Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.

Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.

Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis.

BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.

Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.

Overcoming barriers to informed consent in neurological research: Perspectives from a national survey.

The ethical recruitment of participants with neurological disorders in clinical research requires obtaining initial and ongoing informed consent. The purpose of this study is to characterize barriers faced by research personnel in obtaining informed consent from research participants with neurological disorders and to identify strategies applied by researchers to overcome those barriers. This study was designed as a web-based survey of US researchers with an optional follow-up interview. A subset of participants who completed the survey were selected using a stratified purposeful sampling strategy and invited to participate in an in-depth qualitative interview by phone or video conference. Data were analyzed using a mixed methods approach, including content analysis of survey responses and thematic analysis of interview responses. Over 1 year, 113 survey responses were received from US research personnel directly involved in obtaining informed consent from participants in neurological research. Frequently identified barriers to informed consent included: cognitive and communication impairments (e.g. aphasia), unrealistic expectations of research participants, mistrust of medical research, time constraints, literacy barriers, lack of available social support, and practical or resource-related constraints. Strategies to enhance informed consent included: involving close others to support participant understanding of study-related information, collaborating with more experienced research personnel to facilitate training in obtaining informed consent, encouraging participants to review consent forms in advance of consent discussions, and using printed materials and visual references. Beyond conveying study-related information, researchers included in this study endorsed ethical responsibilities to support deliberation necessary to informed consent in the context of misconceptions about research, unrealistic expectations, limited understanding, mistrust, and/or pressure from close others. Findings highlight the importance of training researchers involved in obtaining informed consent in neurological research to address disease-specific challenges and to support the decision-making processes of potential research participants and their close others.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.

Assisted ambulation to improve health outcomes for older medical inpatients (AMBULATE): study protocol for a randomized controlled trial.

BACKGROUND: Hospitalized older adults spend as much as 95% of their time in bed, which can result in adverse events and delay recovery while increasing costs. Observational studies have shown that general mobility interventions (e.g., ambulation) can mitigate adverse events and improve patients' functional status. Mobility technicians (MTs) may address the need for patients to engage in mobility interventions without overburdening nurses. There is no data, however, on the effect of MT-assisted ambulation on adverse events or functional status, or on the cost tradeoffs if a MT were employed. The AMBULATE study aims to determine whether MT-assisted ambulation improves mobility status and decreases adverse events for older medical inpatients. It will also include analyses to identify the patients that benefit most from MT-assisted mobility and assess the cost-effectiveness of employing a MT. METHODS: The AMBULATE study is a multicenter, single-blind, parallel control design, individual-level randomized trial. It will include patients admitted to a medical service in five hospitals in two regions of the USA. Patients over age 65 with mild functional deficits will be randomized using a block randomization scheme. Those in the intervention group will ambulate with the MT up to three times daily, guided by the Johns Hopkins Mobility Goal Calculator. The intervention will conclude at hospital discharge, or after 10 days if the hospitalization is prolonged. The primary outcome is the Short Physical Performance Battery score at discharge. Secondary outcomes are discharge disposition, length of stay, hospital-acquired complications (falls, venous thromboembolism, pressure ulcers, and hospital-acquired pneumonia), and post-hospital functional status. DISCUSSION: While functional decline in the hospital is multifactorial, ambulation is a modifiable factor for many patients. The AMBULATE study will be the largest randomized controlled trial to test the clinical effects of dedicating a single care team member to facilitating mobility for older hospitalized patients. It will also provide a useful estimation of cost implications to help hospital administrators assess the feasibility and utility of employing MTs. TRIAL REGISTRATION: Registered in the United States National Library of Medicine clinicaltrials.gov (# NCT05725928). February 13, 2023.

Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial.

BACKGROUND: Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. METHODS: DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. FINDINGS: 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. INTERPRETATION: We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. FUNDING: Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

BACKGROUND: Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. METHODS: This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. RESULTS: Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. CONCLUSIONS: In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis.

BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Severity and worsening of fatigue among individuals with multiple sclerosis.

