Carl Gustav Carus University Hospital
Center of Clinical Neuroscience

Author Of 1 Presentation

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.01 - Safety of Alemtuzumab Over 9 Years in Patients With Non-MS Autoimmunity

Speakers
Presentation Number
FC02.01
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:00 - 13:12

Abstract

Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

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Author Of 15 Presentations

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

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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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 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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Imaging Poster Presentation

P0560 - Comparative Myelin Water Imaging in Relapsing Remitting and Secondary Progressive Multiple Sclerosis (ID 1088)

Speakers
Presentation Number
P0560
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI) is applied to monitor multiple sclerosis (MS) evolution and to evaluate disease progression. Unfortunately, conventional MRI is non-specific for myelin. Therefore, the in vivo whole brain myelin imaging technique Multi-Component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) [1], that allows the assessment of relative myelination by measuring the myelin water fraction (MWF) [2], is expected to quantify myelination of the entire brain and thus assesses intra- and interindividual differences.

Objectives

The aim of this study was to explore MWF as a biomarker to analyse myelination differences in relapsing remitting (RRMS) and secondary progressive (SPMS) MS patients. In this study MWF was retrieved in WM of healthy controls (HC), normal appearing WM (NAWM) and T2 lesions (T2L) to parse differences in global and focal myelin loss in RRMS and SPMS.

Methods

A 1.5T MR scanner (Siemens Sonata) and an 8-channel head RF coil was used to derive 3D-fluid attenuated inversion recovery (FLAIR) images of n=112 RRMS (EDSSmean=2.7±1.2) and n=24 SPMS (EDSSmean=5.4±1.4) patients. WM, NAWM and T2L were segmented into binary masks. Common data post processing involving brain extraction and co-registration of scans was used (FSL/ANTs)[3,4]. MWF maps were derived using the established mcDESPOT processing method [1]. A matched control group (n=63) was acquired. Differences in MWF of healthy controls, RRMS and SPMS were determined with a wilcoxon rank sum test (p < 0.05).

A 1.5T MR scanner (Siemens Magnetom Sonata equipped with a 8-channel radio-frequency coil was used and sets of 3DFluid-Attenuated Inversion Recovery (FLAIR), Spoiled Gradient Recalled (SPGR) and Balanced Steady- State Free-Precession (bSSFP) images were

obtained. According to the mcDESPOT protocol SPGR and bSSFP scans were acquired over a range of flip angles at constant echo time (TE) and repetition time (TR) using the following specifications: field of view (FOV) = 22 cm, slice thickness = 1.7 mm; SPGR: TE/TR = 2.0/ 5.7 ms, flip angle (α)= [5, 6, 7, 8, 9, 11, 13, 18]°; bSSFP: TE/ TR = 1.71/3.42 ms, α = [9, 14, 19, 24, 28, 34, 41, 51, 60]°; acquisition time ~13min.

Results

The MWF in WM of HC was (MWFmean, SD=0.230 ± 0.007) versus MWF in NAWM of RRMS (MWFmean, SD=0.224 ± 0.01) and SPMS (MWFmean, SD=0.213 ± 0.012) patients. Significant MWF differences (p <0.05) were found for HC vs. MS patients. Mean T2L volume was significantly higher in SPMS patients (T2L volumeRRMS= 4,3ml±6,4ml vs. T2L volumeSPMS= 16.8ml±14.9ml). MWF in T2L of RRMS patients was MWFmean, SD =0.117 ± 0.03 ranging from MWFmin=0.032 to MWFmax = 0.201 and for SPMS patients MWFmean, SD =0.130 ± 0.02 ranging from MWFmin=0.088 to MWXmax = 0.177. Significant MWF differences were found for T2L of the RRMS vs. SPMS group.

Conclusions

Our findings demonstrate varying degrees of myelination within T2L in MS patients, indicating a heterogeneous MWF loss in RRMS and SPMS patients.

