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Background: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. Objective: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). Methods: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. Results: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. Conclusions: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections. Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570). Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model. Results: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen’s d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a ( p Conclusion: Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

BACKGROUND AND PURPOSE: Changes in cerebral perfusion occur early in relapsing and progressive multiple sclerosis (MS) patients though whether cerebral blood flow (CBF) can be altered by therapy is unknown. We sought to characterize the time course of change in CBF (cerebral vascular reactivity - CVR), following intravenous (IV) acetazolamide (ACZ) in whole brain and within various gray and white matter brain regions in MS patients. METHODS: We enrolled five relapsing MS patients on injectable therapies. Participants received a 1000 mg IV bolus of ACZ and CBF was measured using pseudo-continuous arterial spin labeling MRI. To quantify differences in time course between patients, we calculated the numerical integration of CVR over time using the trapezoidal rule to estimate area under the curve [AUC((CVR))]. RESULTS: A change in whole brain CBF of 30% - 65% was seen in all participants at 15 minutes after ACZ challenge. CBF increases >20% above baseline were sustained for 90 minutes within whole-brain, normal-appearing white matter and total T2-hyperintense lesioned tissue. AUC((CVR)) values for both gray (cortical and deep gray matter) and white (normal-appearing and T2-lesioned) matter regions were similar between patients. CONCLUSION: Our findings show a prolonged time course in vascular reactivity after ACZ stimulus in MS patients with a similar time course for both gray and white matter brain regions, including in previously injured tissue. Our preliminary results suggest that blood flow can be augmented in the established MS lesion suggesting that even previously injured tissue might be responsive to treatment.

Background and ObjectivesClinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25-ft walk (T25FW) and 9-hole peg test (NHPT) may be more useful and patient relevant. The objective of this work was to compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset.MethodsWe used the dataset from Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening vs similarly defined improvement, unconfirmed vs confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves vs cross-sectional disability worsening.ResultsCombiRx included 1,008 participants. A comparison of confirmed and sustained worsening events showed that, throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning were the findings that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the 3 years of follow-up and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of DiscussionOur analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.

Background and ObjectivesTo investigate the association of age and the presence of contrast-enhancing lesions (CELs) on cranial MRI scans in different disease courses of multiple sclerosis (MS), we describe the frequency of CELs as a function of age in 4 large randomized controlled trial (RCT) datasets.MethodsUsing original trial data from CombiRx (Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis;clinicaltrials.govidentifierNCT00211887), a trial in relapsing-remitting MS; ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis;clinicaltrials.govidentifierNCT01416181), a trial in secondary progressive MS; and the 2 primary progressive MS trials PROMISE and INFORMS;clinicaltrials.govidentifierNCT00731692), we describe the occurrence of CELs per age group at baseline for the entire trial cohort and at 1 year follow-up in the treatment arms.ResultsCombiRx included 1,008, ASCEND 889, PROMISE 943, and INFORMS 970 participants. At baseline, CEL frequency differed between datasets according to disease course: 39.6% of CombiRx, 23.9% of ASCEND, 14.0% of PROMISE, and 12.3% of INFORMS participants had CELs. This distribution by disease course was largely preserved within each age group. In all datasets, there was an almost linear decrease of the percentage of participants with CELs with advancing age. After 1 year of experimental treatment, CEL occurrence was reduced in all trial datasets, and almost absent in ASCEND. The decrease of CEL occurrence with advancing age was preserved in CombiRx, PROMISE, and INFORMS after 1 year of treatment. We investigated the association of the baseline factors age, disease duration, sex, and EDSS with having CELs at baseline with multivariable binary logistic regression models. Age was the only characteristic associated with the risk of CELs at baseline in all datasets, with higher age associated with a lower risk of CELs (odds ratios for having CELs at baseline per year increase in age: CombiRx: 0.96, 95% confidence interval [CI] 0.95–0.98; ASCEND: 0.94, 95% CI 0.92–0.97; PROMISE: 0.94, 95% CI 0.91–0.96; INFORMS: 0.97, 95% CI 0.94–0.99).DiscussionOur analysis of 4 large, well-characterized RCT datasets shows that the association of age and CEL occurrence is a general phenomenon across the spectrum of MS disease courses. Our findings should be replicated in real-world MS datasets.

