may participate in the second-year extension to study disease progression and various biomarker endpoints.

7. One-third of patients will participate in a substudy to assess CSF-specific biomarkers at two time points.

Conclusions

Findings from CHIMES are expected to improve current understanding of MS disease biology, treatment response and clinical trial participation among AA and HA patients with MS, with the ultimate goals of increasing high-quality standard of care to traditionally underserved populations and enhancing equality through clinical research.

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Clinical Trials Poster Presentation

P0243 - VISIONARY-MS: A Phase 2 clinical trial of catalytic gold nanocrystals, CNM-Au8, for the treatment of chronic optic neuropathy (ID 431)

Abstract

Background

Therapies that promote neuroprotection and remyelination are a high priority for multiple sclerosis (MS). CNM-Au8 is an orally delivered suspension of clean-surfaced, faceted gold nanocrystals. CNM-Au8 acts as a nanocatalyst, enhancing cellular bioenergetics, with robust activity in multiple preclinical models of neuroprotection and remyelination. Phase 1 studies identified 15mg and 30 mg per day as well-tolerated doses, with human exposures exceeding those demonstrating preclinical efficacy. No safety issues emerged.

Objectives

To present the rationale for, and design of, the VISIONARY-MS study (NCT03536559), provide clinical trial baseline demographics and visual characteristics, and report interim, blinded efficacy data.

Methods

VISIONARY-MS is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, and pharmacokinetics of CNM-Au8 (15 mg or 30 mg daily) versus placebo for 24 weeks in stable relapsing multiple sclerosis (RMS) patients with chronic optic neuropathy, currently receiving disease-modifying therapy (DMT). Key inclusion criteria: age 18-55 years, diagnosis of RMS, disease duration £ 15 years, no history of optic neuritis (ON) for 6 months prior to entry (+/- ON prior to that), clinically stable on an approved DMT, Best Corrected Low Contrast Letter Acuity (BC-LCLA) ≤ 20/40 in the affected eye and ≤ 20/32 in the unaffected eye [BC-LCLA ≤ Best Corrected High Contrast Letter Acuity (BC-HCVA) in both eyes], and mean retinal nerve fibre layer thickness ³ 70 mm in both eyes.

Primary endpoint: mean change in BC-LCLA, as measured by 2.5% Sloan letter chart, from baseline to week 24. Key secondary endpoint: mean change in average mf-VEP latency in the mf-VEP affected eye (greatest mf-VEP latency delay at Baseline) from baseline to Week 24.

Other exploratory outcomes: changes in mf-VEP amplitude and latency measures, retinal morphology, nerve fibre layer thickness, magnetic resonance imaging metrics [T1 Black Hole lesion volume, diffusion tensor imaging, magnetization transfer imaging (MTR) and myelin water imaging], EDSS, 25-Foot Timed Walk, Symbol Digit Modality Test, 9-Hole Peg Test and quality of life from baseline to Week 24.

Results

The study commenced in December 2018. Enrolment is ongoing at selected sites in Australia and North America. Baseline demographics and visual characteristics will be presented. Available interim, blinded efficacy data will be presented.

Conclusions

VISIONARY-MS represents the first efficacy study for a completely novel therapeutic catagory. CNM-Au8 is a nanotherapeutic agent providing bioenergetic, catalyitc support to neurons and oligodendroglia precursor cells, resultng in neuroprotection and improved remyelination in an MS population.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0244 - A simple two-step test based on CSF flow cytometry helps to discriminate MS from other inflammatory and non-inflammatory neurologic disorders (ID 1943)

Speakers
Presentation Number
P0244
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Several studies have shown that relative proportions of B-lineage cells are increased in CSF of patients with MS as compared to other inflammatory (OIND) and non-inflammatory (NIND) neurologic disorders. We hypothesized that the relative proportion of CD19+ and plasma (CD19+138+) cells in CSF, as assessed with commercially available flow cytometry, could be useful for improving the specificity of MS diagnostics.

Objectives

1. To determine whether a combination of elevated CD19+ cells and plasma (CD19+138+) cells in CSF (‘CD19/Plasma Cell Test’) allows for accurate differentiation of MS from OIND (e.g. MOG Ab disorder, neurosarcoidosis, Susac syndrome) and between MS and NIND (e.g. stoke, malignancies, conversion disorder). 2. To compare the sensitivity and specificity of CD19/Plasma Cell Test to that of oligoclonal bands (OCB) in CSF.

Methods

We retrospectively reviewed the charts of consecutive patients evaluated at NYU Langone Medical Center between 1/2013 - 3/2020 for whom lymphocyte subtyping in CSF was available. We defined ‘elevated CD19 count’ as >1% of total lymphocyte count in CSF and ‘elevated plasma cell count’ as >0.1% of total lymphocyte count in CSF. We calculated proportions of patients with elevated CD19 and, within this subset, of patients with elevated plasma cell counts for MS, OIND, and NIND. We calculated the sensitivity and specificity of the CD19/Plasma Cell Test for discriminating MS from OIND and from NIND.

Results

The cohort was comprised of 69 patients with MS (age at LP: 39.1 ±11.7 years; 64% female, 65% white), 25 with OIND (age - 45.3±13.7; 56% female; 48% white), and 43 with NIND (age - 48.5 ±14.8; 63% female; 70% white). OCB (2 or more) were present in 51/67 MS patients (76%), 10/13 IND (77%) and 0/38 NIND (0%). Thus, OCB had sensitivity 76% for MS, and specificity of 56% for MS when compared to OIND, and 100% when compared to NIND. Elevated CD19 count was found in 45/69 MS patients (65%), 10/25 OIND (40%), and 8/43 of NIND (18%). Of the patients with elevated CD19 count (N=63), 27 MS patients, 3 OIND and 0 NIND patients had an elevated plasma cell count. Thus, a two step-test that sequentially assesses for elevated CD19 count and elevated plasma cell count, has sensitivity of 39% for MS, specificity of 88% for discriminated MS from OIND, and 100% for discriminating MS from NIND.

Conclusions

OCB have high sensitivity for MS, but lack specificity for discriminating MS from OIND. A simple, two-step CD19/Plasma Cell Test, based on widely available flow cytometry assay, was inferior to OCB with regard to sensitivity for MS (39% v. 76%), but superior with regard to specificity (88% v 56%) for discriminating MS from OIND. Both tests had excellent specificity for differentiating MS from NIND.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0245 - An unusual mimic of progression in Multiple Sclerosis patients (ID 253)

Speakers
Presentation Number
P0245
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Superficial siderosis (SS) is a rare disease caused by hemosiderin deposition in central nervous system and typically leads to neurological dysfunction and progressive irreversible symptoms. Multiple Sclerosis is most common demyelinating disease which usually courses with relapses and remissions but some patients can have a progressive course. Progression in MS patients is defined as a worsening of functional systems over one year.

We are presenting MS patient since 1994 who developed in last three years a progressive ataxia which was initially attributed to MS progression, nevertheless MRI showed hypointensities on cerebellum that led us to diagnose SS. Recognizing this entity is important because it could be a cause of pseudo progression in MS patients.

Objectives

We want to disclose the superficial siderosis as an unusual cause of pseudo-progression in patients affected by multiple sclerosis.

Methods

A 63 year-old woman with history of relapsing-remitting MS (RRMS) treated with Glatiramer acetate. She was stable until 2017, but since then she started to notice clumsiness of her both hands and difficulties to walk. She even had some falls because of unsteady gait.

Her Expanded Disability Status Scale (EDSS) passed from 2.0 to 4.5 due to worsening of cerebellar functional system and the using of a cane for walking. Over next three years she had progressive impairment of gait and coordination of all limbs. Sensorineural hearing loss of unknown cause was also diagnosed during this time. On last neurological examination she presented mild cerebellar dysarthria, moderate ataxia of all limbs, ataxic gait and need to walk with bilateral support. Other signs of the neurological examination were mild decrease of vibration and brisk reflexes on lower extremities. Currently her EDSS is 6.5

A cerebellar relapse was ruled out as cause of her symptoms because of progressive course, no recovery after steroids and no evidence of new T2 lesions on cerebellum. A RRMS turning into SPMS was initially accepted as responsible of her worsening.

Results

A comprehensive approach was performed, as there was an almost exclusive deterioration of the cerebellar functional system. So, a new brain MRI was requested and hemosiderin effect was seen along cerebellar folias. This finding was the key to diagnose superficial siderosis.

A neuroaxis MRI evaluation was done and there was no evidence of SS in other parts of CNS nor evidence of chronic bleeding that causes SS on cerebellum.

We proposed to initiate treatment with Deferiprone but the patient rejected to take it after we exposed lack of clear effectiveness. She is still being treated with Glatiramer acetate for MS.

Conclusions

Superficial siderosis can be a mimic of progression in patients affected by multiple sclerosis, that is why we recommend to take into account this entity in those patients with progressive worsening of walking secondary to exclusive affectation of cerebellar functional system.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0246 - Clinical relevance of Kappa Free Light Chain index to evaluate intrathecal IgG synthesis: prospective study compared to oligoclobal bands (ID 1489)

Speakers
Presentation Number
P0246
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

An early and specific diagnosis of MS leads to an early treatment to better control the disease and its progression. Importance of immunoglobulin G (Ig G) synthesis in cerebrospinal fluid (CSF) has been re-emphasized for multiple sclerosis (MS) diagnosis since Mc Donald 2017 criteria. This synthesis is currently measured through the oligoclonal bands (OCB) using isoelectric focusing (ISE) technic, which is a time-consuming, expensive and may be difficult to interpret. Measurement of kappa free light chain (KFLC) in CSF and serum could offer a faster, standardized and less expensive way to evaluate the intrathecal Ig G synthesis.

Objectives

Primary objective is to test the relevance of KFLC index measurement in the diagnosis of MS compared with OCB measurement, using sensitivity and specificity of KFLC index in the diagnosis of MS. Secondary objective is to calculate a KFLC index threshold defining the IgG intrathecal synthesis. Methods: This is a prospective study including consecutively patients admitted in MS centre and/or other department of neurology at Lille University Hospital, who needed to undergo CSF lumbar puncture for CSF analysis. OCB and KFLC indexes were performed for all of them. KFLC index measured by turbidimetric assay on a SPAplus@ (The Binding Site Birmingham, UK).

Methods

We plan to include 250 patients in the study. Preliminary results concern 94 patients: 28 MS patients fulfilling 2017 MS criteria, 9 patients presenting CIS, 15 patients having other inflammatory disease (OID), 42 patients having non inflammatory disease (NOID). All MS patients who had OCB in CSF presented a KFLC index with a median value of 104.9 [6.43-649.7]; 3 MS patients who did not have OCB in CSF presented a median KFLC of 21.6 [10.1-23.4]. Height OID patients and 2 NOID patients had OCB in CSF; OID patients had a median KFLC value of 3.71 [1.7-600.8] and NOID of 3.2 [1.1-162.2].

Results

We plan to include 250 patients in the study. Preliminary results concern 94 patients: 28 MS patients fulfilling 2017 MS criteria, 9 patients presenting CIS, 15 patients having other inflammatory disease (OID), 42 patients having non inflammatory disease (NOID). All MS patients who had OCB in CSF presented a KFLC index with a median value of 104.9 [6.43-649.7]; 3 MS patients who did not have OCB in CSF presented a median KFLC of 21.6 [10.1-23.4]. Height OID patients and 2 NOID patients had OCB in CSF; OID patients had a median KFLC value of 3.71 [1.7-600.8] and NOID of 3.2 [1.1-162.2].

Conclusions

KFLC index seems to be more sensitive than OCB in the diagnosis of MS. Sensitivity, specificity and threshold of KFLC index defining the intrathecal synthesis will be evaluated with the next patients studied.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0247 - Comparison of the 2017 and 2010 revisions of the McDonald criteria in patients with cis suggestive of MS: a multicentre MAGNIMS study (ID 1121)

Abstract

Background

In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.

Objectives

To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.

Methods

Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.

Results

At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).