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Observational Studies Poster Presentation

P0837 - Assessing the real-world effectiveness of ocrelizumab in patients with multiple sclerosis – CONFIDENCE one-year interim analysis (ID 1133)

Speakers
Presentation Number
P0837
Presentation Topic
Observational Studies

Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory neurological disease that requires life-long treatment, and new therapies must be safe and effective over a long treatment duration. Ocrelizumab is a humanized antibody that selectively targets CD20+ B cells and has been shown to be efficacious for the treatment of both relapsing MS (RMS) and primary progressive MS (PPMS). Effectiveness data in large, real-world populations are needed for better informed clinical treatment.

Objectives

CONFIDENCE (ML39632, EUPAS22951) evaluates the safety and effectiveness of ocrelizumab in patients with RMS & PPMS in a real-world setting. Here, we present the first analysis of one-year effectiveness data from patients newly treated with ocrelizumab.

Methods

CONFIDENCE is a non-interventional study in patients with RMS or PPMS newly treated (up to 30 days prior or 60 days after enrolment) with ocrelizumab or other selected disease modifying therapies (DMTs) during the course of their disease. Data will be collected for 3000 ocrelizumab-treated patients and 1500 patients treated with other DMTs according to label at ~250 centers in Germany for up to 10 years. Here, we analyze effectiveness outcomes for patients treated with ocrelizumab for the first year, including treatment success (the proportion of patients with no relapse, progression or treatment discontinuation due to an adverse event) and change in Expanded Disability Status Scale (EDSS) from baseline. In addition, we will present patient-reported outcomes. Safety assessments are presented separately.

Results

As of 30 June 2020, 2,129 patients have been recruited for ocrelizumab treatment. The interim analysis is expected to include data from approximately 559 patients newly treated with ocrelizumab that had one year of follow up. Of these patients, ~82% had RMS and ~18% had PPMS. Mean (standard deviation [SD]) baseline EDSS was 3.3 (1.9) for patients with RMS and 4.5 (1.7) for patients with PPMS. Preliminary data show that 64% of patients were female (66% female RMS; 55% female PPMS). Over an observational period of one year, 83.6% of RMS and 93.2% of PPMS patients experienced treatment success. About 85.3% of patients with RMS experienced no relapses. The mean (SD) change in EDSS from baseline after one year of treatment was 0.0 [0.6] for patients with RMS and 0.1 [0.6] for patients with PPMS.

Conclusions

This analysis of one-year interim data in the CONFIDENCE study shows the effectiveness of ocrelizumab in a real-world setting.

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Observational Studies Poster Presentation

P0839 - Baseline Characteristics of AMASIA: First Real World Data of Siponimod Treated Patients with Secondary Progressive Multiple Sclerosis (ID 692)

Speakers
Presentation Number
P0839
Presentation Topic
Observational Studies

Abstract

Background

Hallmarks of secondary progressive multiple sclerosis (SPMS) are amongst others progressive motoric dysfunction and cognitive decline. Siponimod (Mayzent®), a selective sphingosine-1-phosphate receptor modulator, has been approved by the EMA for the treatment of active SPMS, evidenced by relapses or imaging features of inflammatory activity. AMASIA (ImpAct of Mayzent® (Siponimod) on secondAry progressive multiple Sclerosis patients in a long-term non-Iinterventional study in GermAny) is the first prospective non-interventional study to assess long-term effectiveness and safety of siponimod in clinical routine and the impact on quality of life and socioeconomic conditions.

Objectives

Characterization of the siponimod patient profile and SPMS diagnostic criteria based on clinical routine in Germany.

Methods

In AMASIA treatment effects of siponimod will be analyzed in 1,500 SPMS patients over 3 years. Disability progression and cognitive changes are evaluated every 6 months by the expanded disability status scale (EDSS) and the symbol digit modalities test (SDMT). Additional measures including MS activity by magnetic resonance imaging (MRI), assessments of functional domains, and questionnaires from patient’s, physician’s, and relatives’ perspectives of disability progression, cognitive worsening, and quality of life as well as socioeconomic aspects are analyzed.

Results

Results of the first interim analysis will be presented and will show patient characteristics of the first approx. 200 patients in Germany treated with siponimod in clinical routine. These data will include demography, but also all relevant clinical information including disease and therapy history, allowing for a comparison with data from phase II and III clinical studies with siponimod.