Background and ObjectivesObservational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS.MethodsWe generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10−8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modifiedpvalue threshold for inclusion in the PGS (5 × 10−5) and applying Mendelian randomization (MR) rather than using PGS.ResultsInitial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%;p= 4.33e-06; R2= 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87–1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87–1.28), change in T25FW (per 1SD: 0.07%; 95% CI: −0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: −0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using otherpvalue thresholds or those applying MR.DiscussionGenetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Background CombiRx was a randomized, double-blind, placebo-controlled phase 3 trial in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients randomized to intramuscular interferon beta-1a (IM IFN beta-1a), glatiramer acetate (GA), or both therapies. Objective This analysis investigated changes in serum neurofilament light-chain (sNfL) levels in response to treatment and assessed baseline sNfL as a predictor of relapse. Methods RRMS patients treated with IM IFN beta-1a 30 µg weekly + placebo (n = 159), GA 20 mg/mL daily + placebo (n = 172), or IM IFN beta-1a + GA (n = 344) were included. A linear mixed model compared sNfL values over time. Cox regression models analyzed baseline sNfL and gadolinium-enhancing (Gd+) lesions as predictors of relapse. Results In all treatment arms, the proportion of patients with sNfL ≥16 pg/mL decreased significantly from baseline to 6 months and was maintained at 36 months. A significantly higher percentage of patients with both baseline sNfL ≥16 pg/mL and ≥1 Gd+ lesion experienced relapses within 90 days compared to patients with sNfL Conclusion sNfL levels were reduced within 6 months and remained low at 36 months. Results suggest that the combination of lesion activity and sNfL was a stronger predictor of relapse than either factor alone.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.

Background Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. Objectives The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing–remitting multiple sclerosis. Methods EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing–remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. Results DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39–0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). Conclusions DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. Clinical Trials Registration ClinicalTrials.gov (NCT03093324). Electronic supplementary material The online version of this article (10.1007/s40263-020-00700-0) contains supplementary material, which is available to authorized users.

BACKGROUND: Magnetic resonance images with multiple contrasts or sequences are commonly used for segmenting brain tissues, including lesions, in multiple sclerosis (MS). However, acquisition of images with multiple contrasts increases the scan time and complexity of the analysis, possibly introducing factors that could compromise segmentation quality. OBJECTIVE: To investigate the effect of various combinations of multi-contrast images as input on the segmented volumes of gray (GM) and white matter (WM), cerebrospinal fluid (CSF), and lesions using a deep neural network. METHODS: U-net, a fully convolutional neural network was used to automatically segment GM, WM, CSF, and lesions in 1000 MS patients. The input to the network consisted of 15 combinations of FLAIR, T1-, T2-, and proton density-weighted images. The Dice similarity coefficient (DSC) was evaluated to assess the segmentation performance. For lesions, true positive rate (TPR) and false positive rate (FPR) were also evaluated. In addition, the effect of lesion size on lesion segmentation was investigated. RESULTS: Highest DSC was observed for all the tissue volumes, including lesions, when the input was combination of all four image contrasts. All other input combinations that included FLAIR also provided high DSC for all tissue classes. However, the quality of lesion segmentation showed strong dependence on the input images. The DSC and TPR values for inputs with the four contrast combination and FLAIR alone were very similar, but FLAIR showed a moderately higher FPR for lesion size < 100 μl. For lesions smaller than 20 μl all image combinations resulted in poor performance. The segmentation quality improved with lesion size. CONCLUSIONS: Best performance for segmented tissue volumes was obtained with all four image contrasts as the input, and comparable performance was attainable with FLAIR only as the input, albeit with a moderate increase in FPR for small lesions. This implies that acquisition of only FLAIR images provides satisfactory tissue segmentation. Lesion segmentation was poor for very small lesions and improved rapidly with lesion size.

BACKGROUND AND PURPOSE Cerebellar damage is a valuable predictor of disability, particularly in progressive multiple sclerosis. It is not clear if it could be an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. AIM We aimed to determine whether cerebellar damage is an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. METHODS Cerebellar lesion loads and volumes were estimated using baseline magnetic resonance imaging from the CombiRx trial (n = 838). The relationship between cerebellar damage and time to disability worsening (confirmed disability progression [CDP], timed 25-foot walk test [T25FWT] score worsening, nine-hole peg test [9HPT] score worsening) was tested in stagewise and stepwise Cox proportional hazards models, accounting for demographics and supratentorial damage. RESULTS Shorter time to 9HPT score worsening was associated with higher baseline Expanded Disability Status Scale (EDSS) score (hazard ratio [HR] 1.408, p = 0.0042) and higher volume of supratentorial and cerebellar T2 lesions (HR 1.005 p = 0.0196 and HR 2.211, p = 0.0002, respectively). Shorter time to T25FWT score worsening was associated with higher baseline EDSS (HR 1.232, p = 0.0006). Shorter time to CDP was associated with older age (HR 1.026, p = 0.0010), lower baseline EDSS score (HR 0.428, p

