Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland Clinic

Author Of 9 Presentations

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

Collapse
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

Collapse
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.

Collapse
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.

Collapse
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.

Collapse
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.

Collapse
Disease Modifying Therapies – Risk Management Poster Presentation

P0300 - Baseline features in DISCOntinuation of disease modifying therapies in Multiple Sclerosis (DISCOMS) (ID 791)

Speakers
Presentation Number
P0300
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

New relapses and magnetic resonance imaging (MRI) abnormalities diminish as people age with multiple sclerosis (MS). Data supporting use of disease modifying therapies (DMTs), from studies with typical inclusion ages of 18-55, suggest diminished benefit in older compared with younger individuals. Whether it is beneficial to continue, or safe to discontinue, DMTs as people age beyond 55 remains unknown. Retrospective studies show those at greatest risk of new inflammatory disease activity upon DMT discontinuation are younger and had recent new relapse and/or MRI scan activity.

Objectives

Present the design and baseline data in our study evaluating whether older individuals with MS who discontinue their DMT have no worse risk of new disease activity compared to those who remain on DMT.

Methods

This is a randomized (1:1), controlled, rater-blinded study in which 260 MS participants aged 55 and older and continuously taking DMTs (at least 5 years, minimum 2 years on current DMT) were enrolled at 19 sites in the United States. They have no evidence of MS relapse for 5+ years or new MRI lesion for 3+ years, and will be followed for up to 2 years, with study visits every 6 months. Primary outcome is either a new MS relapse or T2 brain MRI lesion. Secondary outcomes are 6-month confirmed increase in Extended Disability Status Scores (EDSS), and worsening of Symbol Digit Modality Test or patient-reported outcomes.

Results

Mean age of participants is 63 ± 5 years, and 83.7% are female. Racial/ethnic breakdown is 89.2% White, 9.2% Black or African American, 0.8% Hispanic/Latino, and 0.8% Other. Participants average 22.3 ± 10.5 years since symptom onset, and 13.5 ± 7 years since last relapse. Most have Relapsing-Remitting MS (83.7%), with 13.1% Secondary Progressive and 3.2% Primary Progressive MS. At enrollment, 42.6% were on an interferon, 30.3% on glatiramer acetate, 15.1% dimethyl fumarate, 6.4% fingolimod, 3.2% teriflunomide, 1.6% natalizumab, and 0.8% ocrelizumab. EDSS scores average 3.3 ± 1.8, and 77.8% of participants rate their treatment satisfaction as Satisfied or Very Satisfied at enrollment.

Conclusions

The DISCOMS study is the first controlled trial to address whether it is safe to discontinue DMTs in MS. Enrolled participants represent a unique cohort of stable, older MS patients with relatively low disability. Upon completion, the study will increase our understanding of the utility of MS DMTs throughout the lifespan of MS.

Collapse
Imaging Poster Presentation

P0547 - Axonal injury in multiple sclerosis: a multi-compartment diffusion MRI study using high-resolution probabilistic tractography (ID 1749)

Speakers
Presentation Number
P0547
Presentation Topic
Imaging

Abstract

Background

Axonal injury is a key contributor to physical disability in persons with multiple sclerosis (pwMS). Yet, assessing axonal damage in vivo is challenged by the lack of pathologically and topographically specific imaging methods.

Objectives

We use the spherical mean technique (SMT) and neurite orientation density and dispersion index (NODDI) combined with high-resolution probabilistic tractography and propose an improved assessment of the degree of regional axonal injury and its association with measures of disability in pwMS.

Methods

Eighteen pwMS and nine age-sex matched heathy controls underwent a brain MRI inclusive of clinical scans, SMT and NODDI. Parametric maps of the apparent axonal volume fraction (Vax), intrinsic diffusivity (Dax), neurite density index (ndi), orientation dispersion index (odi), and isotropic volume fraction (isovf) were estimated. Tract-specific values were measured in transcallosal (TC) and corticospinal (CS) white matter tracts implicated with motor functions. This included the TC bundles from the paracentral lobules, and both the TC and the CS fibers from the ventral premotor areas, dorsal premotor areas, presupplementary motor areas, supplementary motor areas, and primary motor cortex, all of which were reconstructed by probabilistic tractography. Unpaired t-tests assessed group-differences in tract-specific SMT and NODDI-derived metrics between healthy controls and pwMS, and Spearman rank correlations analyses assessed associations between SMT and NODDI metrics and physical disability metrics.

Results

Differences (p<=0.018) were seen only for the isovf of the TC bundles from the paracentral lobules, the presupplementary motor areas and supplementary motor areas, and both the TC and the CS fibers from the ventral premotor areas. However, associations were seen between several NODDI derived metrics and clinical scores of motor impairment (p<=0.054).

Conclusions

Our preliminary findings show that NODDI-derived isovf has a higher radiological discriminatory capacity compared to SMT and NODDI-derived measures, but several NODDI and SMT indices measured in topographically specific regions explain motor disability variations in pwMS.

Collapse
Patient-Reported Outcomes and Quality of Life Poster Presentation

P1039 - Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial (ID 977)

Speakers
Presentation Number
P1039
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

SymptoMScreen is a patient-reported outcome tool designed to rapidly assess symptom limitations across 12 symptoms commonly affected in people with multiple sclerosis (MS). Each domain is scored on a 7-point Likert scale (0 [not affected] to 6 [total limitation]) and domain scores are summed to calculate a total score ranging from 0 to 72. SymptoMScreen is used in the ongoing, open-label, single-arm, Phase IIIb CASTING clinical trial (NCT02861014).

Objectives

To report 2-year changes in SymptoMScreen scores among patients with relapsing-remitting MS (RRMS) from CASTING.

Methods

In CASTING, patients with RRMS (Expanded Disability Status Scale [EDSS] score ≤4.0 at screening; disease duration ≤10 years) and a prior suboptimal response to ≥6 months of treatment with one or two disease-modifying therapies (DMTs; including orals and injectables) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. SymptoMScreen was performed at baseline, Week 48 (1-year interim data) and Week 96 (2-year final data).

Results

A total of 680 patients (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]) who were previously treated with one (n=414 [60.4%]) or two (n=269 [39.6%]) DMTs were enrolled (most frequently for MRI with relapse activity [40.4%]) and evaluated in the intent-to-treat population; 644 patients completed treatment. Total SymptoMScreen mean (SD) score reflected mild symptom burden at baseline (15.19 [12.67]) and improved significantly through Year 2 (13.62 [12.51]; p<0.001 [p values were not adjusted for multiplicity]). Statistically significant improvements after 2 years were observed for sensory symptoms (Δ-0.28; p<0.001), fatigue (Δ-0.23; p<0.001), vision (Δ-0.21; p<0.001), depression (Δ-0.15; p<0.01) and dizziness (Δ-0.14; p<0.01) domains. Non-significant improvements in symptom burden after 2 years (p>0.05) were observed in walking (Δ-0.1), cognition (Δ-0.10), anxiety (Δ-0.07), bodily pain (Δ-0.05), hand function (Δ-0.03) and bladder control (Δ-0.01), while a non-significant worsening was observed in the spasticity domain (Δ+0.04). The proportion of patients with at least one symptom causing at least moderate limitation (domain score ≥4) decreased from 31.6% at baseline to 26.3% at Year 2.

Conclusions

Patients with RRMS and a suboptimal response to therapy who switched to ocrelizumab experienced an improvement in symptom burden in the majority of SymptoMScreen domains after 2 years, which was most pronounced in sensory, fatigue and vision.

Collapse