Conclusions

The combination of clinical parameters and patient reported outcomes including quality of life and socioeconomics allows a more detailed insight in the siponimod treated SPMS patient population in clinical routine in Germany. This will contribute to a better understanding of SPMS management in the medical community.

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Observational Studies Poster Presentation

P0884 - MS disease modifying therapy sequencing – natalizumab to cladribine tablets – experience in 46 patients (ID 566)

Speakers
Presentation Number
P0884
Presentation Topic
Observational Studies

Abstract

Background

Natalizumab proved to be very effective in patients with active relapsing-remitting multiple sclerosis but harbors the risk of progressive multifocal leukoencephalopathy (PML), especially in combination with specific risk factors. Accordingly, a safe and an equally effective therapeutic alternative is warranted in this patient group. A high efficacy therapy for Relapsing Multiple Sclerosis are cladribine tablets, representing a short course oral therapy. It has been approved in Europe since 2017 and in the USA since April 2019.

Objectives

Safety of switching from natalizumab to cladribine tablets has been investigated in a limited number of patients and with limited observational time. We therefore analyzed this safety issue with a longer follow-up time in the subgroups of post-natalizumab patients in 2 non-interventional studies (NIS).

Methods

46 patients who switched from natalizumab to oral cladribine were reviewed. They originated from 2 cohorts analyzed separately: 23 patients each from the still ongoing NIS CLEVER (in Germany, 24 weeks follow-up as per study duration) and CLADQoL (in Germany and Austria, mean follow-up 11 months). Different study designs accounted for different timings in data collection. Patients were closely monitored, and data was collected regarding MS relapses, disease progression, or possible adverse events.

Results

The NIS CLEVER provides data from 23 patients (mean age 41.6 years; 78% female; 87% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML or lack of efficacy. Median time on natalizumab was 26.6 months and median gap between therapies 3.2 months. 1 out of 15 evaluable patients at week 24 experienced relapses. For 7 patients at least one AE was reported and no SAE.

The NIS CLADQoL provides data from 23 patients (mean age 38.8 years; 70% female; 91% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML. Median time on natalizumab was 40.1 months and median gap between therapies 3.4 months. 2 out of 10 evaluable patients at month 12 experienced relapses. 6 patients experienced at least one AE and 3 patients one SAE (Anterior Myocardial Infarction (among underlying risk factors), Multiple sclerosis relapse, Dyspnoea).

Conclusions

Based on data from 46 patients, switching from natalizumab to cladribine tablets continued to be safe in a larger patient population and after a longer follow-up. Especially no cases of PML were observed.

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Observational Studies Poster Presentation

P0896 - PANGAEA 2.0 EVOLUTION: Unraveling patient and treatment characteristics for SPMS and at risk for SPMS patients in clinical routine (ID 690)

Speakers
Presentation Number
P0896
Presentation Topic
Observational Studies

Abstract

Background

Diagnosis of secondary progressive multiple sclerosis (SPMS) patients and the identification of the transition phase from relapsing-remitting multiple sclerosis (RRMS) to SPMS remain a challenge as reliable clinical diagnostic criteria and diagnostic tools are lacking.

Objectives

This analysis evaluates disability parameters and patient reported outcomes in patients with RRMS at risk for SPMS and SPMS to:

– compare clinical parameters including magnetic resonance imaging (MRI), quality of life and socioeconomic aspects of patients with SPMS to patients at risk for SPMS

– characterize patients in the transition phase from RRMS to SPMS

– evaluate performance of the novel progression questionnaire (MSProDiscuss) in clinical routine

Methods

PANGAEA 2.0 EVOLUTION is part of the non-interventional real-world study PANGAEA 2.0 including approximately 2,500 RRMS patients. Additionally up to 1,000 patients diagnosed with SPMS or on risk for SPMS are currently being recruited and will be prospectively followed independently of treatment for up to 2 years. Diagnosis for risk for SPMS is made by the physician after a comprehensive evaluation of the patient's symptoms including for example relapses, fatigue, progression or impact on quality of life as there are no standard criteria for the transition state for RRMS to SPMS. Routine clinical measurements including EDSS, relapse rate, MRI and cognition measurements, quality of life (EQ-5D, MSIS-29) and socioeconomic conditions (MS-HRS, WPAI) as well as observational parameters from the physician’s perspective (UKNDS, CGI) are collected at 6-month intervals.