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Background Multiple sclerosis (MS) is an autoimmune disease leading to physical, emotional and cognitive disability. High body mass index (BMI) may impact cognitive function and brain volume in MS. Yet, there is paucity of evidence addressing the impact of BMI on cognitive function and brain volume in MS. Objectives The purpose of this study was to examine the effects of BMI on normal appearing brain volume and cognitive function in patients with relapsing–remitting MS. Methods A secondary data analysis of the NIH CombiRx study was conducted. Multivariate regression and mixed model analyses were executed to analyze the effect of BMI on brain volume and cognitive function. Results The mean baseline age of the 768 participants was 38.2(SD = 9.4) years. 73% were female and 88.8% were Caucasian. The mean BMI was 28.8 kg/m2(SD = 6.7). The multivariate regression and mixed model analyses failed to show a clinical effect of BMI on brain volume and cognitive function. Conclusion BMI did not show an effect on cognitive function and brain volume among MS patients. Although there is increased interest in the effects of modifiable factors on the course of MS, the effects of BMI on brain volume and cognitive function are debatable and warrant further research. ClinicalTrials.gov NCT00211887

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population ( n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Chronic active and slowly expanding/evolving lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis. Elliott et al. report that T1-weighted measures of chronic lesion activity predict clinically progressive multiple sclerosis, may represent a longitudinal neuroimaging correlate of smouldering demyelination and axonal loss, and are reduced by ocrelizumab., Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

Background In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study. Methods Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS. Results Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively. Conclusions Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg.

Background Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20+ B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). Methods OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo. Results Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. Conclusion Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.

Objective: The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations. Methods: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions. Results: The significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs. Conclusions: The treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.

BackgroundOngoing safety reporting is crucial to understanding the long-term benefit-risk profile of ocrelizumab in multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterised in Phase II (NCT00676715) and III (NCT01247324/NCT01412333/NCT01194570) trials in relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). Here, we report safety evaluations from ocrelizumab clinical trials and open-label extensions up to January 2019, and selected post-marketing data.MethodsSafety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb trials. To account for different exposure lengths, rates per 100 patient years (PY) are presented.ResultsIn clinical trials, 4,611 patients with MS received ocrelizumab (14,329 PY exposure). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 252 (249–254); serious AEs, 7.33(6.89–7.79); infections, 76.7 (75.3–78.2); serious infections, 1.99 (1.77–2.23); malignancies, 0.46 (0.35–0.58); and AEs leading to discontinuation, 1.08 (0.92–1.27). Updated ocrelizumab all-exposure population data and selected post-marketing data will be presented.ConclusionsReported event rates in the ocrelizumab all-exposure clinical trial population and post-mar- keting settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue.k.schmierer@qmul.ac.uk

BackgroundEfficacy/safety of ocrelizumab in relapsing multiple sclerosis were demonstrated in the OPERA I/II (NCT01247324/NCT01412333) double-blind period (DBP). We assessed the efficacy of switching to or maintaining ocrelizumab after 4 years of the open-label extension (OLE).MethodsAt OLE commencement, patients continued ocrelizumab (OCR-OCR) or switched from interferon-β-1a to OCR (IFN-OCR). Adjusted annualised relapse rate (ARR), time-to-onset of 24-week confirmed disability progression (CDP24) and risk of requiring a walking aid (Expanded Disability Status Scale score ≥6.0) from DBP baseline were analysed.ResultsAmong IFN-OCR switchers, ARR decreased year-on-year from 0.2 in the pre-switch year to 0.04 in OLE Year 4; OCR-OCR continuers maintained low ARRs (pre-switch, 0.13; OLE Year 4, 0.05). CDP24 was lower year-on-year in OCR-OCR continuers versus IFN-OCR switchers in the pre-switch year (7.7% vs 12.0%) and at OLE Year 4 (19.2% vs 23.7%); pConclusionsAfter 6 years of follow-up, rates of patients with CDP24 and risk of requiring a walking aid remained lower in earlier initiators of ocrelizumab (OCR-OCR) versus those initially receiving IFN (IFN-OCR), demonstrating maintained benefits of earlier treatment with ocrelizumab.g.giovannoni@qmul.ac.uk