Background: Fatigue is associated with reduced quality of life and social participation, and poor employment outcomes. However, most studies examining fatigue are limited by small sample sizes or short follow-up periods. Objective: To characterize the natural history of fatigue. Methods: The North American Research Committee on Multiple Sclerosis Registry participants with ≥7 years of longitudinal data between 2004 and 2019 and a relapsing disease course were included. A subset of participants enrolled within 5 years of diagnosis was identified. The Fatigue Performance Scale assessed fatigue and ≥1-point increase in Fatigue Performance Scale sustained at the next survey defined fatigue worsening. Results: Of 3057 participants with longitudinal data, 944 were within 5 years of multiple sclerosis diagnosis. Most participants (52%) reported fatigue worsening during follow-up. Median time to fatigue worsening ranged from 3.5 to 5 years at lower levels of index fatigue. Fatigue worsening was associated with lower annual income, increasing disability, lower initial fatigue level, taking injectable disease-modifying therapies and increasing depression levels in the relapsing multiple sclerosis participants. Conclusion: Most multiple sclerosis participants early in their disease suffer from fatigue and at least half reported fatigue worsening over time. Understanding factors associated with fatigue may help to identify populations most at risk of fatigue worsening will be informative for the overall management of patients with multiple sclerosis.

Long-Term Effectiveness and Safety of Natalizumab in African American and Hispanic/Latino Patients with Early Relapsing-Remitting Multiple Sclerosis: STRIVE Data Analysis.

INTRODUCTION: In STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino. METHODS: Clinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab. RESULTS: Clinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year 1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year 1; these differences were not observed in years 2-4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years 1 and 2; 66.7% and 90.0% achieved clinical NEDA at years 3 and 4. Annualized relapse rate was reduced by 93.0% at year 1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4 years, 37.5-50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8-100.0% and 90.9-100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers. CONCLUSION: These results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino. CLINICALTRIALS: GOV: NCT01485003.

Attitudes of people with multiple sclerosis toward brain donation.

Objective: Research directly examining brain tissue has played an important role in understanding the pathology and pathogenesis of multiple sclerosis (MS) and other diseases of the central nervous system. Such research relies heavily on donations of post-mortem brain tissue yet little is known about the attitudes of people with multiple sclerosis (MS) about brain donation. We aimed to assess the attitudes of people with MS toward brain donation, their preferences related to discussions of brain donation, and factors associated with attitudes toward brain donation including sociodemographic and clinical characteristics, health literacy and religiosity. Methods: In a cross-sectional study, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their attitudes toward brain donation, reasons for participating or not participating in brain donation, and related communication preferences. We used multivariable logistic regression analyses to test factors associated with attitudes regarding brain donation. Results: Most of the 4,520 participants were women (80.8%), self-identified as white (88.1%), with a post-secondary education, functional health literacy and moderate-severe disability. Sixty-two percent of participants would consider brain donation. Factors associated with considering brain donation included female gender, having a post-secondary education, being physically active, having moderate-severe disability and more comorbidities, and alcohol intake. Seventy-five percent of participants indicated that they preferred to receive information regarding brain donations from physicians. Conclusion: Two-thirds of people with MS would consider brain donation. People with MS desire to hear about brain donation from their health care providers rather than other sources.

Correction to: Improvements in Cognitive Processing Speed, Disability, and Patient­Reported Outcomes in Patients with Early Relapsing­Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4­year, Real­World, Open­Label Study.

BACKGROUND: STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). METHODS: Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS: At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥ 4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤ 0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. CONCLUSION: These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. CLINICALTRIALS: GOV: NCT01485003 (5 December 2011).

Treatment preferences in relation to fatigue of patients with relapsing multiple sclerosis: A discrete choice experiment.

Background: Treatment decisions for multiple sclerosis (MS) are influenced by many factors such as disease symptoms, comorbidities, and tolerability. Objective: To determine how much relapsing MS patients were willing to accept the worsening of certain aspects of their MS in return for improvements in symptoms or treatment convenience. Methods: A web-based discrete choice experiment (DCE) was conducted in patients with relapsing MS. Multinomial logit models were used to estimate relative attribute importance (RAI) and to quantify attribute trade-offs. Results: The DCE was completed by 817 participants from the US, the UK, Poland, and Russia. The most valued attributes of MS therapy to participants were effects on physical fatigue (RAI = 22.3%), cognitive fatigue (RAI = 22.0%), relapses over 2 years (RAI = 20.7%), and MS progression (RAI = 18.4%). Participants would accept six additional relapses in 2 years and a decrease of 7 years in time to disease progression to improve either cognitive or physical fatigue from "quite a bit of difficulty" to "no difficulty." Conclusion: Patients strongly valued improving cognitive and physical fatigue and were willing to accept additional relapses or a shorter time to disease progression to have less fatigue. The impact of fatigue on MS patients' quality of life should be considered in treatment decisions.