Results

Real world data of approximately 400 patients will be shown. Profiles of patients with different progression states will be compared and assessed for differences. MRI findings will be correlated with clinical and patient reported outcomes. Status of disease progression will be correlated with quality of life and socioeconomic measures collected within this study.

Conclusions

PANGAEA2.0 EVOLUTION allows to compare SPMS patient profiles with RRMS patients at risk for SPMS in a real world setting. By combining clinical and non-clinical parameters a clearer picture can be generated for the establishment of standard early diagnosis criteria and therapy of SPMS patients.

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Observational Studies Poster Presentation

P0916 - Safety and tolerability in patients with multiple sclerosis receiving ocrelizumab in a real-world setting – CONFIDENCE one-year interim analysis (ID 1136)

Speakers
Presentation Number
P0916
Presentation Topic
Observational Studies

Abstract

Background

As of April 2020, >160,000 patients with relapsing forms of multiple sclerosis (RMS) or primary progressive MS (PPMS) worldwide had started treatment with ocrelizumab (OCR), a humanized monoclonal antibody selectively targeting CD20+ B-cells.

Pivotal studies established the risk-benefit profile of OCR under controlled trial conditions.

Objectives

Real-world data are needed to further characterise the safety of OCR in clinical practice. Here we present 1-year, real-world safety data for patients receiving OCR.

Methods

CONFIDENCE (ML39632, EUPAS22951), a non-interventional, post-authorization safety study, aims to enrol 3,000 patients with RMS or PPMS newly treated (up to 30 days prior or 60 days after enrolment) with OCR and 1,500 patients newly treated with other selected DMTs according to label at ~250 German neurological practices. Each patient is followed for 7.5–10 years. Study visits, documented circa every 6 months, follow routine clinical practice. The primary outcome is the incidence and type of uncommon adverse events (AEs) (incidence of 0.1% to 1% [1 to 10 out of 1000 patients] or less). Statistical analyses are mainly descriptive and exploratory. Assessments of effectiveness (secondary objectives) are presented separately.

Results

As of 30 June 2020, 2,129 patients treated with OCR had been recruited. The interim analysis is expected to include approximately 559 OCR-treated patients, ~82% with RMS and ~18% with PPMS, with 1-year follow-up data (mean baseline age [SD], 45.5 [11.4] years; 64.4% female; mean baseline EDSS [SD] RMS 3.3 [1.9], PPMS 4.5 [1.7]). Preliminary data showed that ~63.0% of patients had ≥1 AE during OCR treatment; ~26.8% had treatment-related AEs (TRAEs). The most common AEs were infections and infestations (~31.5%), nervous system disorders (~14.7%), and general disorders and administration site conditions (~12.3%). The incidence of serious AEs was ~14.0%, most frequently infections and infestations (~3.6%; RMS, ~3.9% [n=18]; PPMS, ~1.9% [n=2]), nervous system disorders (~3.2%), and injury, poisoning and procedural complications (~2.1). The most frequent serious infections were urinary tract infections (~1.3% [n=7]) and pneumonia (~0.5% [n=3]). Seven patients overall (1.3%) had treatment-related serious infections.

Conclusions

The safety profile of OCR in this first interim analysis of the CONFIDENCE study, representing a real-world population currently treated with OCR in Germany, was consistent with controlled clinical trials.

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Observational Studies Poster Presentation

P0929 - Two-Year Interim Analysis of the TREAT-MS Alemtuzumab Study in Germany Differentiated by the Number of Previous Disease-Modifying Therapies (ID 293)

Speakers
Presentation Number
P0929
Presentation Topic
Observational Studies

Abstract

Background

The TREAT-MS study (Paul-Ehrlich-Institut registry: 281) is assessing real-world effectiveness of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS) patients in Germany.