Conclusions

The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0248 - Consensus guidelines for the timely detection and diagnosis of disease progression in multiple sclerosis patients (ID 1328)

Abstract

Background

Secondary Progressive Multiple Sclerosis (SPMS) is a clinical form of MS characterized by gradual accrual of disability independent of relapses over time. Limited information is available on decision-making in the management of MS. As a consequence, it is frequently diagnosed retrospectively, thus reducing treatment options.

Objectives

To establish consensus on patient monitoring and definition of relevant clinical variables that can support decision making in the early identification and management of disease progression.

Methods

A two-round RAND-UCLA method was used, involving a panel of 15 MS specialists in Spain. A questionnaire consisting of 72 open-ended questions from 3 dimensions (clinical, radiological and biomarkers) was circulated to the experts in Round I. Eleven additional items were included in Round II based on panel feedback in Round I. Items were rated on a 4-point Likert scale and consensus was defined as ≥66% agreement on an item. Final data are presented.

Results

Panellists agreed on the need of monitoring the patients remaining clinically and radiologically stable while on immunomodulators (93%) or immunosuppressors (73%) every 6 months, leaving the special situations to clinical judgement (80% and 93%, respectively). EDSS is the best variable to define progression (93%); six months is the minimum time to confirm disability progression independent of relapses (87%); a worsening of 2-points in any functional system (except the visual), even without changes in EDSS, suggests progression (80%), regardless of disease duration (> 20 years: 93%; 10-20 years: 87%) and age (87%). 20% time increase in T25-FW and 9HPT, together with an increase in EDSS score, are confirmatory of progression (87%). Panellists agreed to perform an annual cognitive exploration (80%), such as SDMT (100%), BRB-N (93%), BICAMS (93%). Experts agreed to evaluate QoL (80%), depression (73%) and fatigue (73%) once annually. A sustained change in brain atrophy suggests progression (80%) provided major physiological factors have been ruled-out (83%). Sustained medullary atrophy suggests progression (100%) but more precise techniques should be used to confirm a diagnosis (93.3%).

Conclusions

The overall consistency in the level of agreement in the different items is high and reinforces the results obtained. These areas of collective agreement could guide neurologists in anticipating progression and planning informed clinical and therapeutic interventions.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0249 - Demyelinating events following initiation of anti-TNFɑ therapy in the British Society for Rheumatology Biologics Registry in Rheumatoid Arthritis (ID 1695)

Speakers
Presentation Number
P0249
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Anti-tumour necrosis factor-ɑ (anti-TNFɑ) monoclonal antibodies are used to treat a number of autoimmune diseases. They have been associated with de novo central nervous system (CNS) demyelination and increased relapse rate in MS. The British Society for Rheumatology Biologics Register in Rheumatoid Arthritis (BSRBR-RA) is a large, prospective pharmacovigilance study which aims to monitor the safety of anti-TNFɑ.

Objectives

To establish the clinical characteristics, timing and incidence of demyelination in patients who have received anti-TNFɑ therapy.

Methods

BSRBR-RA data were used to identify adverse events reported in patients receiving anti-TNFɑ therapies. MedDRA codes and associated verbatim reports were searched for terms related to CNS demyelination. Patients with no reported demyelination prior to BSRBR-RA entry with at least one completed follow-up form were included. Demyelinating events were classified as definite, probable or possible based on available clinical information, with reference to MacDonald 2017 criteria. Crude rates of demyelination were calculated. Exploratory analyses calculated standardised incidence rates (SIRs) compared to the English population (HES/GPRD data; Mackenzie 2014) in the whole cohort and limited to those with definite/probable demyelination.

Results

38 individuals with demyelinating events were identified from a total pool of 12,980. Median age at study entry was 47 years and median disease duration 8 years; 69% were female. Median age at demyelinating event was 51. Events occurred a median of 3 (IQR 1-5) years from start of first anti-TNF therapy; 27 (71%) occurred within 5 years. Kaplan Meir plots indicated a steady event rate. 28 events occurred in individuals still taking anti-TNFɑ therapy; of the other 10, 6 were within 90 days of drug withdrawal. The crude incidence of demyelination was 21.4/100,000 patient years (95%CI 15.1-29.4). SIR in the whole population was 1.50 (95%CI 1.06-2.05) and 0.91 (0.57-1.36) when limited to definite/probable cases. Males showed a higher point estimate than females in both analyses.

Conclusions

Patients receiving biological therapy for the treatment of RA show a marginally increased SIR; this signal is lost when restricting to those with probable or definite demyelination. The BSRBR-RA provides a robust resource for pharmacovigilance. Patients concerned about demyelination associated with anti-TNFɑ can be relatively reassured that new development of demyelination is unlikely.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0250 - Diagnostic Dilemma in a case of suspected Anti-phospholipid Syndrome (ID 88)

Speakers
Presentation Number
P0250
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Antiphospholipid Syndrome (APS) was first described in 1983 by G R Hughes. Defined as arterial and/or venous thrombosis and recurrent fetal loss in the setting of antiphospholipid antibodies (aPL). It can occur on its own (primary APS) or in association with other diseases (secondary APS), most commonly Systemic lupus erythematosus (SLE). Neurologic manifestations of APS can present with a wide spectrum of clinical symptoms which mimic Multiple Sclerosis (MS)

Objectives

To increase awareness of Antiphospholipid Syndrome as a mimicker of Multiple Sclerosis and the urgency of rapid diagnosis

Methods

We report a case of a 30 year old female patient with recurrent relapses of neurologic symptoms while on near maximum medical therapy for SLE. Utilizing clinical data, Magnetic Resonance Imaging (MRI), and laboratory findings during hospitalization and during follow up. In addition to literature review.

Results

A 30-year-old woman presents with new onset diplopia and imbalance for 24 hours. Past medical history includes a diagnosis of SLE on the basis of diffuse arthralgias, malar rash, two early pregnancy losses and one late term pregnancy loss, livedo reticularis, thrombocytopenia, and ANA, dsDNA, and anti-neuronal autoantibodies. Previous treatment included prednisone, mycophenolate, rituximab, hydroxychloroquine sulfate, and methotrexate for refractory SLE symptoms. For two years prior the patient had intermittent left sided tingling, horizontal diplopia, and spells of weakness. Exam was significant for right incomplete ptosis, weakness of right medial rectus, left internuclear ophthalmoplegia, and vertical nystagmus. MRI revealed: acute punctate infarct in the left medial longitudinal fasciculus, new T2 hyperintensities in the left pons and medulla, and scattered areas of left meningeal enhancement (notably in the posterior fossa). Extensive work-up included cerebrospinal fluid (normal WBC, proteins, glucose, and IgG index, negative oligoclonal bands, and elevated myelin basic protein) and serum (negative for infection, positive for lupus anticoagulant: 1.7 and dsDNA: 1:160, and negative for anticardiolipin and beta 2 glycoprotein). Slight clinical improvement was seen after a five day course of high-dose IV steroids.The patient received an IV infusion of cyclophosphamide and was started on warfarin and daily steroid therapy. Symptom improvement continued at three month follow-up, with stable repeat imaging

Conclusions

Antiphospholipid Syndrome is a rare and challenging yet important to diagnose disease with considerable overlap with other neuroinflammatory conditions. Awareness and timely diagnosis of the disease is important so that the benefit of treatment is not lost.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0251 - Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis (ID 1848)

Speakers
Presentation Number
P0251
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

In patients presenting with ‘transverse myelitis’ without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system (i.e. isolated myelitis), it remains challenging to predict risk of later conversion to multiple sclerosis (MS).

Objectives

To identify early clinical and paraclinical factors that may help predict later conversion to MS in patients presenting with isolated myelitis.

Methods

In this retrospective cohort study, we examined a carefully defined population of patients who attended our specialized myelopathy clinic from 2010 to 2018. We included patients diagnosed with isolated myelitis who were followed clinically and radiologically for at least 1 year. We excluded patients with known MS (defined by the 2017 revised McDonald criteria), aquaporin-4 (AQP4)-IgG seropositivity, myelin oligodendrocyte glycoprotein (MOG)-IgG seropositivity, or other identified etiology of myelitis. Logistic regression was used to identify factors predictive of conversion to MS during follow-up.

Results

We included 100 patients (mean age 40.5 years [SD 12.6], 60% female). Over a median follow-up period of 4.3 years (range, 1.0-17.4 years), 25 patients (25%) converted to MS. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest cord lesion spanning <3 vertebral segments on MRI) as compared to zero of 23 patients with longitudinally-extensive myelitis (0%, p=0.002). Amongst patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariable logistic regression included positive cerebrospinal fluid (CSF)-restricted oligoclonal bands (adjusted odds ratio [OR] 9.18, 95% CI 2.06 to 41.02, p=0.004), younger age (adjusted OR 1.06 for each year younger, 95% CI 1.00 to 1.12, p=0.04) and longer follow-up period (adjusted OR 1.25 for each year longer, 95% CI 1.01 to 1.55, p=0.04). Conversion to MS occurred at a median of 2.77 years (range 0.20-4.39) after onset of myelitis.

Conclusions

Short-segment MRI cord lesion(s), positive CSF-restricted oligoclonal bands, younger age, and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis. Conversion to MS typically occurs within a few years after a bout of isolated myelitis, emphasizing the importance of close clinical and radiological follow-up after such an attack.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0252 - Evolving diagnosis and treatment of secondary progressive multiple sclerosis in the United States (ID 400)

Speakers
Presentation Number
P0252
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

In 2019, the FDA changed the prescribing information to include active SPMS for siponimod, in addition to natalizumab, ocrelizumab, cladribine, fingolimod, dimethyl fumarate, interferons, and glatiramer acetate.

Objectives

Evaluate how US Neurologists are diagnosing secondary progressive (SP) multiple sclerosis (MS) over time. Determine how treatment choices for SPMS are evolving.

Methods

US Neurologists contributed online chart reviews for a cross-sectional audit of patients with SPMS in Q3 2018 (n=168 physicians; 431 SPMS patients) and Q3 2019 (n=147 physicians; 423 SPMS patients).

Results

SPMS transition was diagnosed most commonly by a progressive accumulation of disability independent of relapse activity (57% of patients). SPMS diagnosis in 2019 relied more upon confirmed disability progression (CDP) over 6 months (25% vs. 16% in 2018) and increased rate of brain atrophy (15% vs. 9%). Neurologists relied less upon absence of relapses (12% vs. 24% in 2018), length of time since MS diagnosis (11% vs. 16%), and a decreased annualized relapse rate (6% vs. 11%). In 2019, MS Specialists (n=85) were more likely to identify SPMS by CDP-6M (33% vs. 14%), whereas General Neurologists (n=61) relied more on worsening MRI findings (50% vs. 30%) and decreased walking speed (26% vs. 14%). Compared to the prior year, the proportion with active SPMS increased (66% vs. 58%), with MS Specialists more likely to categorize SPMS patients active compared to General Neurologists (73% vs. 59%). SPMS patients were most likely to be treated with an oral DMT (34%), followed closely by monoclonal antibodies (32%). Siponimod and cladribine use was introduced in 2019, while fingolimod and dimethyl fumarate use declined from 2018 levels.

Conclusions

US Neurologists continue to evolve in diagnosing SPMS, using the active SPMS subtype, and in treatment choices for such patients.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0253 - Gaps in characterization of bladder dysfunction in clinical care and research (ID 1934)

Speakers
Presentation Number
P0253
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Neurogenic bladder dysfunction (BD) affects up to 90% of patients with multiple sclerosis (MS) at some point during the disease course and is a highly debilitating symptom. Despite its prevalence, there are no consensus guidelines for screening and ascertaining BD. These discrepancies could underrepresent the impact of BD on neurological decline.

Objectives

In a cohort of women with MS, we compared clinical notes and research registry scores pertaining to BD. We secondarily evaluated how often Bowel/Bladder Functional System (B/B FS) scores reflected the severity of bladder (rather than bowel) scores.

Methods

For 100 adult women with MS in the University of California, San Francisco longitudinal observational EPIC cohort (epicstudy.ucsf.edu), we retrospectively extracted data on bladder and bowel symptoms and treatments from prospectively collected clinical notes in the electronic medical record and compared them with research-grade B/B FS scores annually collected in the EPIC registry. We performed descriptive statistics to evaluate agreement between the clinical notes (BD) and research B/B FS scores at matching timepoints (within 6 months). Finally, seeking to understand whether the severity of BD could be inferred by the B/B FS, we calculated the frequency that bladder (vs. bowel) symptoms drove a higher B/B FS.