The relevance of fatigue to relapse rate in multiple sclerosis: Applying patient preference data to the OPTIMUM trial.

BACKGROUND: In the OPTIMUM trial in patients with relapsing MS, treatment differences in annualized relapse rate (ARR, 0.088) and change in fatigue at week 108 (3.57 points, measured using the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis, symptom domain (FSIQ-RMS-S)) favored ponesimod over teriflunomide. However, the importance of the fatigue outcome to patients was unclear. OBJECTIVE: To assess the importance of the OPTIMUM FSIQ-RMS-S results using data from an MS discrete choice experiment (DCE). METHODS: The DCE included components to correlate levels of physical and cognitive fatigue with FSIQ-RMS-S scores. Changes in relapses/year and time to MS progression equivalent to the treatment difference in fatigue in OPTIMUM were determined for similar fatigue levels as mean baseline fatigue in OPTIMUM. RESULTS: DCE participants would accept 0.06 more relapses/year or a 0.15-0.17 year decrease in time to MS progression for a 3.57-point difference in physical fatigue on the FSIQ-RMS-S. To improve cognitive fatigue by 3.57-points on the FSIQ-RMS-S, DCE participants would accept 0.09-0.10 more relapses/year or a 0.24-0.28 year decrease in time to MS progression. CONCLUSION: MS patients would accept 0.06 more relapses/year to change their fatigue by a similar magnitude as the between-treatment difference observed in the OPTIMUM trial.

Improvements in Cognitive Processing Speed, Disability, and Patient-Reported Outcomes in Patients with Early Relapsing-Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4-year, Real-World, Open-Label Study.

BACKGROUND: STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). METHODS: Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS: At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥ 4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤ 0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. CONCLUSION: These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. CLINICALTRIALS: GOV: NCT01485003 (5 December 2011).

Physical and Mental Health-Related Quality of Life Trajectories Among People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Most studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) have been cross-sectional. The few longitudinal studies have not accounted for potential heterogeneity in HRQOL trajectories. There may be groups of individuals with common physical and mental HRQoL trajectories over time. Identification of early risk factors for membership in trajectories with poor HRQoL would inform on those at risk. We aimed to identify physical and mental HRQoL trajectories among people with MS and early risk factors for membership in the trajectory groups with the worst HRQoL. METHODS: Between 2004 and 2020, we queried NARCOMS participants regarding HRQoL using the RAND-12, demographics, fatigue, and physical impairments (using Patient Determined Disease Steps). We included participants who were enrolled in the NARCOMS registry within three years of MS diagnosis, lived in the United States, reported physician-confirmed MS, and had ≥3 HRQoL observations. We used group-based trajectory modelling to determine whether there were distinct clusters of individuals who followed similar HRQoL trajectories over time. We evaluated whether baseline participant characteristics associated with the probability of trajectory group membership using a multinomial logit model. RESULTS: We included 4,888 participants who completed 57,564 HRQoL questionnaires between one and 27 years after MS diagnosis. Participants had a mean (SD) age of 41.7 (9.5) years at diagnosis, and 3,978 participants (81%) were women. We identified five distinct physical HRQoL trajectories and four distinct mental HRQoL trajectories. Older age at diagnosis, worse physical impairments, and worse fatigue were associated with increased odds of being in the group with the worst physical HRQoL when compared to the four other groups. Income ≤$50,000 and no post-secondary education were associated with increased odds of membership in the group with the lowest mental HRQoL when compared to the other three groups. DISCUSSION: We identified groups of people with MS who reported similar physical and mental HRQoL trajectories over time. There are early risk factors for membership in the groups with the worst HRQoL that are easily identifiable by clinicians, providing an opportunity for early interventions.

COVID-19 in the pregnant or postpartum MS patient: Symptoms and outcomes.

Women with multiple sclerosis (MS) are often of childbearing age. Thirty-six women with MS who were pregnant (n = 27) or within 6 weeks postpartum (n = 9) were reported in the North American COViMS registry and their COVID-19 outcomes were described. One pregnant and one postpartum woman were hospitalized. No deaths occurred. To compare COVID-19 clinical outcomes in pregnant and postpartum females with females who were not pregnant or postpartum, a 1:2 propensity score match was performed. While not powered to detect small differences, it was reassuring that no increased risks for those with MS who were pregnant/postpartum were revealed.