Objectives

Subgroup analysis of TREAT-MS to investigate the effect of the number of prior disease-modifying therapies (DMTs) on the efficacy and safety of alemtuzumab 1 year after the 2nd treatment cycle with alemtuzumab.

Methods

TREAT-MS is a 5-year, observational, longitudinal, noninterventional, open-label, multicenter study of alemtuzumab-treated patients.

Results

As of February 2020, 883 patients were enrolled and 571 patients were observed for 2 years after treatment initiation. Of these, 565 (98.9%) patients entered the first treatment period, 538 (94.2%) patients entered two treatment periods. 13.3% of patients were treatment-naive at baseline, 83.7% had received prior DMTs, and in 3.0% pretreatment was unknown. The interim analysis focussed on the data of patients 1 year after the 2nd treatment phase and was differentiated by the number of previously received DMTs. Patients with 0, 1, 2, and ≥3 pretreatments had a mean number of 1.6, 1.7, 1.4, and 1.8 relapses, respectively, during the last 12 months before alemtuzumab treatment. After alemtuzumab treatment initiation, annualized relapse rate (ARR) in patients with 0, 1, 2, ≥3 pretreatments reached levels of 0.13, 0.18, 0.25, and 0.24. ARR after alemtuzumab initiation was significantly higher in patients who received 2 or ≥3 prior DMTs when compared with treatment-naive patients.

The majority of patients were relapse-free 1 year after the 2nd course of alemtuzumab. 82.2%, 77.0%, 66.5%, 73.1% of the patients with 0, 1, 2, ≥3 pretreatments, respectively, had no relapses during the observational period. The proportion of relapse-free patients 1 year after the second alemtuzumab course was highest in treatment-naive patients.

Mean expanded disability status scale (EDSS) score at baseline was 2.2, 2.4, 2.6, and 3.6 for those who received 0, 1, 2, and ≥3 prior DMTs, respectively, and changed by a mean EDSS value of –0.5, –0.2, –0.2, and –0.5 one year after the 2nd treatment phase.

Adverse events were reported for 64.5%, 66.9%, 66.9%, 73.6% of the patients treated with 0, 1, 2, and ≥3 DMTs. No new safety signals were observed.

Conclusions

The interim subgroup analysis of patients 1 year after the 2nd treatment cycle with alemtuzumab has shown that relapse rates were reduced, and EDSS scores were stable regardless of the number of prior DMTs received. These data confirm registration trial findings (CARE-MS I and II) in the real-world setting in patients with longer disease duration and varying treatment history.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1036 - Impact of natalizumab on quality of life in a real-world cohort of patients with multiple sclerosis: results from MS PATHS (ID 1794)

Speakers
Presentation Number
P1036
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

Understanding patient-reported changes in physical, mental, and social health after starting MS therapy is important in optimizing treatment.

Objectives

Assess changes in the Quality of Life in Neurological Disorders (Neuro-QoL; NQ) questionnaire after starting natalizumab (NAT) and compare to another high efficacy therapy - ocrelizumab (OCR).

Methods

T-scores of 12 NQ domains were obtained at routine visits in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network. NQ scores from visits post NAT initiation were compared to last previous NQ (baseline, BL) to calculate the annualized rate of change and the likelihood of clinically meaningful change (≥5-point) in the overall cohort and in patients with abnormal BL NQ (T-score worse than 50; 36%-76% of the population). Subgroup analyses in NAT- and OCR-treated patients were conducted with multivariate mixed-effects regression models after propensity score weighting and adjustment for antidepressants, year and drug*year interaction.

Results

164 NAT patients were analyzed; mean (SD) follow-up was 6 (6) months and number of assessments was 2.3 (1.6). Significant improvements from pre-NAT BL were seen in 8 of 12 NQ domains. Patients with BL impairment had significant improvements in 10 NQ domains and higher rates of improvement compared to the overall cohort (p<0.05). In this subgroup, the largest number of patients with ≥5-point improvement was seen for positive affect and well-being (PAF) (43%), emotional and behavioral dyscontrol (EBD) (38%) and sleep disturbances (35%). In the subgroup of NAT (n=145)- and OCR (n=520)-treated patients, the annualized improvement rates were higher with NAT than with OCR, reaching statistical significance for PAF (p=0.02), sleep disturbances (p=0.003), and satisfaction with social roles and activities (SRA) (p=0.03). In patients with impaired BL NQ, significantly higher rates of improvement were seen with NAT than with OCR for EBD (p=0.01), participation in SRA (p=0.0001) and satisfaction with SRA (p=0.02). The percentage of patients with ≥5-point improvement was numerically higher with NAT than OCR for 9 of 12 NQ domains; differences in the likelihood of ≥5-point improvement were not significant.