Results

We included 89 women, aged 37 to 77, with at least one matching clinical and research visit; a total of 316 visits were examined. Overall, 63 of the 89 participants (70.7%) experienced BD symptoms per clinical notes. BD symptoms were described in 284 of the 316 visits (89.9%), and research B/B FS scores were available for 283 of these. The severity of BD symptoms matched the research B/B FS in 203 (71.5%) of visits. For the rest, BD symptoms were more severe than research B/B FS for 46 visits and less severe for 34. BD severity “drove” the overall B/B FS score in 280 (98.6%); in contrast, in only 4 visits (1.4%) bowel symptoms were more severe.

Conclusions

We noted moderate discrepancy between clinical notes and research B/B FS; in 10% visits, BD symptoms were not ascertained; and in 16.3% research evaluations, BD symptoms were underscored. Inconsistencies in screening for both clinical care and research point to the need for consensus around consistency of BD symptom ascertainment and B/B FS scoring. Of relevance to interpreting B/B FS in the context of understanding the impact of BD on clinical course, B/B FS in most cases reflected the severity of bladder symptoms.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0254 - Healthcare Professionals (HCPs) categorisation of active and non-active Secondary Progressive Multiple Sclerosis (SPMS) patients (ID 322)

Speakers
Presentation Number
P0254
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Disease Modifying Therapies (DMTs) are increasingly indicated for use in specific patient types, notably ‘active’ Multiple Sclerosis (MS). The need to understand how these patients are categorised amongst HCPs is growing and is of importance in SPMS, with the advent of novel treatments for this patient group.

Objectives

To assess patient profiles of those categorised by HCPs as having active (a-SPMS) and non-active SPMS (na-SPMS) in both the 5EU (UK/France/Germany/Italy/ Spain) and the United States.

Methods

The Ipsos Global MS Therapy Monitor, a multi-centre cross-sectional survey of HCPs (Neurologists; MS nurses included in UK) and retrospective chart-review study of patients with MS runs on a bi-annual basis in 5EU and US. De-identified HCP perceptions and de-identified patient data are collected. HCPs are screened for practice duration (≥3yrs), patient volume (≥15 MS patients/mo.) and recruited from a large panel. HCP perceptions and charts of patients with SPMS abstracted from 10/2019-12/2019 were included in this analysis.

Results

n=344 (5EU) and n=85 (US) patients with na-SPMS and n=275 (5EU) and n=122 (US) patients with a-SPMS were included. Mean average EDSS is similar in na-SPMS versus a-SPMS patients in EU5 and US; 5.41 vs 5.07 (5EU), 4.54 vs 4.45 (US). Despite literature definitions 75.0% of na-SPMS patients (5EU) and 75.0% (US) experienced at least 1 relapse in the last 24 mo. compared to 90.4% (5EU) and 94.4% (US) among a-SPMS patients. Increased lesion load on most recent MRI scan is the key difference between na-SPMS and a-SPMS patient profiles. Of n=333 (5EU) and n=80 (US) na-SPMS patients, 10.5%/3.3% (5EU) and 15.0%/3.8% (US) have ‘increased’ proportion of T2/Gd lesions, respectively. Compared to n=267 (5EU) and n=119 (US) a-SPMS patients where 47.2%/30.7% (5EU) and 60.5%/37.0% (US) have ‘increased’ proportion of T2/Gd lesions, respectively. 259 HCPs (5EU) and 99 HCPs (US) were asked how they monitor progression. Most reported using neurological exam (EU5: 92.3%, US: 94.9%), compared to T2 lesion load (5EU: 68.7%, US:71.7%) and Gd lesion load (5EU: 74.5%, US:73.7%).

Conclusions

In this cohort there is overlap in profiles of a-SPMS patients and na-SPMS patients. Although lesion load change is a key differentiator, the use of MRI to measure progression is not universal. Further investigation is warranted to fully understand diagnosis and categorisation of SPMS patients to ensure successful patient outcomes.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0255 - Improvement during the last decades in the time of diagnosis but not in the time of starting DMD in MS patients in Argentina (ID 1297)

Speakers
Presentation Number
P0255
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

There has been a significant shortening of time from multiple sclerosis (MS) onset to diagnosis in parallel with the adoption of new diagnostic criteria. However, it is not clear whether that time has been accompanied by a shortening in the time since diagnosis to the initiation of disease modifying treatment (DMD).

Objectives

The objective of the study was described and compare the interval from first symptom of MS to the date of diagnosis and the interval between date of diagnosis and DMD initiation regarding the introduction of upgraded MS diagnosis criteria.

Methods

retrospective cohort study that included relapsing remitting MS patients between January 2005 and January 2018. To be included, date of disease onset (first relapse), date of diagnosis (confirmed disease) and date of DMD initiation must be available. Kaplan-Meier estimator and plots were applied. Survival probabilities were evaluated for the 2 diagnosis epoch groups according to the diagnostic criteria advised at the time: group 1, for diagnosis performed between 2005-2009 (2005 revised McDonald criteria) and group 2, for diagnosis performed between 2010-2017 (2010 revised McDonald criteria). Survival curves were compared by log-rank method. P-value less than 0.05 was considered statistically significant

Results

654 patients were revised, 586 included (278 in group 1 and 308 in group 2) and 68 excluded due to missing data. Most of patients in group 1 were treated with beta interferons (82%), while in group 2, 32% were on beta interferons, 45% on oral treatments (fingolimod, teriflunomide and dymethil-fumarate), 15% on natalizumab and 8 % on alemtuzumab. There were no differences in mean age at disease onset between group 1 and 2 (33 ± 5 and 31 ± 6 years, p=0.45). The mean time since disease onset to diagnosis in group 1 was 1.35 ± 0.32 vs. 1.11 ± 0.22 years (p 0.001). Mean time since disease diagnosis to first DMD was 4.6 ± 2.1 months in group 1 vs. 5.8 ± 1.5 months in group 2 (p=0.07).

Conclusions

despite a shorten in time of diagnosis was described a trend to increase the time to initiate a DMD was noted in group 2. An improvement in access to treatments must follow the improvement in diagnosis if it is intended to treat patients earlier to prevent disease progression.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0256 - Inclusion of optic nerve assessed by visual evoked potentials in dissemination in space criteria for the diagnosis of Multiple Sclerosis (ID 1526)

Speakers
Presentation Number
P0256
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Optic nerve (ON) involvement is frequent in multiple sclerosis (MS) and its inclusion as the fifth anatomical location for dissemination in space (DIS) for the diagnosis of MS has been proposed in 2016 by the Magnetic Resonance Group Imaging in Multiple Sclerosis (MAGNIMS). However, there was insufficient evidence to support this recommendation.

Objectives

To investigate the effect of including ON involvement assessed by visual evoked potentials (VEP) as the fifth location in DIS criteria for MS diagnosis, in patients with a typical clinically isolated syndrome (CIS).

Methods

We studied consecutive patients presenting with CIS between 2012 and 2019 from two Portuguese hospitals with complete initial evaluation, including brain and spine MRI and VEP.

McDonald 2017 criteria and a set of modified criteria that included ON involvement in DIS assessed by VEP were applied retrospectively. Performance of the two sets of criteria to predict development of clinically definite multiple sclerosis (CDMS) and/or MRI activity during follow-up was evaluated.

Results

76 patients were included, 25% of which had an ON CIS. ON asymptomatic involvement on VEP was found in 12.3% of non-ON CIS. 27 (35.5%) patients converted to CDMS and 37 (48.7%) had MRI activity during follow-up (mean=3.79 years, range 1.04 – 8.36 years). 59.2% of the patients began disease modifying treatment (DMT) before conversion to CDMS.

Modified DIS criteria in combination with dissemination in time (DIT) was slightly more sensitive to predict CDMS (77.8% vs 74.1%), but less specific (57.1% vs 61.2%). When the outcome was CDMS or MRI activity during follow-up, modified DIS+DIT criteria were more sensitive (73.2% vs 65.9%) with equal specificity (65.7% vs 65.7%), but these differences were not statistically significant.

Modified criteria allowed for the diagnosis of 3 additional patients at baseline (42/76 vs 39/76), in average 6 months before fulfilment of McDonald2017 criteria and subsequent initiation of DMT.

Conclusions

Although inclusion of ON involvement on DIS criteria led to accurate identification of more MS patients, in our sample it did not allow for statistically significant increase in sensitivity for MS diagnosis despite asymptomatic involvement of ON assessed by VEP at CIS diagnosis being frequent.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0257 - Infratentorial MS relapse presenting as hemifacial continuous myokymia (ID 1146)

Speakers
Presentation Number
P0257
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Acute movement disorders are infrequent manifestations of central nervous system demyelination. Our purpose is to highlight an extremely unusual relapse presentation in an MS patient with highly active disease.

Objectives

Non-applicable......................................................................................

Methods

Non-applicable......................................................................................

Results

We present the case of a 26-year-old female patient, diagnosed with Relapsing-Remitting MS at age 16. She was initially non-compliant with disease-modifying therapies and clinical follow up, experiencing multiple relapses during an eight-year period. She resumed follow-up at our institution in 2018, following two episodes of cervical myelitis without clinical motor involvement. Her neurological examination was noticeable for vertical non-fatigable nystagmus, asymmetric left-predominant hyperreflexia, and truncal ataxia. Re-baseline MRI performed in 2019 revealed multiple T2 lesions involving infratentorial, spinal cord, juxtacortical, and periventricular regions, none of which showed gadolinium enhancement. She was started on dimethyl fumarate 240mg bid in March 2020 with adherence.

The patient consulted our MS outpatient clinic in May 2020, because of a 4-day history of continuous involuntary wavelike movements localized to the right side of her face. The patient’s spouse reported that the movements were unremitting during sleep. A video recording of this manifestation was obtained. Neurological examination at this time revealed continuous right-sided facial myokymia, more prominent around the orbicular and peri-labial muscles, not influenced by voluntary activity. There was no concurrent hemifacial spasm. Brain MRI documented a new hyperintense T2/FLAIR non-enhancing lesion in the pontine tegmentum, adjacent to the traject of the facial nerve and multiple gadolinium-enhancing lesions in the supratentorial compartment. The patient was offered intravenous methylprednisolone treatment but denied. She subsequently experienced full recovery within 3 weeks, with no abnormal facial movements detected at clinical reevaluation one-month later.

Conclusions

We described the case of an MS patient with a highly active disease course, presenting with continuous hemifacial wavelike movements related to a pontine demyelinating lesion. Although infrequent, strictly unilateral facial myokymia is a possible presentation of infratentorial MS relapse.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0258 - MS Progression Discussion Tool (MSProDiscuss™) Usability and Usefulness Assessment in Clinical Practice in Chile. (ID 568)

Speakers
Presentation Number
P0258
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Multiple Sclerosis (MS) is the most common chronic immune-mediated and neurodegenerative disease of the Central Nervous System, affecting around 2.3 million people worldwide. Approximately 25-40% of patients will transition to SPMS within 10 years of MS onset. Defining the transition from RRMS to SPMS can be challenging and may result in delayed diagnosis and impact treatment decision making. MSProDiscuss™ is a freely available educational tool developed and validated to facilitate physician-patient discussion on subtle early signs of MS progression and enable patient-HCP conversation.

Objectives

Evaluate the usefulness and usability of the MSProDiscuss™ clinician-completed tool in clinical practice in Chile.

Methods

Eight neurologists were consulted on feedback for MSProDiscuss™ implementation into daily clinical practice. The physician entered details of patient disease activity, symptoms and their impact experienced in the last six months. After completion, a traffic-light output displayed the level of progression. After that, physicians completed questionnaires about understanding, usefulness, usability and integration/adoption of the tool into daily clinical practice.

Results

The tool was implemented during 275 MS patient medical appointments. All neurologists indicated that the time to complete the tool was satisfactory, 96.8% said that patients well-understood the questions and 93.5% agreed that the traffic light colors helped to discuss MS progression. In addition, regarding the discussion of MS progression symptoms, and their impact on daily activities and on cognitive functions, 89.7% and 80.2% referred that the tool helped to discuss them, respectively. Lastly, 98.9% would use the tool with patients in the future.