BackgroundEfficacy/safety of ocrelizumab in primary progressive multiple sclerosis were demonstrated in the ORATORIO (NCT01194570) double-blind period (DBP). Here we assessed the efficacy of switching to, or earlier initiation of, ocrelizumab after 6.5-study years (312 weeks), in the open-label extension (OLE).MethodsDuring the DBP, patients were randomised to ocrelizumab or placebo for ≥120 weeks until a prespecified number of confirmed disability progression (CDP) events occurred. Patients continued blinded treatment until the outcome was ascertained (extended controlled period [ECP]). At OLE initia- tion, patients continued ocrelizumab (OCR-OCR) or switched from placebo to ocrelizumab (PBO-OCR). Time to onset of 24-week-CDP and time-to-wheelchair-confinement (Expanded Disability Status Scale≥7.0) were analysed.ResultsDuring the DBP, ocrelizumab reduced the risk of 24-week-CDP by 25% (p=0.037) vs placebo. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 24-week-CDP in PBO-OCR and OCR-OCR was 44.7% vs 33.3% (Δ=11.4%; p=0.005), and at Week 312 was 64.8% vs 51.7% (Δ=13.1%; p=0.002), respectively. During DBP+ECP+OLE, risk of wheelchair confinement was 42% lower (p=0.011) and of 24-week-CDP was 28% lower (p=0.002) in OCR-OCR vs PBO-OCR.ConclusionsCompared with PBO-OCR, initiating ocrelizumab 3–5 years earlier significantly reduced the risk of wheelchair confinement and 24-week-CDP.k.schmierer@qmul.ac.uk

Background: Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). Objective: To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. Methods: We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. Results: Compared with RMS patients, PPMS patients had higher numbers of SELs ( p = 0.002) and higher T2 volumes of SELs ( p Conclusion: We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

Background and purpose Requiring a walking aid is a fundamental milestone in multiple sclerosis (MS), represented by an Expanded Disability Status Scale (EDSS) score ≥6.0. In the present study, we assess the effect of ocrelizumab (OCR) on time to EDSS score ≥6.0 in relapsing MS. Methods Time to EDSS score ≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over the course of 6.5 years (336 weeks) in the double-blind period (DBP) and open-label extension (OLE) period of the OPERA I (NCT01247324) and OPERA II (NCT01412333) studies. Results Time to reach EDSS score ≥6.0 was significantly delayed in those initially randomized to OCR versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated OCR earlier versus delayed treatment (average hazard ratio [HR] DBP + OLE 0.66, 95% confidence interval [CI] 0.45-0.95; p = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE 0.54, 95% CI 0.35-0.83; p = 0.004). Conclusion The reduced risk of requiring a walking aid in earlier initiators of OCR demonstrates the long-term implications of earlier highly effective treatment.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.

BACKGROUND AND PURPOSE Although global and regional brain volume has been established as a relevant measure to define and predict multiple sclerosis (MS) severity, characterization of specific trends by race/ethnicity is currently lacking. We aim to (1) characterize racial disparities in disability-specific patterns of brain MRI volumetric measures between Hispanic and Caucasian individuals with MS and (2) explore the relevance of these measures as predictors of clinical disability progression. METHODS Brain MRI scans from 94 Hispanic and 94 age- and gender-matched Caucasian MS patients were analyzed using automatic and manual segmentation techniques. Select global and regional volume measures were correlated to Expanded Disability Status Scale (EDSS) scores at baseline and subsequent follow-up visits. RESULTS Hispanic patients had a higher baseline median EDSS score (interquartile range [IQR], 2.0; [1.0-3.5]) compared to Caucasians (median [IQR], 1.0 [.0-2.0]) and an increased risk of requiring ambulatory assistance (hazard ratio [HR], 9.7; 95% confidence interval [CI], 2.8-32.5). Normalized thalamic volume was moderately associated with EDSS scores (rs = -.42, P < .001 in Hispanics; rs = -.32, P = .002 in Caucasians) and was the best predictor of sustained disability worsening in both racial groups in a time-to-event analysis. CONCLUSIONS The confounding impact of race on quantitative brain volume measures may affect the interpretation of outcome measures in MS clinical trials.