Conclusions

NAT can lead to clinically meaningful improvements in mental and social health. Such improvements are unlikely to be primarily driven by expectation bias as their magnitude exceeded improvements with another high-efficacy therapy (OCR).

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1063 - Treatment persistence and adherence to Ocrelizumab in the real-world setting- an ad-hoc analysis of the CONFIDENCE study (ID 1731)

Speakers
Presentation Number
P1063
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (RMS and PPMS). Real-world evidence on adherence and persistence with OCR is limited.

Objectives

To examine the persistence and adherence to OCR in a real-world setting.

Methods

CONFIDENCE (ML39632, EUPAS22951) is an ongoing non-interventional, post-authorization safety study, aiming to enroll 3,000 patients newly treated with OCR and 1,500 patients newly treated with other DMTs at ~250 centers in Germany. Follow up regardless of discontinuation of treatment will be for up to 10 years. In this ad-hoc analysis of CONFIDENCE, persistence and adherence were measured exclusively for patients treated with OCR with at least one post-initiation (i.e., first two 300mg doses IVs') assessment visit. Persistence was examined as a survival function of event-free time from discontinuation. Patients were considered at-risk until the last assessment visit recorded prior to data cut-off (31 March 2020) or censored at time of OCR discontinuation, whichever occurred first. Adherence was assessed using median time intervals between infusions.

Results

Overall, 1614 patients treated with OCR were included in this analysis; 1296 patients with RMS and 318 with PPMS. Median [IQR] age at OCR initiation was 42 [44, 57] years and 52 [33, 51] years in patients with RMS and PPMS, respectively. Most RMS patients were females (66.7%) while gender distribution in PPMS patients was approximately equal (51.6% females). Median [IQR] disease duration from diagnosis up to OCR initiation was longer in RMS (7.9 [3.0, 14.7] years) than in PPMS patients (3.4 [0.8, 9.7] years). Median [IQR] EDSS at OCR start was 3.0 [2.0, 4.5] and 4.5 [3.5, 6.0] in the RMS and PPMS population, respectively. At data cut-off, the median [IQR] OCR exposure duration was 7.85 [5.5, 13.1] months for RMS and 6.87 [0.5, 12.5] months for PPMS patients. Overall, the median time between infusions ranged from 5.9 and 6.0 months and did not differ between RMS and PPMS cohorts. Treatment persistence at 18 months was 96.6% (95% CI: 95.3-97.8%) and very consistent between RMS and PPMS patients.

Conclusions

Adherence to disease-modifying therapy (DMT) is critical for achieving therapeutic goals in MS. This analysis shows high treatment persistence for OCR patients at 18 months and strong adherence to recommendations to administer OCR infusions every 24 weeks.

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Rehabilitation and Comprehensive Care Poster Presentation

P1111 - Timely Intervention, Monitoring and Education MATTERS in MS (TIME MATTERS in MS): global piloting of the MS Brain Health quality improvement tool (ID 1386)

Speakers
Presentation Number
P1111
Presentation Topic
Rehabilitation and Comprehensive Care

Abstract

Background

A strategy for timely multiple sclerosis (MS) care was described in the policy report, Brain health: time matters in multiple sclerosis. Building on this report, multiple stakeholder groups participated in a modified Delphi process to define acceptable, good and high-quality brain health-focused MS care. These benchmarks were incorporated into an Excel-based quality improvement (QI) tool. The first prototype of this tool was piloted in three MS centers; local analysis of results led to improvements in clinical practice in those centers.

Objectives

We aimed to improve the clinical usability of the QI tool and to test the applicability of a refined version in different healthcare settings.