Conclusions

Neurologists indicated that MSProDiscuss™ was very useful for evaluating and consulting about the MS progression and its impact on daily life. According to their feedback, it provided an idea of the degree of disability and transition to SPMS. Besides, it facilitated an informed doctor-patient discussion.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0259 - Multiple Sclerosis, variant Marburg, an uncommon form: about a case.  (ID 1158)

Presentation Number
P0259
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Marburg disease is an inflammatory demyelinating syndrome related to multiple sclerosis (MS) with different clinical, radiological and pathological presentation, belonging to the swelling variants. The clinical presentation varies from paucisymptomatic patients to others with confusion, hemiparesis, hemineglect syndrome or epileptic seizures.

Objectives

Given its malignant course and infrequency, the objective of this study is to review the literature on the diagnosis and management of a case.

Methods

We present the case of a 34-year-old woman, with no history of interest, who attended the Emergency Department in September 2019 for two episodes compatible with secondary, complex generalized seizures and headache. She also has intermittent paresthesias in the right lower limb associated with tonic contraction for 8 months. In its follow-up, development of asymmetric paraparesis with right predominance and dyslexic cognitive disorder has been observed.

Results

Cranial CT: three bilateral subcortical hypodense focal lesions. Neurological examination: normal at the start of the study. MRI September 2019: multiple bilateral lesions with enhancement, edema and mass effect (22mm the largest), associating spinal cord injuries, suggesting swelling demyelinating origin. EEG: abnormal. CSF: normal. CSF PCRs: negative. Autoimmunity: no findings. Neurotropic virus serologies: negative. Treatment with Lacosamide 50mg / 12 hours begins, no new crises have occurred since November 2019. MRI January 2020: multiple new enhancing lesions (from 19 to 50). Following diagnosis, steroid boluses have been prescribed and treatment with Ocrelizumab (positive anti-JC Acs) will begin.

Conclusions

The clinical course of the Marburg variant is unpredictable, sometimes with poor clinical-radiological correlation as indicated in the literature. It is very important to take it into account in the differential diagnosis of demyelinating diseases and of these with swelling-like neoplastic lesions for their adequate follow-up and early treatment.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0260 - Obinutuzumab use complicated by progressive multifocal leukoencephalopathy: a case report. (ID 764)

Speakers
Presentation Number
P0260
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a severe, untreatable, and often fatal brain disease caused by reactivation of the latent John Cunningham virus (JCV). PML is almost exclusively seen in immunosuppressed patients or associated with specific immunotherapies. Obinutuzumab is a humanized anti-CD20 monoclonal antibody approved for use in combination with chlorambucil as treatment of chronic lymphocytic leukemia. As of July 2, 2020, EudraVigilance reports 16 PML cases with obinutuzumab. However, most of these cases represent a carryover effect from previous rituximab therapy.

Objectives

To describe a case of non-carryover obinutuzumab PML occuring in a female patient with chronic lymphocytic leukemia.

Methods

A 76-year-old, HIV-negative female was admitted in our institution in May 2020 for evaluation of progressive cerebellar syndrome. Her husband had noticed progressive neurobehavioral symptoms and insidious onset of ataxia in the beginning of 2020, but neurological symptoms had significantly worsened over the 2 weeks before admission. Her medical history was significant for previously untreated chronic lymphocytic leukemia that was diagnosed in 1996. Due to disease progression, she started obinutuzumab and chlorambucil in April 2020 and received a total of 6 cycles ending in September 2020.

Results

Brain magnetic resonance imaging revealed multiple lesions highly suggestive of PML, as characterized by T2/ FLAIR hyperintensities and T1 hypointensities involving both cerebellar hemispheres as well as the sub-cortical white matter in the right parietal lobe, without gadolinium enhancement and mass effect. PML was confirmed by detection of JCV-DNA in the CSF (81711 copies/ml). Absolute lymphocyte count was 1151/µl. The peripheral CD4+ T-cell count was 651/mm³, CD8+ at 348/mm³. Follow-up MRI at 2 weeks showed progression of the lesion. At the time of writing, neurological deterioration is ongoing and the patient has recently been transferred to a palliative care facility.

Conclusions

This case highlights that PML should be ruled out in any obinutuzumab-treated patient displaying neurological deficits. Although the reported patient had a higher risk to develop PML resulting from the underlying predisposing disease (CLL), it is however conceivable that the introduction of obinutuzumab triggered JCV reactivation and development of PML in the reported case. Further investigations are needed to determine whether PML could be a class effect of anti-CD20 antibodies.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0261 - Paramagnetic rim lesions are specific to multiple sclerosis: an international multicenter 3T MRI study (ID 1025)

Abstract

Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0262 - Searching for Fabry disease in previously diagnosed CIS and defined MS patients: a cohort study. (ID 1693)

Speakers
Presentation Number
P0262
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Fabry disease (FD) is a rare panethnic x-linked lysosomal storage disorder that can mimic MS, and thus must be considered in differential diagnosis. While clinical profile and MRI studies can overlap, some other considerations help distinguish them, like presence of CSF oligoclonal bands and medullary demyelinating lesions for MS and multi-organ involvement and positive familiar history for FD. In our center a patient was diagnosed with MS in 2004, and with FD in 2015, due to in depth-analysis following the clue of a positive family history.

Objectives

To identify the possible presence of unacknowledged FD in a cohort of Italian patients previously diagnosed with CIS or MS.

Methods

We enrolled consecutive CIS and MS patient that fulfilled McDonald revised criteria referred to our center. In female subjects, the GLA gene was analyzed by PCR and sequencing of the entire coding region. In male subjects the concentration of the alpha-galactosidase enzyme in dry blood spot was measured with fluorescence spectroscopy. For these purposes we used Centogene diagnostic kit for Fabry disease.

Results

411 patients (300 females) were enrolled, 21 with a diagnosis of CIS and 390 with definite MS, mean age 45.5 years (SD:12.0), mean disease duration 15.3 years (SD:10.1), mean EDSS 2.5 (SD:1.9). No one of them presented pathogenic mutations of GLA gene or alpha-galactosidase deficiencies.

Conclusions

Although the diagnosis of FD must be ruled out when studying a patient with suspected MS, the systematic genetic or enzymatic analysis of every patient doesn’t appear necessary in everyday clinical practice. The analysis of GLA gene and of alpha-galactosidase activity should be reserved for patients with elements suspicious for FD, like a positive family history and multi organ involvement (especially renal impairment and angiokeratomas). Our patient with both the diagnosis, other than positive family history, later developed proteinuria as systemic dysfunction; she also showed demyelinating lesions on brain and spinal cord MRI, sometimes with Gadolinium enhancement, and intrathecal synthesis of oligoclonal bands (type 3). Clarifying the correct diagnosis is of fundamental importance due to the different therapeutic approaches.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0263 - Serum neurofilament predicts clinical progression and increases diagnostic accuracy in patients with early multiple sclerosis (ID 1336)

Abstract

Background

Up to date prognostic estimation in newly diagnosed patients is hardly possible while the differentiation between disabling versus more benign courses is of utmost relevance. Reliable blood-based biomarkers that are associated with diagnosis and prognosis of multiple sclerosis (MS) have not been established.

Objectives

Can serum neurofilament light chain measurements serve as a reliable biomarker for diagnostic accuracy and prognosis for multiple sclerosis patients at the time point of diagnosis?

Methods

In a multicenter prospective longitudinal observational cohort, patients with a first diagnosis of multiple sclerosis (MS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers and assessed yearly with a standardized protocol. Patients were offered standard immunotherapies according to national treatment guidelines. Serum NfL concentrations were measured using an ultrasensitive single-molecule array (Simoa).

Results

A possible association between sNfL levels and clinical diagnosis, relapses, MRI parameters and treatment decisions was tested in 814 patients classified according to current (2017) and older (2010) McDonald criteria at time point of diagnosis and two years after study inclusion sNfL levels correlated with number of T2 and Gd+ lesions and clinical relapses. After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036) and increased accuracy of distinction between CIS and RRMS, when including ≥ 90th percentile of sNfL values. Patients receiving disease-modifying treatment (DMT) during the first two years had higher sNfl baseline levels (11.8 pg/ml, 7.5-20.9 pg/ml, n = 727) than patients never receiving DMT (9.5 pg/ml, IQR 6.4-14.1 pg/ml, n = 87, p = 0.002). Longitudinal sNfL levels reflected treatment decisions within the first four years.

Conclusions

sNfL is associated with diagnosis and prognosis of MS patients at the time point of first diagnosis and may be of use for initial treatment stratification.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0264 - Simultaneous bilateral optic neuropathy and myelitis revealing paraneoplastic neurological syndrome associated with multiple onconeuronal antibodies (ID 772)

Speakers
Presentation Number
P0264
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Paraneoplastic neurological syndromes (PNS) are immune-mediated complications of cancer associated with a broad spectrum of clinical manifestations. Optic neuropathy (ON) and myelitis are frequent manifestations of multiple sclerosis (MS) and neuromyelitis optic spectrum disorders (NMOSD) but are considered as non-classical in PNS. Here, we report a case of PNS revealed by simultaneous bilateral ON and myelitis related to multiple co-existing paraneoplastic antibodies (Abs), in the setting of small cell lung cancer (SCLC).

Objectives

To describe a patient with concomitant bilateral ON and myelitis as revealing neurological manifestations of paraneoplastic autoimmunity.

Methods

A 70-year-old man with a 50-pack-year smoking history was admitted because of subacute bilateral and painless vision loss and left lower limb weakness. Visual acuity was 7/10 in the right eye and 3/10 in the left eye. Fundoscopy showed bilateral disc swelling and peripapillary hemorrhages. Brain MRI did not reveal any optic nerve lesion nor lesions suggestive of MS. Spinal cord MRI showed a T2-weighted hyperintensity at the C2 level, with gadolinium enhancement. The visual evoked potentials showed significant bilateral increase of P100 latencies. CSF analysis showed lymphocytic pleocytosis (149 cells/μl), elevated protein concentration (99 mg/dl), and positive CSF-restricted IgG oligoclonal bands. No malignant cells were found in the CSF. Immunologic and infectious workup was unremarkable. Testing for anti-AQP4 and -MOG Abs was negative. Lung cancer was highly suspected on whole body FDG-PET. Transbronchial needle aspiration of hilar lymph nodes revealed SCLC.

Results

The paraneoplastic antibody panel showed a significant signal for anti-Hu Abs in the serum (EUROLINE Neuronal Antigen Profile blots, EUROIMMUN), confirming the diagnosis of PNS. Anti-CV2/CRMP5 and -amphiphysin Abs were also detected, albeit at lower levels. Treatment with intravenous methylprednisolone and plasma exchange resulted in poor clinical improvement. A second malignancy (prostate cancer) was highly suspected but the patient elected to withdraw from further evaluation or treatment and received palliative care at home.

Conclusions

Simultaneous involvement of optic nerves and spinal cord is a rare manifestation of PNS. This presentation should prompt screening for a panel of onconeuronal Abs and for an underlying malignancy, particularly in older adult smokers who are unlikely to have MS or NMOSD.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0265 - Sjogren-larsson Syndrome:Another Differential Diagnosis of Multiple Sclerosis in Imaging of White Matter Diseases. (ID 970)

Speakers
Presentation Number
P0265
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Sjogren-Larsson syndrome is an inherited autosomal recessive neurocutaneous disorder with congenital ichthyosis, spastic diplegia or quadriplegia and mental retardation.So this rare syndrome can be another differential diagnosis of MS.

Objectives

Sjogren-larsson Syndrome:Another Differential Diagnosis of Multiple Sclerosis in Imaging of White Matter Diseases.