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment. Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years. Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG MS study ( N = 215). Incidence rates (IRs) of infection-related adverse events (infAEs)/100 patient-years were analysed by on-study nadir ALC. Results: With fingolimod, ALC rapidly reduced to 29.9%–34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of infAEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2–0.4 × 109/L: 1.13 and >0.4 × 109/L: 0.91. Three patients had a single episode of ALC 9/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase. Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Author(s): Wolinsky, Jerry S; Montalban, Xavier; Hauser, Stephen L; Giovannoni, Gavin; Vermersch, Patrick; Bernasconi, Corrado; Deol-Bhullar, Gurpreet; Garren, Hideki; Chin, Peter; Belachew, Shibeshih; Kappos, Ludwig | Abstract: ObjectiveNo evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis.MethodsThe proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/g5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients.ResultsThe majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p l 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p l 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.InterpretationCompared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536.

none 39 si OBJECTIVE: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. METHODS: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001). CONCLUSIONS: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice. open Bovis F.; Kalincik T.; Lublin F.; Cutter G.; Malpas C.; Horakova D.; Havrdova E.K.; Trojano M.; Prat A.; Girard M.; Duquette P.; Onofrj M.; Lugaresi A.; Izquierdo G.; Eichau S.; Patti F.; Terzi M.; Grammond P.; Bergamaschi R.; Sola P.; Ferraro D.; Ozakbas S.; Iuliano G.; Boz C.; Hupperts R.; Grand'Maison F.; Oreja-Guevara C.; van Pesch V.; Cartechini E.; Petersen T.; Altintas A.; Soysal A.; Ramo-Tello C.; McCombe P.; Turkoglu R.; Butzkueven H.; Wolinsky J.S.; Solaro C.; Sormani M.P. Bovis F.; Kalincik T.; Lublin F.; Cutter G.; Malpas C.; Horakova D.; Havrdova E.K.; Trojano M.; Prat A.; Girard M.; Duquette P.; Onofrj M.; Lugaresi A.; Izquierdo G.; Eichau S.; Patti F.; Terzi M.; Grammond P.; Bergamaschi R.; Sola P.; Ferraro D.; Ozakbas S.; Iuliano G.; Boz C.; Hupperts R.; Grand'Maison F.; Oreja-Guevara C.; van Pesch V.; Cartechini E.; Petersen T.; Altintas A.; Soysal A.; Ramo-Tello C.; McCombe P.; Turkoglu R.; Butzkueven H.; Wolinsky J.S.; Solaro C.; Sormani M.P.

Background Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability. Objective In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials. Methods During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon β-1a 44 μg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan–Meier and Cox survival analyses were used to assess disability outcome measures. Results Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients. Conclusions In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon β-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

ObjectiveTo assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).MethodsBrain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).ResultsIn patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.ConclusionEpoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.Classification of evidenceThis study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

ObjectiveTo evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.MethodsINFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).ResultsOverall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.ConclusionsIn patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.Classification of evidenceBecause this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.

Background To report the long-term results of the blinded extension phase of the randomized, controlled study of the combined use of interferon beta-1a (IFN) 30 μg IM weekly and glatiramer acetate (GA) 20 mg daily compared to each agent alone in relapsing-remitting multiple sclerosis (RRMS). Methods 1008 RRMS patients were followed on protocol until the last participant enrolled completed 3 years, allowing some subjects to be followed for up to 7 years. The primary endpoint was reduction in annualized relapse rate. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. Results Similar to the core study, combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed EDSS worsening or change in MSFC. Also similar to the core result, the combination was superior to either agent alone in reducing new lesion activity, but the 3 year MRI result did not presage a clinical benefit over the extended observation interval. Conclusion Combining GA & IFN did not produce a significant clinical benefit over the entire study duration. The earlier effect on reducing MRI activity did not result in a later clinical advantage. The combination showed a sustained advantage in reducing disease activity free status.