Methods

The recommendations from all three centers that participated in the initial pilot study were gathered and used to prepare a refined prototype of the QI tool (prototype II). MS centers worldwide have been invited to conduct a service evaluation using prototype II as part of a larger pilot study of 10–20 MS centers across a broad geographical area. Each participating site will review the medical records of 36 adults with MS (at representative stages of the care pathway) and input the data requested into the tool. To assess whether the QI tool can be applied in MS centers globally, study sites will be asked to complete a survey following their service evaluation. The survey asks about ease of use of the tool, its usefulness for facilitating local change, relevance of the data captured and key data for repeated use.

Results

Prototype II has separate spreadsheets for entering information on patients at different stages of the care pathway; fields are tailored to the different patient populations so there is less data to input per patient. Data validation programming prevents the insertion of invalid information. To assist MS centers in analyzing their findings, improved visual summaries of clinic-level and patient-level results are generated within the tool; these auto-populate when the required fields in the data input spreadsheets are completed. Prototype II will also support future language translations. More than 18 MS centers have so far expressed interest in trialing prototype II of the QI tool; preliminary insights from selected study sites will be presented.

Conclusions

Following further refinements, widespread roll-out of the QI tool will enable MS centers to collect data to benchmark their clinical standards and to support service improvement.

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Gender Differences, Hormones and Sex Chromosomes Poster Presentation

P1124 - Health resource utilization in relapsing remitting multiple sclerosis from a gender perspective - evidence from more than 2000 patients in Germany (ID 1640)

Speakers
Presentation Number
P1124
Presentation Topic
Gender Differences, Hormones and Sex Chromosomes

Abstract

Background

For the case of multiple sclerosis, research on gender differences from a health economic perspective has not received much attention. However, cost-of-illness analyses provide valuable information about the diverse impact of the disease and thus help decision-makers to allocate scarce resources.

Objectives

The aim of this study was to describe resource use and associated societal costs from a gender perspective. In particular, the aim was to determine how resource utilization potentially differs in certain cost components between men and women.

Methods

Data were extracted from two prospective, non-interventional, observational multicentre studies in Germany. Information on (health) resource use was obtained from all patients on a quarterly basis using a validated questionnaire. Cost analyses were conducted from the societal perspective, including all direct (healthcare-related) and indirect (work-related) costs, regardless of who ultimately pays them. Costs for men and women were analysed within subgroups of two-year clinical disease activity. Gender-related differences were analysed by multivariate negative binomial regression models (mean quarterly costs) and binary logistic regression models (patients using resources).

Results

In total, 2095 patients (72.9% females) presented a median EDSS of 2 (IQR 1-3.5) and disease duration of 7.55 ±6.12 years (p>0.05 for gender-related differences). Women and men did not statistically differ in total quarterly costs (2329 Euro (€) ±2570€ vs 2361€ ±2612€). For both sexes, costs were higher with advancing disability and indirect costs were the main societal cost driver. Regarding healthcare-related resources, women incurred higher costs for outpatient consultations, complementary medicine, medical consumables and informal care. Among indirect costs, we found higher costs for men for presenteeism and higher costs for women for disability pension (all p<0.05).

Conclusions

Multiple sclerosis poses a significant economic burden on patients, families and society. While the total economic burden did not differ between males and females, we found gender differences in specific cost items that are similar to those in the wider non-MS population. Furthermore, indirect costs were highly dependent on the cost categories included and the way in which they were valued.

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Presenter Of 3 Presentations

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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Observational Studies Poster Presentation

P0884 - MS disease modifying therapy sequencing – natalizumab to cladribine tablets – experience in 46 patients (ID 566)

Speakers
Presentation Number
P0884
Presentation Topic
Observational Studies

Abstract

Background

Natalizumab proved to be very effective in patients with active relapsing-remitting multiple sclerosis but harbors the risk of progressive multifocal leukoencephalopathy (PML), especially in combination with specific risk factors. Accordingly, a safe and an equally effective therapeutic alternative is warranted in this patient group. A high efficacy therapy for Relapsing Multiple Sclerosis are cladribine tablets, representing a short course oral therapy. It has been approved in Europe since 2017 and in the USA since April 2019.