Methods

Case presentation:

Index patient was 34 year-old female who was admitted because of weakness and inability to walk., the child attained sitting without support at second year of age.She had global developmental delay.Stiffness in lower limbs started in 4 years before,with progressive increase up to the time of presentation.Physical examination showed generalized dryness of skin most prominent on lower limbs with severe pruritus, that is icthyotic lesion .The nail ,plams and soles were affected.She had short stature.In neurological examination she revealed mental retardation,spasticity in both lower limbs;brisk deep tendon reflexes and symmetric bilateral extensor plantar respones.She had photophobia and decreased visual acuity but her fundoscopy was normal. EEG showed mild slowing over both hemispheres.CSF analysis was normal.MRI of the brian showed diffuse and no symmetrical plaques with high signal intensity on T2 weighted sequence in bilateral deep periventicular white matter and corpus callosum.Some of these lesion were also plumb to ventricular.

Results

Sjogren_larsson is a recessively inherited neurocutaneous disorder that is Caused by mutatiation in ALDH3A2 gene .The cutaneous symptoms are in form of ichthyosis which is a generalized hyperkeratosis of the trunk,joints,and the dorsal asepect of the hands and the feet.Pruritus is a prominent feature that is not found is other of ichthyotic skin disorders.The occurrence of glistening clots on funduscopic examination strongly suggestes SLS.Spasicity impedes motor development and prevents many patients from mild to modrate severity.Most cases with SLS have learning disability and speech disorders.The hallmark of SLS is demyelination of the cerebral white matter and of the corticospinal and vestibulospinal tracts.MRI reveals abnormal high signal intensity on T2 weighted and FLAIR sequences especially in periventicular frontal,parietal lobes,corpus callosum and corona radiata are spared.

Conclusions

The diagnosis of SLS should be cosidered in a neonate or infant with congenital ichthyosis and neurological features.The hallmark of SLS is demyelination of cerebral white matter and of the corticospinal and vesibulospinal tracts.MRI reveals abnormal high signal intensity on T2 weight and FLAIR sequences especially in periventicular frontal,parietal lobes,corpus callosum and corona radiata.Typically,subcortical white matter U fibers are spared.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0266 - Susac syndrome: A rare cause of encephalopathy (ID 1544)

Speakers
Presentation Number
P0266
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Susac Syndrome is a rare disease affecting brain, inner ear and retinal microvasculature thought to be immune mediatied. Clinical triad consists of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss. This triad is not always initially observed delaying diagnosis.

Objectives

Describe a rare presentation of Susac Syndrome recognizing the importance and difficulty of early diagnosis/management.

Methods

Describe a rare presentation of Susac Syndrome recognizing the importance and difficulty of early diagnosis/management.

Results

37-year-old female with hypertension and hyperlipidemia presented to an outside hospital with 2 month history of progressive headaches, confusion and gait difficulties. Initial MRI brain demonstrated diffuse gyriform enhancement and acute lacunar infarcts involving bilateral frontoparietal lobes and corpus callosum. LP was remarkable for lymphocytic pleocytosis. CT angiogram head/neck and infection/malignancy screening was negative. She was diagnosed with ADEM and completed high dose Solumedrol. Subsequent deterioration led to transfer to Medical University of South Carolina. Review of outside images was concerning for other etiologies including Susac Syndrome. Repeat LP remained with lymphocytic pleocytosis, elevated protein and no unique bands. Interim MRI brain for worsened encephalopathy showed new bilateral punctate infarcts strongly suggestive of vasculitis. Cyclophosphamide was started and Asprin continued for vascular prophylaxis. Repeat conventional angiogram and EEG monitoring was normal. Brainstem Auditory Evoked Responses (BAER) and Flourescien Angiogram (FA) were unremarkable. Biopsy of right frontal leptomeninges and parenchyma did not show vasculopathy or lymphoma. Repeat MRI revealed increased burden of punctate infarcts and IVIG was trialed with minimal response. Given poor clinic picture, Rituximab was initiated for what was thought to be refractory small vessel vasculitis. The patient was transferred to another tertiary care center for a second opinion. Diagnosis of presumed Intravascular Lymphoma was made and she underwent 2 cycles of Cytarabine, High Dose-Methotrexate, Rituximab combination therapy. MRI following cycle 1 showed resolution of previous parenchymal lesions and improvement of prior enhancement. MRI following cycle 2 showed no changes. She developed decubitus ulcers and prolonged cytopenia. Chemotherapy was paused and she was transferred back to our facility.

Conclusions

The case was discussed with our multidisciplinary Tumor Board. On further review of data including pathology without evidence of lymphoma and pathognomonic corpus callosum lesions on imaging, the diagnosis of Susac Syndrome was favored. She continued on Rituximab. Prior to discharge, multiple bilateral BRAO were observed on repeat FA with normal BAER testing. Current functionality and cognition continues to improve.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0267 - The Contribute of CSF Free Ligh Chain assay in the diagnosis of Multiple Sclerosis and other Neurological Diseases in an Italian multicentric study (ID 1734)

Speakers
Presentation Number
P0267
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Detection of IgG Oligoclonal bands (OCB) in CSF by Isoelectric focusing (IEF) is an important criteria for multiple sclerosis (MS) diagnosis. Recently, quantitative measurement of CSF Free Light Chains (FLC), has been proposed as a faster, standardized and cheaper alternative to detect intrathecal Immunoglobulin (Ig) synthesis. However, FLC indexes (FLCI) cut off often varies depending on the selected population, with a lack of consensus.

Objectives

To assess, in a large and heterogeneous population, the diagnostic accuracy of CSF k and λ FLC in MS and other neurological diseases.

Methods

406 patients were selected in 5 Italian centres. OCB were detected by IEF, followed by immunodetection, FLCs were measured in paired CSF (LFLC) and serum (SFLC) using Freelite MX assays on the Optilite turbidimeter (Binding Site), as well as serum (SAlb) and CSF Albumin (LAlb). FLCI= (LFLC/SFLC)/(LAlb/SAlb).

Results

Patients: 174 MS, 149 non-inflammatory neurological disorders (NIND), 50 inflammatory CNS disorders (IND), 33 peripheral neurological disorders (PIND). KFLCI was significantly higher in patients with MS compared to the other groups (p <0.0001). The best kFLCI cut off for the prediction of MS was 6.4 (kFLCI+) with a diagnostic accuracy comparable to OCB (sensitivity 82.2% vs 82,7%; specificity 88.4% vs 90,5%). 7% MS patients were kFLCI+ and OCB negative (-), 7% were kFLCI- and OCB positive (+), with 86% concordance of both tests. 40% IND were kFLCI+, 35% of which OCB-. 4% NIND were kFLCI+, with only 1 patient OBC+. 27% PIND were kFLCI+ and 21% OBC+. λFLCI values were higher in the MS group, but gave few additional information (optimal cut off 13.5). In MS group, OCB results were highly variable across the centres, while kFLC were more consistent, confirming that FLCI is less subject to personal interpretation.

Conclusions

Our findings support the combined use of KFLCI and OCB to detect intrathecal Ig synthesis. KFLCI can accurately discriminate MS from NIND and PIND patients. IND patients showed high KFLCI in higher proportion than OCB, hence clinical, imaging and other laboratory data are necessary for a correct diagnosis. On the other hand, OCB has technical limitations and showed high variability across the centres to support MS diagnosis. In conclusion, KFLC performances in our heterogeneous population, with patients coming from 5 geographically distinct centres, support the robustness of this test implying that it can be easily used across our country.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0268 - Time interval between disease onset and MS diagnosis during the last decades in Latin America (ID 1201)

Speakers
Presentation Number
P0268
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

Previous studies have shown a significant shortening of time from multiple sclerosis (MS) onset (first relapse) to diagnosis in parallel with the adoption of new diagnostic criteria. However, the observation was not evaluated in Latin America.

Objectives

The objective of the study was to study the interval from first symptom of MS to the date of diagnosis in relation to the introduction of upgraded MS diagnostic criteria in a Latin American population.

Methods

Cross-sectional study based on a self-reported survey. Patients with MS completed a regional survey in 12 Latin American countries. To be included, date of disease onset (first relapse) and date of diagnosis (confirmed disease) should be completed. Survival probabilities were evaluated for 5 diagnosis epoch groups according to the diagnostic criteria advised at the time: group 1- 1983-2000 Poser; group 2- 2001-2004 McDonald's first version; group 3- 2005-2009 revisions of 2005; group 4- 2010-2016 revisions of 2010; and group 5 -2017-2019 revisions of 2017.

Results

1434 patients were included. 1108 (75%) females, mean age at study entry 39 ± 11 years. The mean time since disease onset to diagnosis in group 1 was 21 ± 8 months; in group 2, 19 ± 7 months; in group 3, 16 ± 10 months; in group 4, 9.6 ± 8.5 months and in group 5, 8.2 ± 10 months. Significant differences were observed between groups 1, 2, 3 vs. 4 and 5 (p<0.001) while no differences were observed between group 4 and 5 (p=0.08).

Conclusions

This study showed a significant shortening of time from MS onset to diagnosis in parallel with the adoption of new diagnostic criteria in Latin America in recent decades.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0269 - Vitamin B12 deficiency or MS!? Vitamin B12 deficiency can mimic Multiple Sclerosis. (ID 983)

Speakers
Presentation Number
P0269
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

.One of the diseases that is usually considered in differential diagnosis of MS is vitamin B12 deficiency.Differential diagnosis howere maybe difficult because neurological and hematological disorder may develop independently and with various intensity,pernicious anemia may respond to steroid therapy,MRI finding in vitamin B12 deficiency maybe similar to that in MS and multiple sclerosis may coexist with low vitamin B12 level

Objectives

heterogeneous manifestations of MS an incorrect diagnosis is not uncommon.One of them is usually considered in DD of MS is Cobalamin deficiency

Methods

A 43 years old male was referred our neurologic clinic with primary diagnosis of multiple sclerosis.The patient was admitted because of subacute and progressive weakness and parasthesia of lower limbs.He had hypothyroidism in medical story ,but had no remarkable family and social history.No obvious abnormalities were detected in general examination.The neurological symptoms of gait disturbances and paresthesia.In neurological examination he revealed spasticity in both lower limbs ,brisk deep tendon reflexes and symmetric bilateral extensor plantar response and sensory examination showed abnormalities in vibration and position sense.Sensory level was not detected.The patient had marked sensory ataxia.The laboratory tests revealed RBC count:2/19 million/dl ,Hb:9/7,MCV:127,MCH:44,ESR:30,Retic:0/8.Furthermore peripheral blood smear showed macro-ovalocytes and hypersegmeted neutrophils.B12 level:30.Brain MRI was normal,cervical MRI showed long T2 hyper signal lesion at posterior of cord from C2-C7 .

Results

Cobalamin deficiency Pathology is demyelination involving the lower cervical and upper thoracic regions,it eventually involves the entire dorsal columns symmetrically.That is manifest with neurological features .sing of dorsal column involvement .lateral column involvement and spinotalamic tracts .The diagnosis of B12 deficiency is made by a low serum B12 level or elevated levels of metabolites .MRI findings ;vertical segment can be seen at the posterior aspect of spinal cord. On axial images,bilateral paired areas of T2 hyperintensey are seen as inverted V in dorsal columns.Contrast enhancement areas of a normal signal intensity on T2-weighted image in the cerebral white matter.the most important differential diagnosis of Vitamin B12 deficiency is multiple sclerosis.MS plaques in dorsal column are not bilaterally symmetrical and longitudinal exent is less than two vertebral bodies and may show contrast enhancement,finally are seen younger population

Conclusions

Differential diagnosis howere maybe difficult because neurological and hematological disorder may develop independently and with various intensity,pernicious anemia may respond to steroid therapy,MRI finding in vitamin B12 deficiency maybe similar to that in MS and multiple sclerosis may coexist with low vitamin B12 level.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0270 - 2-Chlorodeoxyadenosine (Cladribine) preferentially inhibits the biological activity of microglia cells (ID 1011)

Speakers
Presentation Number
P0270
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background and goals: 2-chlorodeoxyadenosine (CdA, Cladribine) is a compound used in the treatment of MS, which crosses the BBB and is activated by intracellular phosphorylation in specific cell types. We previously demonstrated that CdA inhibits microglial cell proliferation, induces apoptosis and suppress IL-1, IL-6 and TNF-α secretion; effects not observed in the case of astrocytes.

Objectives

To expand previous findings to better explain differences observed between these two cell populations in response to cladribine.