Introduction L’efficacite et la tolerance d’OCR dans la SEP-R ont ete demontrees dans les 2 etudes de phase III OPERA I et OPERA II menees sur 96 semaines. Les resultats de la periode d’extension en ouvert (OLE) sont etudies. Objectifs Evaluer l’efficacite d’OCR ou du changement de traitement vers OCR (switch) dans la SEP-R sur l’activite de la maladie et la progression confirmee du handicap (CDP) apres 4,5 ans de suivi dans la periode OLE des etudes OPERA. Patients et methodes Au debut de la periode OLE, tous les patients (pts) ayant complete la periode en double aveugle (PA) ont continue OCR (OCR-OCR) ou sont passes de l’interferon (IFN) β-1a a OCR (IFN-OCR). Le taux annualise de poussees (TAP), la CDP48 et la progression du score Expanded Disability Status Scale (EDSS) jusqu’a ≥ 6 (necessite d’une aide pour marcher) confirmee a 48 semaines ont ete analyses jusqu’a la semaine 336. Resultats Au total, 80,1 % des pts IFN-OCR et 78,3 % des pts OCR-OCR entres dans la periode OLE ont atteint la 4,5e annee de cette periode. Chez les pts IFN-OCR, le TAP a diminue de 0,20 pre-switch a 0,06 a 4,5 ans. Les pts OCR-OCR ont maintenu un TAP bas (0,12 pre-switch et 0,04 a 4,5 ans d’OLE). Une proportion plus faible de pts avec CDP48 est observee dans le groupe OCR-OCR vs IFN-OCR en pre-switch (4,1 % vs 8,5 % ; p Discussion Les benefices d’OCR sur le TAP et CDP48 observes dans la PA ont ete maintenus apres 4,5 annees de la phase OLE. Dans la periode PA + OLE, le risque de CDP48 etait plus faible dans le groupe OCR-OCR vs IFN-OCR (HR [IC95 %] : 0,72 [0,56–0,93], p = 0,012), ainsi que le risque de necessiter une aide a la marche (HR [IC95 %] : 0,54 [0,35–0,83] ; p = 0,004). Le profil de tolerance dans la periode OLE a ete coherent avec celui de la PA. Conclusion Apres 4,5 ans de periode OLE, le « switch » INF-β1a vers OCR est associe a une reduction maintenue du TAP. Les pts ayant initie OCR 2 ans plus tot ont un benefice significatif sur le CDP48 et le recours a l’aide a la marche.

Introduction Le suivi de la tolerance est primordial pour evaluer le benefice a long terme d’OCR. La tolerance et l’efficacite d’OCR ont ete montrees dans la SEP-R (1 phase II ; 2 phases III [OPERA I/II]) et la SEP-PP (phase III ORATORIO). Objectifs Rapporter les evaluations de tolerance d’OCR dans les etudes cliniques et leurs extensions en ouvert (OLE ; janvier 2019) et les donnees de tolerance post-marketing (avril 2019). Patients et methodes Les donnees de tolerance ont ete rapportees pour tout patient (pt) expose a OCR aux cours des etudes de phase II, III et leurs periodes OLE et de phase IIIb en cours (VELOCE, CHORDS/CASTING, OBOE, ENSEMBLE et etudes associees). Le nombre de pts exposes a OCR en post-marketing a ete estime d’apres le nombre de lots vendus et les donnees d’assurance aux Etats-Unis. Les taux d’incidence sont presentes pour 100 patients-annees (PA) afin de prendre en compte les durees d’exposition au traitement. Resultats En juillet 2018, 4501 pts avaient recu OCR dans les etudes cliniques, soit 12559 PA d’exposition. Les taux evenements indesirables (EI) pour 100 PA ont ete : 255 (IC 95 % : 252–258), EI graves : 7,52 (7,05–8,02), infections : 77,1 (75,5–78,6), infections graves : 2,01 (1,77–2,27), cancers : 0,47 (0,36–0,61) et EI entrainant une interruption du traitement : 1,15 (0,97–1,35). En avril 2019, environ 96000 pts avaient initie OCR et les donnees rapportees restent coherentes avec celles des etudes cliniques. Discussion Dans la population totale exposee a OCR, les evaluations ponctuelles des taux d’infections graves/100 PA fluctuent chaque annee et semblent augmenter. Six infections opportunistes graves potentielles avaient ete identifiees lors des etudes cliniques. En avril 2019, aucun cas de leucoencephalopathie multifocale progressive impute a OCR. Le taux de cancer est reste dans les limites des donnees epidemiologiques. Conclusion Les taux rapportes d’EI/100PA sur l’ensemble des pts exposes a OCR continuent d’etre globalement coherents avec ceux observes pendant la periode de traitement controlee des etudes cliniques dans la SEP-R et la SEP-PP.