Objectives

Safety of switching from natalizumab to cladribine tablets has been investigated in a limited number of patients and with limited observational time. We therefore analyzed this safety issue with a longer follow-up time in the subgroups of post-natalizumab patients in 2 non-interventional studies (NIS).

Methods

46 patients who switched from natalizumab to oral cladribine were reviewed. They originated from 2 cohorts analyzed separately: 23 patients each from the still ongoing NIS CLEVER (in Germany, 24 weeks follow-up as per study duration) and CLADQoL (in Germany and Austria, mean follow-up 11 months). Different study designs accounted for different timings in data collection. Patients were closely monitored, and data was collected regarding MS relapses, disease progression, or possible adverse events.

Results

The NIS CLEVER provides data from 23 patients (mean age 41.6 years; 78% female; 87% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML or lack of efficacy. Median time on natalizumab was 26.6 months and median gap between therapies 3.2 months. 1 out of 15 evaluable patients at week 24 experienced relapses. For 7 patients at least one AE was reported and no SAE.

The NIS CLADQoL provides data from 23 patients (mean age 38.8 years; 70% female; 91% RRMS). The most frequent reason for therapy switch was increased JCV antibody titer/risk of PML. Median time on natalizumab was 40.1 months and median gap between therapies 3.4 months. 2 out of 10 evaluable patients at month 12 experienced relapses. 6 patients experienced at least one AE and 3 patients one SAE (Anterior Myocardial Infarction (among underlying risk factors), Multiple sclerosis relapse, Dyspnoea).

Conclusions

Based on data from 46 patients, switching from natalizumab to cladribine tablets continued to be safe in a larger patient population and after a longer follow-up. Especially no cases of PML were observed.

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Observational Studies Poster Presentation

P0896 - PANGAEA 2.0 EVOLUTION: Unraveling patient and treatment characteristics for SPMS and at risk for SPMS patients in clinical routine (ID 690)

Speakers
Presentation Number
P0896
Presentation Topic
Observational Studies

Abstract

Background

Diagnosis of secondary progressive multiple sclerosis (SPMS) patients and the identification of the transition phase from relapsing-remitting multiple sclerosis (RRMS) to SPMS remain a challenge as reliable clinical diagnostic criteria and diagnostic tools are lacking.

Objectives

This analysis evaluates disability parameters and patient reported outcomes in patients with RRMS at risk for SPMS and SPMS to:

– compare clinical parameters including magnetic resonance imaging (MRI), quality of life and socioeconomic aspects of patients with SPMS to patients at risk for SPMS

– characterize patients in the transition phase from RRMS to SPMS

– evaluate performance of the novel progression questionnaire (MSProDiscuss) in clinical routine

Methods

PANGAEA 2.0 EVOLUTION is part of the non-interventional real-world study PANGAEA 2.0 including approximately 2,500 RRMS patients. Additionally up to 1,000 patients diagnosed with SPMS or on risk for SPMS are currently being recruited and will be prospectively followed independently of treatment for up to 2 years. Diagnosis for risk for SPMS is made by the physician after a comprehensive evaluation of the patient's symptoms including for example relapses, fatigue, progression or impact on quality of life as there are no standard criteria for the transition state for RRMS to SPMS. Routine clinical measurements including EDSS, relapse rate, MRI and cognition measurements, quality of life (EQ-5D, MSIS-29) and socioeconomic conditions (MS-HRS, WPAI) as well as observational parameters from the physician’s perspective (UKNDS, CGI) are collected at 6-month intervals.

Results

Real world data of approximately 400 patients will be shown. Profiles of patients with different progression states will be compared and assessed for differences. MRI findings will be correlated with clinical and patient reported outcomes. Status of disease progression will be correlated with quality of life and socioeconomic measures collected within this study.

Conclusions

PANGAEA2.0 EVOLUTION allows to compare SPMS patient profiles with RRMS patients at risk for SPMS in a real world setting. By combining clinical and non-clinical parameters a clearer picture can be generated for the establishment of standard early diagnosis criteria and therapy of SPMS patients.

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