Methods

Primary cultures of microglial cells and astrocytes were prepared from neonatal C57BL/6 mice following the McCarthy and de Vellis protocol. After harvesting, cells were treated with different concentrations of CdA (20 to 200 µM), for periods lasting between 6 and 72 hours. Caspase 3 expression was evaluated by immunocytochemistry. CdA effect on mitochondrial function of microglial cells was measured using an extracellular flux analyzer (Seahorse). Expression of DCK and 5-NT enzymes, as well as of the ABCG2 receptor were measured using RT-PCR. DCK enzyme activity was assessed by ELISA.

Results

Caspase-3 expression was measured in microglial cells, 6-12 hours after exposure to CdA, preceding induction of apoptosis. CdA showed no effect on mitochondrial bioenergetics when cells were treated with a wide range of CdA concentrations (20-200 µM). To investigate differences in response to CdA between microglia and astrocytes, we measured DCK and 5-NT expression as well as expression of the CdA receptor ABCG2 in both cell populations. DCK expression was significantly higher in microglial cells than in astrocytes. By contrast, 5-NT expression was higher in astrocytes than in microglial cells; whereas expression of the ABCG2 receptor was significantly higher in microglia compared to astrocytes. Finally, incubation of microglial cells in the presence of CdA induced significant DCK enzyme activity, which increased further after LPS activation.

Conclusions

Data presented complements previous findings on biological effects induced by CdA on microglial cells, leading to a better understanding of differences in microglia and astrocyte cell responses. We observed that microglia showed: 1) greater expression of the CdA receptor ABCG2, increasing intracellular pro-drug penetration; and 2) higher expression of the phosphorylating enzyme DCK, which transforms CdA into an active drug.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0271 - A Case of Drug Induced Myocarditis Associated With the Administration of Alemtuzumab (ID 1233)

Speakers
Presentation Number
P0271
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Over the past decade, a number of Disease Modifying Therapies (DMTs) for Multiple Sclerosis (MS) have been made available to help slow the progression of MS. The efficacy of these therapies depends on the extent of lymphocyte suppression, offering favorable outcomes in disease suppression, but present safety concerns that should be balanced. Alemtuzumab has been FDA approved for aggressive forms of Relapsing Remitting MS (RRMS) since 2014. It acts on the CD52 antigen present on B and T cells, thereby achieving lymphopenia. while it is highly efficacious, it has several warnings of autoimmunity, infusion reactions, strokes, and malignancies.

Objectives

The purpose of this abstract is to highlight a novel case study of possible alemtuzumab induced myocarditis. A quick literature review did not yield any findings of prior reports.

Methods

We present a 27 year old woman with a 10-year history of MS who had previously been treated with interferon, dimethyl fumarate, and fingolimod – all switched for either disease activity or intolerance. Alemtuzumab was initiated following these DMT failures.

Alemtuzumab was administered in January 2020 with pre-medications as per the package insert. On day 2 of her infusion, she developed asymptomatic bradycardia. Upon arrival on day 3, she reported intermittent epigastric pain overnight. Facial flushing was noted by the nurse and the infusion was held. In addition, she was having palpitations with fluctuations in heart rate. The RN hooked her up to EKG, which was significant for multiple PVCs, ST abnormalities and a right bundle branch block. At this point she was quickly transferred to the Emergency Department.

While in the ED, she quickly developed dyspnea and a productive cough. Due to desaturation, tachycardia and hypotension, she was admitted to the Intensive Care Unit for cardiogenic shock. Repeat chest Xray showed bilateral pulmonary edema. Troponins were uptrending and echocardiogram showed an ejection fraction of 10%. The diagnosis of acute drug induced myocarditis was made.

Results

The patient was treated with bipap and diuretics, after which heart rate and saturation progressively improved. Initial Cardiac MRI revealed an EF of 42%. Diffuse "mild" Late Gadolinium Enhancement, more consistent with inflammation and edema than myocardial fibrosis (scar).She was discharged home with a lifevest and on Digoxin, Toprol XL, Aldactone, and Losartan.

At four month follow up, repeat cardiac MRI showed improved EF to 54% with resolution of myocardial edema.

Conclusions

To our knowledge this is the first report of alemtuzumab induced myocarditis and while an isolated event, prescribers should be aware of this potential adverse effect.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0272 - A case series of late onset neutropenia following Ocrelizumab therapy in Multiple Sclerosis (MS) (ID 1918)

Speakers
Presentation Number
P0272
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab, an anti-CD20 monoclonal antibody similar in action to rituximab, has demonstrated efficacy in relapsing and primary progressive MS. Late onset neutropenia (LON) is a rare, but serious side-effect of rituximab occurring in 1.3% of patients. There only 2 reported cases of LON related to ocrelizumab. A single case of grade 4 LON occurred during the phase three studies.

Objectives

Increase awareness of the features of late onset neutropenia and improve risk management of disease modifying treatments.

Methods

We discuss a case series of 3 treatment naive patients with active RRMS who developed severe LON (grade 4) after ocrelizumab treatment in MS specialist centres in the United Kingdom.

Results

A 31y female presented with neutropenic sepsis (neutrophils 0.0) 115 days after her third ocrelizumab infusion, requiring treatment with intravenous antibiotics and granulocyte colony stimulating factor (G-CSF). Subsequent multiple episodes of recurrent grade 4 neutropenia (neutrophils 0.0-0.2) occurred over the next 6 months, often requiring G-CSF treatment. Bone marrow aspiration demonstrated normocellular granulopoiesis.

A 35y male developed neutropenic sepsis (neutrophils 0.2) 119 days after the first ocrelizumab infusion which recovered rapidly with G-CSF. He received the 2nd and 3rd ocrelizumab doses with no recurrence of neutropenia.

A 22y female developed fever and cough with neutropenia (0.28), 150 days after initial treatment with ocrelizumab. She was treated with IV antibiotics and the neutropenia recovered spontaneously.

Conclusions

The 3 cases demonstrate the spectrum of LON with ocrelizumab. The aetiology of LON is poorly understood, but hypothesised to be mediated by autoimmune destruction, neutrophil apoptosis or failure of release from the bone marrow. The normal bone marrow aspirate suggests peripheral consumption. The cases are important to raise the clinical suspicion of this life threatening complication of disease modifying therapy and the need for serial blood monitoring. Further experience is required to understand risk of recurrence and when it is safe to re-challenge with ocrelizumab.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0273 - A multicentre, real-life study on the risk of lymphopenia and infections discloses a favourable safety profile of cladribine in MS patients. (ID 1086)

Speakers
Presentation Number
P0273
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background. Lymphopenia monitoring during treatment with disease modifying drugs for MS is relevant because of the potential increased risk of infections. Lymphopenia is an anticipated effect of cladribine (CLD) treatment, given its mechanism of action.

Objectives

Objectives. We aimed to i) characterize the absolute lymphocyte count (ALC) changes, and ii) evaluate the risk of infections in CLD-treated RRMS patients. ALCs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Methods

Materials and methods. In this observational multicentre study, demographic, clinical and MRI data of the patients included in the Free Of Charge CLD program were collected. ALC was also collected at baseline (before therapy initiation) and at month 3, 7, 12, 15, 19 and 24.

Results

Results. 236 patients were enrolled in 56 Italian MS Centres (71% F; mean age: 39+11.5 years; mean disease duration: 10+8.5 years). The median baseline EDSS was 3.0 (quartiles 1.5-3.5; range 0-6.5). 53 patients (22.5%) were treatment naïve, 107 (45.3%) switched to CLD from first line DMDs (for inefficacy), 76 (32.2%) switched to CLD after a second line therapy (33/76 for safety reason, 43/76 for inefficacy). Mean follow up was 12.2+5 months. At baseline, median ALC was 1615.0 cell/mm3 (quartiles, 1300.0-2200.0). At month 3, ALC was available in 190/236 and 101/190 had lymphopenia: 12 (6.3%) grade 3, 47 (24.7%) grade 2 and 42 (22.1%) grade 1. Among patients presenting grade 3 at month 3, only one had persistent ALC <500 cell/mm3 at month 7. At month 7, ALC was available in 180/236 and 77/180 had lymphopenia: 1 (0.6%) grade 4, 1 (0.6%) grade 3, 43 (23.9%) grade 2 and 32 (17.8%) grade 1. Up to date, 159/236 patients were re-treated. No retreatment was delayed because of grade 4 lymphopenia. No patient presented grade 4 lymphopenia at month 15, 6/89 (6.6%) experienced grade 3, 37/89 (40.7%) grade 2, 17/89 (18.7%) grade 1. At month 19, 1/38 (2.6%) presented grade 3 lymphopenia, 11/38 (29.0%) grade 2 and 9/38 (23.7%) grade 1. At month 24, 1/9 (11.1%) patient presented grade 3 and 1/9 (11.1%) presented grade 4 lymphopenia. During treatment course, 15 patients experienced infections (1 VZV, 3 HSV), none occurring in grade 3 or 4 lymphopenia.

Conclusions

Conclusions. In our study, the risk of grade 3 and 4 lymphopenia was lower compared to that observed in RCT. Moreover, grade 3 lymphopenia was transient in the majority of the patients. Compared to RTC, a more favourable CLD safety profile emerged in our study.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0274 - A Swedish post-market surveillance study of the long-term effectiveness and safety of alemtuzumab (IMSE 3) for patients treated for at least 36 months (ID 696)

Speakers
Presentation Number
P0274
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) is an approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long-term safety and effectiveness in a real-world setting. ALZ has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) upon launch in Sweden (March 2014).

Objectives

To track effectiveness and long-term safety of ALZ in a real-world setting, with focus on patients treated with ALZ for at least 36 months.

Methods

Swedish MS patients are registered into the nationwide Swedish MS Registry (NeuroReg). IMSE 3 includes all patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS).

Results

A total of 118 patients (59% female; 95% RRMS) were included in IMSE 3 between March 2014 and June 2020. Out of 118 patients, 93 had been treated for at least 36 months (62% female), of which 10 patients had switched to another DMT. Mean age at treatment start for patients treated ≥ 36 months was 34 years and mean treatment duration was 54 months. Mean number of drugs prior ALZ initiation was 2.4. Most of the patients (40%, n=37) switched to ALZ from natalizumab or were treatment naïve (13%, n=12) prior ALZ. The mean number of relapses was reduced from 0.72 one year before ALZ initiation to 0.10 during the first treatment year, followed by 0.08 the second treatment year and 0.06 the third year of ALZ treatment (n=79, 15% missing data). In patients treated ≥ 36 months significant improvements in mean baseline compared to 36 months were seen for MSSS (3.3 ± 2.7 to 2.3 ± 2.3, n=44) and EQ-5D (0.7 ± 0.3 to 0.8 ± 0.3, n=50), while SDMT showed significantly worsened results after 36 months (64.8 ± 17.5 to 56.2 ± 12.7, n=59). EDSS, MSIS-29 and VAS scores remained stable. A total of 36 adverse events were reported to the Swedish Medical Products Agency, 13 events were classified as serious and 23 events as non-serious. Two patients died during ALZ treatment, one of which was associated to ALZ treatment, and died in association with the first ALZ treatment cycle due to fulminant viral hepatitis.

Conclusions

Patients treated with ALZ for at least 36 months improved or remained stable across all effectiveness measures except SDMT. Continued follow-up is needed to address long term effectiveness and safety of ALZ.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0275 - A Swedish Post-Market Surveillance Study of the Long-Term Effectiveness and Safety of Teriflunomid (IMSE 4) for Patients Treated at least 36 Months (ID 1481)

Speakers
Presentation Number
P0275
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Teriflunomid (TFM) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objectives: To assess the long-term safety and effectiveness of TFM for patients treated in a real-world setting over time.

Methods

Methods: A large majority of MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). The IMSE 4 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

Results: 609 TFM-treated patients had been included in the IMSE 4 study from March 2014 to June 2020, 70% were female and mean age at treatment start was 46 years. Mean treatment duration was 27 months and 89% of the patients had RRMS. The most common prior treatment was interferon beta or glatiramer acetate (39%) and 17% of the patients were treatment naïve. The overall one- two- and three- year drug survival rates were 73%, 59% and 48% respectively. 307 (50%) patients had discontinued treatment at some point, of which 34% started rituximab treatment (36% had no new treatment registered). The most common reasons for discontinuation were AEs (42%) and lack of effect (40%).