Purpose To improve the conspicuity of white matter lesions (WMLs) in multiple sclerosis (MS) using patient-specific optimization of single-slab 3D fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Materials and Methods Sixteen MS patients were enrolled in a prospective 3.0T MRI study. FLAIR inversion time and echo time were automatically optimized for each patient during the same scan session based on measurements of the relative proton density and relaxation times of the brain tissues. The optimization criterion was to maximize the contrast between gray matter (GM) and white matter (WM), while suppressing cerebrospinal fluid. This criterion also helps increase the contrast between WMLs and WM. The performance of the patient-specific 3D FLAIR protocol relative to the fixed-parameter protocol was assessed both qualitatively and quantitatively. Results Patient-specific optimization achieved a statistically significant 41% increase in the GM-WM contrast ratio (P < 0.05) and 32% increase in the WML-WM contrast ratio (P < 0.01) compared with fixed-parameter FLAIR. The increase in WML-WM contrast ratio correlated strongly with echo time (P < 10-11). Two experienced neuroradiologists indicated substantially higher lesion conspicuity on the patient-specific FLAIR images over conventional FLAIR in 3–4 cases (intrarater correlation coefficient ICC = 0.72). In no case was the image quality of patient-specific FLAIR considered inferior to conventional FLAIR by any of the raters (ICC = 0.32). Conclusion Changes in proton density and relaxation times render fixed-parameter FLAIR suboptimal in terms of lesion contrast. Patient-specific optimization of 3D FLAIR increases lesion conspicuity without scan time penalty, and has potential to enhance the detection of subtle and small lesions in MS. Level of Evidence 1 J. Magn. Reson. Imaging 2016;00:000–000

BACKGROUND The dependence of deep-learning (DL)-based segmentation accuracy of brain MRI on the training size is not known. PURPOSE To determine the required training size for a desired accuracy in brain MRI segmentation in multiple sclerosis (MS) using DL. STUDY TYPE Retrospective analysis of MRI data acquired as part of a multicenter clinical trial. STUDY POPULATION In all, 1008 patients with clinically definite MS. FIELD STRENGTH/SEQUENCE MRIs were acquired at 1.5T and 3T scanners manufactured by GE, Philips, and Siemens with dual turbo spin echo, FLAIR, and T1 -weighted turbo spin echo sequences. ASSESSMENT Segmentation results using an automated analysis pipeline and validated by two neuroimaging experts served as the ground truth. A DL model, based on a fully convolutional neural network, was trained separately using 16 different training sizes. The segmentation accuracy as a function of the training size was determined. These data were fitted to the learning curve for estimating the required training size for desired accuracy. STATISTICAL TESTS The performance of the network was evaluated by calculating the Dice similarity coefficient (DSC), and lesion true-positive and false-positive rates. RESULTS The DSC for lesions showed much stronger dependency on the sample size than gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). When the training size was increased from 10 to 800 the DSC values varied from 0.00 to 0.86 ± 0.016 for T2 lesions, 0.87 ± 009 to 0.94 ± 0.004 for GM, 0.86 ± 0.08 to 0.94 ± 0.005 for WM, and 0.91 ± 0.009 to 0.96 ± 0.003 for CSF. DATA CONCLUSION Excellent segmentation was achieved with a training size as small as 10 image volumes for GM, WM, and CSF. In contrast, a training size of at least 50 image volumes was necessary for adequate lesion segmentation. LEVEL OF EVIDENCE 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1487-1496.

Evobrutinib; Multiple sclerosis; Receptors in B cells; Receptors in myeloid cells Evobrutinib; Esclerosis múltiple; Receptores en células B; Receptores en células mieloides Evobrutinib; Esclerosi múltiple; Receptors en cèl·lules B; Receptors en cèl·lules mieloides BACKGROUND: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS). RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.

Objective: To investigate the performance of deep learning (DL) based on fully convolutional neural network (FCNN) in segmenting brain tissues in a large cohort of multiple sclerosis (MS) patients. Methods: We developed a FCNN model to segment brain tissues, including T2-hyperintense MS lesions. The training, validation, and testing of FCNN were based on ~1000 magnetic resonance imaging (MRI) datasets acquired on relapsing–remitting MS patients, as a part of a phase 3 randomized clinical trial. Multimodal MRI data (dual-echo, FLAIR, and T1-weighted images) served as input to the network. Expert validated segmentation was used as the target for training the FCNN. We cross-validated our results using the leave-one-center-out approach. Results: We observed a high average (95% confidence limits) Dice similarity coefficient for all the segmented tissues: 0.95 (0.92–0.98) for white matter, 0.96 (0.93–0.98) for gray matter, 0.99 (0.98–0.99) for cerebrospinal fluid, and 0.82 (0.63–1.0) for T2 lesions. High correlations between the DL segmented tissue volumes and ground truth were observed ( R2 > 0.92 for all tissues). The cross validation showed consistent results across the centers for all tissues. Conclusion: The results from this large-scale study suggest that deep FCNN can automatically segment MS brain tissues, including lesions, with high accuracy.