204 patients had been continuously treated with TFM for ≥36 months and significant changes in mean baseline values compared to values at 36 months were noted only for EDSS (2.0 ± 1.6 to 2.3 ± 1.8, n=49). All other clinical measures were stable.

A total of 68 AEs were reported of which 20 events were classified as serious (S). The most common AE category was skin and subcutaneous tissue disorders for both serious and non-serious (NS) AEs (S: 25%, NS: 21%).

Conclusions

Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. Patients starting TMF are older at treatment start than patients initiating most other DMTs, which may explain the lack of significant improvement in most clinical measures and the negative outcome of the EDSS scores. A longer follow-up period is needed to assess the real-world effectiveness and safety of TMF.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0276 - A Swedish Post-Market Surveillance Study: Long-Term Effectiveness and Safety of Cladribine Tablets (IMSE 10) for Patients Treated at least 12 Months (ID 1477)

Speakers
Presentation Number
P0276
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Cladribine is a deoxyadenosine analogue prodrug. Cladribine tablets (CT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objective: To assess the safety and effectiveness of CT in a real-world setting with focus on patients treated at least 12 months.

Methods

Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and relapse rates were tested using the paired samples T-test.

Results

Results: 85 patients were included in the IMSE 10 study since CT were introduced on the Swedish market in April 2018. 42 patients were treated for at least 12 months. Five AEs were reported since the study start, four were classified as infections and infestations.

25 % of the entire cohort was treated with CT as their first MS drug. 13 % were treated with natalizumab and 12 % with dimethyl fumarate prior to CT. Five AEs were reported since the study start, four were classified as infections and infestations.

Relapse data was available for 27/42 patients in the 12-month cohort. The number of reported relapses decreased significantly from 208.6 per 1,000 patient years before treatment start to 83.6 during treatment. Only three patients in this cohort experienced a relapse during treatment of which two were during the first treatment year.

Significant improvements in mean values at 12 months of treatment compared to baseline were noted for MSSS for the 12-month cohort (n=17). All other tests remained stable but significantly unchanged after one year of treatment.

Lymphocyte levels decreased from a mean of 2.4 x 109/L at treatment start (n=8) to 1.2 x 109/L after 12 months of treatment (n=6) in the 12-month cohort. No patients were below the 0.8 x 109/L limit at 12 months.

Conclusions

Conclusions: CT treatment demonstrates clinical stability in patients treated 12 months. However, continued follow-up is needed to assess the effectiveness and safety of CT over a longer time to assess if these results sustain after the final treatment course has been administered.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0277 - A Swedish Post-Market Surveillance Study: Long-Term Effectiveness and Safety of Dimethyl Fumarate (IMSE 5) for Patients Treated at least 36 Months (ID 1634)

Speakers
Presentation Number
P0277
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives

Objectives: To assess the effectiveness and safety of DMF with focus on patients treated at least 36 months in the IMSE study.

Methods

Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

Results: 2349 DMF-treated patients were included between March 2014 and June 2020 with an overall drug survival rate of 45%. The main reasons for discontinuation were AEs (50%) and lack of effect (30%). 186 AEs were reported to the Swedish Medical Products Agency, of which 59 were serious. A total of 8 patients have died during DMF treatment or within 6 months of treatment discontinuation.

36 month cohort: 940 patients had continuous treatment for at least 36 months. This cohort had a mean age of 42 years and a mean treatment duration of 56 months. The majority (50%) had switched from interferon or glatiramer acetate, and (24%) were treatment naïve (TN).

Significant improvements in mean values at 36 months of treatment compared to baseline for the 36-month cohort were noted for MSSS, SDMT, MSIS-29 Psychological, EQ-5D and VAS. When TN patients were solely assessed (n=230) improvements were noted for all above mentioned measures as well as MSIS-29 Psychological. The remaining patients in the cohort; treatment experienced patients (n=710) displayed significant improvements only for MSSS, MSIS-29 Psychological and EQ-5D. TN patients had a mean duration from diagnosis to treatment start of 5 months compared to 91 months for the remaining cohort. TN were also younger than the remaining cohort (37 years vs 43 years).

Conclusions

Conclusions: DMF demonstrates clinical improvements in patients treated 36 months, more pronounced in TN patients. However; due to the high discontinuation rate there is an unavoidable selection bias. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real world setting.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0278 - A Systematic Review and Meta-analyses of Pregnancy and Fetal Outcomes in Women with Multiple Sclerosis. IMI2 ConcePTION (ID 358)

Speakers
Presentation Number
P0278
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited.

Objectives

The aim of this systematic review and meta-analysis was to evaluate pregnancy outcomes in women with MS treated with DMDs.

Methods

The term “multiple sclerosis” combined with DMDs and pregnancy terms were searched in Embase and Medline databases to identify studies published between Jan 2000 and Jul 2019. Only studies in which the exposure occurred in utero and compared patients exposed to a DMD versus MS patients without treatment were included, regardless of the study design. 1260 studies were identified, and ten studies met our inclusion criteria. MS treated patients were analysed overall and stratified by DMDs class and by type. Pooled relative risk (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed was calculated using a random effects model.

Results

Overall, for MS patients exposed to DMDs the RR (95% confidence interval) for spontaneous abortion was 1.14, (0.99-1.32), for preterm births 0.93 (0.72-1.21) and for major congenital malformations (MCM) in live births 0.86 (0.47-1.56) when compared to MS without treatment. The pooled prevalences of each pregnancy outcome in MS patients exposed to any DMD were: spontaneous abortions 11.6% (7.4-16.7), premature births 12.1% (9.0-15.6) and MCM 3.0% (1.8-4.4). The most common major congenital malformations reported in MS patients exposed to DMDs were atrial septal defect (ASD) (N=4), polydactyly (N=4) and club foot (N=3), which are among the most prevalent birth defects observed in the general population. Each case of ASD was present in patients exposed to different drugs (natalizumab, beta-interferon, glatiramer acetate and mitoxantrone).

Conclusions

Interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, preterm births or MCM. Future studies that assess the effect of individual DMDs are needed to enable decisions on the best treatment options.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0279 - ACAPELLA: B-cell Reconstitution in Ocrelizumab-Treated Patients (ID 444)

Speakers
Presentation Number
P0279
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). In the OPERA trials, circulating CD19+ B-cell counts dropped to zero within 14 days of OCR infusion. Median time to repletion, defined as >79 cells/uL, was 72 weeks (range 27-175 weeks). Up to 5% of patients showed B-cell repletion during treatment. We sought to determine the frequency of patients on OCR who have significant B-cell reconstitution at the time of their next 6-month dose, and to determine if there is a correlation between early B-cell reconstitution and disease breakthrough or adverse events (AEs).

Objectives

As part of the ACAPELLA trial, a prospective study with a primary objective of assessing OCR-associated AEs in a real-world MS population, we sought to evaluate the frequency and duration of early B-cell reconstitution and its relationship to disease activity and AEs.

Methods

All subjects receiving OCR at the Elliot Lewis Center since March 2017 who consented to participate had serum immunoglobulin levels, JCV antibody titers, and lymphocyte subsets on the day of each infusion prior to receiving OCR. Subjects were followed prospectively and monitored for the occurrence of infections and other serious adverse events (SAEs).

Results

As of December 2019, 291 patients had been treated with OCR and enrolled in ACAPELLA: 181 had been treated for at least 12 months, 131 had been treated for 18 months, and 84 subjects had reached 24 months. Of the 291 subjects, 207 had CD19 values drawn at an infusion. One hundred eighteen subjects (57%) displayed ≥1 cell/uL: 81 subjects (39%) had between 1-15 cells/uL, 32 (16%) between 16-79 cells/uL, and 5 (2%) >79 cells/uL. Thirteen patients with B-cell reconstitution at 12 months had early reconstitution with future infusions. Two of the subjects with CD19 values >15 cells/uL experienced clinical or MRI relapse, compared to 8 subjects that did not have B-cell reconstitution.

Conclusions

Although many patients displayed some B-cell repopulation prior to their next dose (113 subjects), CD19 counts of >79 cells/uL were uncommon (5 subjects). Subjects with early B-cell reconstitution at one infusion were likely to continue to show early repopulation at future infusions. Thus far, we have found no significant correlation between B-cell repopulation and either disease activity or adverse events.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0280 - ACAPELLA: Hypogammaglobulinemia and JCV Status in Ocrelizumab-Treated Patients, Year Two Data (ID 387)

Speakers
Presentation Number
P0280
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). Immunoglobulin levels were monitored during the phase III trials, and 1.5% of patients developed low immunoglobulin G (IgG) values after 2-3 years of OCR treatment, potentially increasing the risk of infections. The JCV antibody index used to stratify PML risk in patients treated with natalizumab was not studied and the impact of long-term B-cell suppression on JCV and IgG titers is unknown.

Objectives

As part of the ACAPELLA trial, a prospective study with a primary objective of assessing OCR-associated adverse events (AEs) in a real-world MS population, we sought to evaluate the impact of OCR treatment on immunoglobulin levels and JCV titers over time.

Methods

The study includes all subjects receiving OCR at the Elliot Lewis Center followed prospectively since March 2017. Subjects are monitored for occurrence of infections and other serious adverse events (SAEs) and have biannual assessments of serum immunoglobulin levels and JCV antibody titers.

Results

As of December 2019, 291 patients have been treated with OCR and enrolled in ACAPELLA: 181 have been treated for at least 12 months, 131 have been treated for 18 months, and 84 subjects have reached 24 months. Two hundred eighty-one of the total 291 subjects had IgG levels drawn at baseline. Twenty-seven subjects (10%) had IgG levels below the lower limit of normal (LLN) at baseline. Of the 27 patients with low IgG at baseline, 19 have received treatment for at least 12 months. Of those 19, 4 patients were seen to have a >10% drop in IgG level after 12 months. Ten patients developed at least one low IgG level after 12-24 months of treatment exposure, although many returned to normal.

Two hundred eighty-one of the 291 patients had a baseline JCV index. Ninety-three (33%) had titers <0.4, 73 (26%) between 0.4-1.5, and 115 (41% >1.5. In our two-year data, three patients had a change in JCV status from positive to negative between 12 and 24 months of treatment duration. Year three data is characterized in the poster.

Conclusions

The frequency of persistent hypogammaglobulinemia was low in this cohort of patients and thus far has not been associated with an increased risk of infection. Three patients had a change in JCV status from positive to negative, and the effect of JCV index in the remaining subjects is further characterized.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0281 - ACAPELLA: Real-World Experience with Ocrelizumab: An Observational Study Evaluating Safety in Patients with Relapsing and Progressive MS, Year Three (ID 335)

Speakers
Presentation Number
P0281
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is a humanized, monoclonal antibody targeting CD20+ B cells and is approved for treatment of relapsing remitting (RRMS) and primary progressive MS (PPMS). The ACAPELLA trial is a prospective study with a primary objective of assessing OCR-associated adverse events (AEs) in a real-world MS population. ACAPELLA includes patients with preexisting conditions exempted from the phase II & III clinical trials, such as a prior history of malignancy, prior immunosuppressive treatment, and more advanced age and/or disability. Interim data analyses occur on a biannual basis and findings are reported yearly. This is the third iteration.

Objectives

We sought to determine the frequency of serious infections and malignancy in a real-world population receiving OCR with characteristics outside the inclusion parameters of the phase II and III trials.

Methods

The study includes all subjects treated with OCR at the Elliot Lewis Center since its commercial release in March 2017. Initial assessments include EDSS, brain MRI, mammograms (standard of care), collection of medical history including prior serious or recurrent infections, history of malignancy and exposure to immunosuppressive treatment, JCV index, and CD19 count.

Results

As of interim analysis in December 2019, 291 subjects were enrolled, 181 subjects had reached 12 months of treatment, 131 subjects had reached 18 months, and 84 subjects had reached 24 months. Subjects were 29% male, 71% female, with an age range of 18-73. Sixty three percent had RRMS and 37% PMS (PPMS and progressive RRMS) with an EDSS range of 0–7.5; 25% had a baseline EDSS of ≥ 6.0 with a median of 3.0.

The rate of infections for all OCR-treated patients was 43% (6% bronchitis, 2% zoster, 56% URIs, 30% UTIs, 4% HSV, and 25% other infections). Four percent of subjects had a serious infection (one that required hospitalization, was felt to be life-threatening, or resulted in death). Three percent of subjects had clinical or MRI relapses. 8% of subjects had a history of prior neoplasm (excluding basal cell carcinoma). Two malignancies have occurred during OCR treatment.

Conclusions

Thus far, the incidence of AEs is comparable to that seen in the phase III trials and in previously reported ACAPELLA data. Additional topics of interest in the ACAPELLA population include the effect of continued OCR dosing on JCV index values and immunoglobulin levels, and changes in EDSS and MRI over time.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0282 - Advancing antigen-specific T cell therapy for progressive multifocal leukoencephalopathy (ID 1896)

Speakers
Presentation Number
P0282
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is an often fatal white matter disease caused by the polyomavirus JC virus that affects patients with various types of immunodeficiencies. Some multiple sclerosis disease modifying therapies, including natalizumab, dimethyl fumarate and fingolimod, increase the risk for PML. Successful PML treatment and survival is critically dependent on early recognition and immune reconstitution; unfortunately, rapid immune reconstitution is not always achievable. New therapies are being investigated, including a pilot study conducted at NIH exploring ex vivo T cells generated from polyomavirus-specific partially matched first degree relative donors of PML patients (NCT02694783). Anti-viral specific cell products were generated following 14-day culture with 15mer polyomavirus peptide libraries.

Objectives

To perform T cell immune repertoire sequencing on donor polyomavirus-specific T cell populations with the goal of identifying T cell receptors (TCRs) that might be used to create a new “off the shelf” designer T cell therapy for PML.

Methods

T cells from twelve first degree relative donors and four PML patients from the NIH study were obtained, including donor T cells pre- and post-polyomavirus antigen stimulation. Using immune repertoire sequencing of CD4 and CD8 T cells, V(D)J sequences from post-stimulation donor cells were analyzed to identify clonally expanded TCRs relative to the pre-stimulation, same donor controls. Clonally expanded TCRs were also compared to PML patient V(D)J sequences to look for sequence similarity. Once candidate TCRs are identified, we will perform functional assays to determine their effectiveness against JC virus-infected cells.

Results

Candidate TCRs and their antigen specificity will be presented at the meeting in the hopes that the most effective candidate TCRs can serve as therapeutics for HLA-matched patients with PML.

Conclusions

Candidate TCRs and their antigen specificity will be presented at the meeting in the hopes that the most effective candidate TCRs can serve as therapeutics for HLA-matched patients with PML.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0283 - Adverse event profile differences between rituximab and ocrelizumab: Findings from the FDA Adverse Event Reporting Database (ID 484)

Presentation Number
P0283
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Anti-CD20 monoclonal antibody (mAb) therapies have shown a marked reduction in multiple sclerosis (MS) inflammatory activity by selectively depleting B lymphocytes. Rituximab is a chimeric mAb whereas ocrelizumab is fully humanized. Clinical trial efficacy and safety data suggest a favorable benefit-to-risk profile. However, there is a paucity of literature on comparative real-world safety profile of rituximab and ocrelizumab.

Objectives

To investigate the adverse events (AEs) associated with rituximab and ocrelizumab reported to the Food and Drug Administration adverse event (AE) Reporting System (FAERS) database.

Methods

The FAERS database query was filtered by reason for use (MS) and suspected active component (rituximab or ocrelizumab). In order to identify drug-AE associations, disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted. A signal was detected if the lower limit of the 95% two-sided confidence interval of ROR (ROR025) exceeded 1.

Results

There were 623 and 7,948 reports for rituximab and ocrelizumab, respectively. The most frequently reported AEs with rituximab and ocrelizumab were infusion related reactions (4.82%) and urinary tract infections (10.52%), respectively. The strongest drug-AE association for rituximab and ocrelizumab were ear pruritus (ROR25 47.53) and oral herpes (ROR025 38.99), respectively. When classified by AE class, ocrelizumab was associated with a nearly two-times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively).

Conclusions

This study revealed notable differences between rituximab and ocrelizumab. Specifically, infections were reported more frequently with ocrelizumab. A potentially more robust B cell depletion by ocrelizumab leading to more profound immunosuppression could explain these findings. Additional studies are needed to further investigate these differences.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0284 - Age-related efficacy of cladribine tablets in patients with relapsing-remitting MS in the CLARITY Extension study (ID 867)

Speakers
Presentation Number
P0284
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In the CLARITY study, treatment with cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [yr]) demonstrated significance over placebo on clinical and MRI efficacy outcomes in patients (pts) with relapsing-remitting multiple sclerosis. Pts who completed CLARITY were eligible to participate in CLARITY Extension (EXT).

Objectives

This post hoc analysis explored efficacy outcomes at the end of the core part of CLARITY EXT (Week 96) in pts who were ≤30yr vs >30yr at CLARITY enrollment.

Methods

Analyses were performed by age and treatment (CC7.0 [cladribine-cladribine]: cladribine tablets 3.5 mg/kg in CLARITY and CLARITY EXT; CP3.5 [cladribine-placebo]: cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY EXT). Endpoints included relapse, 3- and 6-month (mo) confirmed disability progression (CDP, based on Expanded Disability Status Scale), MRI activity, and no evidence of disease activity (NEDA; no relapse, 3- or 6-mo CDP, and MRI activity) at Week 96 of CLARITY EXT.

Results

Data from 284 pts were included: ≤30yr: CC7.0 N=49, CP3.5 N=23; >30yr: CC7.0 N=137, CP3.5 N=75. Annualized relapse rate (95% confidence interval [CI]) was similar between age groups for pts receiving CC7.0 (≤30yr, 0.08 [0.04; 0.15]; >30yr, 0.08 [0.05; 0.12]) and numerically higher in younger pts receiving CP3.5 (≤30yr, 0.27 [0.16; 0.47]; >30yr, 0.06 [0.03; 0.11]). The probabilities (Kaplan-Meier estimates) of being free of 3-mo CDP for CC7.0 were 0.98 for ≤30yr and 0.86 for >30yr; and for CP3.5 were 0.79 for ≤30yr and 0.88 for >30yr. The probabilities of being free of 6-mo CDP were similar to those of 3-mo CDP. Mean (95% CI) cumulative numbers of T1 gadolinium-enhancing lesions were similar between age groups for pts receiving CC7.0 (≤30yr, 0.02 [0.01; 0.08]; >30yr, 0.02 [0.01; 0.06]) or CP3.5 (≤30yr, 0.54 [0.16; 1.79]; >30yr, 0.27 [0.10; 0.73]). Mean (95% CI) numbers of active T2 lesions were similar between age groups for pts receiving CC7.0 (≤30yr, 1.36 [0.75; 2.45]; >30yr, 1.12 [0.78; 1.61]) and numerically lower in older pts receiving CP3.5 (≤30yr, 2.95 [1.22; 7.10]; >30yr, 1.40 [0.88; 2.22]). The proportion of pts achieving NEDA based on 3-mo CDP was numerically higher in younger pts receiving CC7.0 (≤30yr, 36.7%; >30yr, 28.5%) and older pts receiving CP3.5 (≤30yr, 21.7%; >30yr, 30.7%). NEDA results based on 6-mo CDP were similar to those based on 3-mo CDP.

Conclusions

Cladribine tablets result in similar clinical and MRI outcomes at Week 96 of CLARITY EXT in both older (>30yr) and younger (≤30yr) pts, providing further evidence of efficacy across age groups.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0285 - Alemtuzumab depletion failure and neutralizing anti-drug antibodies: a case report and call for monitoring (ID 912)

Speakers
Presentation Number
P0285
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a monoclonal antibody that targets CD52 positive T-cells and B-cells, and is used to treat relapsing remitting multiple sclerosis. However, despite humanization and depletion of peripheral T and B cells, alemtuzumab generates the highest frequency of binding and neutralizing antibodies of all humanized antibodies currently in clinical use. In some individuals, antibody neutralization appears to be sufficiently severe to allow disease-breakthrough.

Objectives

The objective of this report is to highlight a need to re-evaluate how we approach and monitor anti-drug antibodies to alemtuzumab during treatment of patients with multiple sclerosis.

Methods

This is a presentation of a case report of a 40 year old woman with a history of MS who was started on alemtuzumab in June 2015.

Results

She had breakthrough disease activity in September 2018, so received her third cycle of alemtuzumab in December 2018. In July 2019 she developed right eye blurry vision and bilateral lower extremity weakness. MRIs demonstrated longitudinally extensive right optic neuritis, 17 enhancing lesions throughout the cerebral hemispheres, corpus callosum, and brainstem, five enhancing cervical cord lesions, and two enhancing thoracic cord lesions. Review of her records revealed that her lymphocytes did not deplete following the third cycle of alemtuzumab. A novel serum assay was performed which demonstrated a very high titer of binding and neutralizing alemtuzumab anti-drug antibodies (>7.7 x 105 Lux) compared to an untreated serum sample (1.22 x 104 Lux).

Conclusions

We concluded that her new lesions were secondary to her multiple sclerosis, unchecked as a result of alemtuzumab depletion failure. We are additionally concerned that depletion failure was secondary to the presence of alemtuzumab neutralizing antibodies. We propose that following lymphocyte counts in the months following treatment should be routine if not imperative, with the goal of monitoring for treatment failure. More pro-actively, it may be appropriate to evaluate for neutralizing antibodies before considering administration of third or fourth cycles of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0286 - Alemtuzumab following natalizumab: a multicentric Italian real-world experience (ID 993)

Speakers
Presentation Number
P0286
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab was approved by EMA in 2013 for active relapsing-remitting multiple sclerosis patients (RRMS). The ideal candidate is an active patient in early phase of disease. iIn real world alemtuzumab is also used when many treatments before have failed. Patients with long-term natalizumab exposure and anti JCV seropositivity who stop natalizumab for the risk of PML are a category of patients for whom no specific therapeutic strategy has been established.

At present, neurologists have may highly active drugs but there are no head to head studies directly comparing the efficacy of alemtuzumab with other efficacious therapies and the decision to chose the most suitable medication depends on different factors, such as the potential side effects. In patients who stop natalizumab alemtuzumab can represent a choice.

Objectives

The aim ot this observational study was to evaluate the efficacy and safety of alemtuzumab when used in patients previously treated with natalizumab.

Methods

This is a multicentric retrospective observational study.

Study population is composed by 50 RRMS patients (18 male and 32 female) with a median EDSS of 2 (range 1-7) from five Italian Multiple Sclerosis Centres who stopped natalizumab treatment after a median number of 22 infusions (range 3-114).

Five out of 50 patients were JCV seronegative and in these patients decision to stop natalizumab was due to radiological activity during natalizumab (2 patients), hypertransaminasemia (2 patients), patient request (1 patient). 45 out of patients were JCV seropositive and for these patients reason for stopping was the risk of PML.

Switch to alemtuzumab was made after a median wash out period of 2 months (range 0,7-5 months).

Patients underwent brain MRI at the end of natalizumab treatment, at 6 and 12 months after alemtuzumab infusion.

Results

Brain MRI at six months after alemtuzumab was available for 48 out of 50 patients and in 43 of them neither signs of disease activity nor new lesions were present; 3 patients showed new lesions and 1 patient had radiological activity. No patient showed clinical activity.

Brin MRI at 12 months after alemtuzumab was available in 46 out of 50 patients and in 42 out of 46 there was no sign of disease activity. In 4 patients brain MRI showed disease activity (1 pt) or new lesions (2 pts ) or both (1 pt).

Clinical relapse after alemtuzumab therapy occurred in 1 out of 50 patients; this patient underwent the third infusion of drug.

No patient developed PML.

Conclusions

Alemtuzumab started shortly after natalizumab interruption was highly efficacious in controlling disease course, as 87% of patients showed no evidence of clinical and radiological activity one year after treatment starting.

The choice of alemtuzumab use in JCV seropositive patients must take in consideration the necessity to treat a very severe disease and the safety profile of the drug to which switching.

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