Multiple sclerosis (MS) is a demyelinating disease that affects the central nervous system (CNS) and is characterized by the presence of CNS lesions. Volumetric measures of tissues, including lesions, on magnetic resonance imaging (MRI) play key roles in the clinical management and treatment evaluation of MS patient. Recent advances in deep learning (DL) show promising results for automated medical image segmentation. In this work, we used deep convolutional neural networks (CNNs) for brain tissue classification on MRI acquired from MS patients in a large multi-center clinical trial. Multi-channel MRI data that included T1-weighted, dual-echo fast spin echo, and fluid-attenuated inversion recovery images were acquired on these patients. The pre-processed images (following co-registration, skull stripping, bias field correction, intensity normalization, and de-noising) served as the input to the CNN for tissue classification. The network was trained using expert-validated segmentation. Quantitative assessment showed high Dice similarity coefficients between the CNN and the validated segmentation, with DSC values of 0.94 for white matter and grey matter, 0.97 for cerebrospinal fluid, and 0.85 for T2 hyperintense lesions. These results suggest that deep neural networks can successfully segment brain tissues, which is crucial for reliable assessment of tissue volumes in MS.

Introduction Evobrutinib (EVO), inhibiteur tres selectif de la tyrosine kinase de Bruton (BTKi), reduit l’activation des lymphocytes B et cellules myeloides impliques dans la pathogenie de la sclerose en plaques (SEP). Objectifs Apres demonstration de l’efficacite d’EVO dans le traitement de la SEP remittente en semaine 24 puis 48 lors d’une etude de phase II, l’objectif est d’evaluer l’efficacite a long terme. Patients et methodes Durant l’essai initial en double aveugle, les patients ont recu EVO 25 mg 1 ×/jour (QD), 75 mg QD, 75 mg 2 ×/jour (BID) ou placebo (PBO) pendant 24 semaines, puis chaque bras a poursuivi le meme traitement jusqu’a la semaine 48 sauf le groupe PBO qui a recu EVO 25 mg QD. Apres la semaine 48, les patients entrant dans la phase d’extension (OLE) ont d’abord ete traites avec EVO 75 mg QD avant de switcher a 75 mg BID. Resultats Pour les patients ayant recu initialement PBO ou EVO 25 mg QD, 75 mg QD ou 75 mg BID, le taux annualise de poussees (TAP) etait de 0,31, 0,37, 0,18 et 0,12 respectivement en semaine 108. Le temps estime pour que 20 % de patients presentent une poussee etait 3 fois plus long chez les patients initialement traite par EVO 75 mg BID versus PBO et egalement plus long par rapport aux patients traites par EVO 25 mg QD, 75 mg QD. Discussion Avec EVO 75 mg BID, l’efficacite (TAP, 0,11) en semaine 48 etait maintenue en semaine 108. Les resultats concernant la probabilite de survenue et duree avant poussee mettent en evidence que les patients traites par EVO 25 mg QD, 75 mg QD ou PBO n’ont pas atteint le meme niveau d’efficacite que ceux traites par EVO 75 mg BID. Conclusion L’efficacite maximum observee avec EVO 75 mg BID est en correlation avec l’occupation optimale de la BTK atteinte grâce a la double prise journaliere d’evobrutinib.

In light of the published 2012 International Pediatric Multiple Sclerosis Group definitions for pediatric multiple sclerosis (MS) and related disorders and given that pediatric-onset MS is now formally included in the 2010 McDonald criteria for MS, we sought to review these criteria and summarize their application in children with acquired CNS demyelination. In addition, proposals are made for definitions of no evidence of disease activity and inadequate treatment response that are important because of new therapeutic options and trials.

BACKGROUND AND PURPOSE Distinct injuries to various limbic white matter pathways have been reported to be associated with different aspects of cognitive dysfunction in multiple sclerosis (MS). Diffusion tensor imaging (DTI) offers a noninvasive method to map tissue microstructural organization. We utilized quantitative magnetic resonance imaging methods to analyze the main limbic system—white matter structures in MS patients with cognitive impairment (CI). METHODS Ten cognitively nonimpaired MS (MSNI) patients and 36 patients with diagnosed CI (MSCI) underwent the minimal assessment of Cognitive Function in MS (MACFIMS) battery. DTI measures of fornix, cingulum, uncinate fasciculus (UF) included tract volume and corresponding fractional anisotropy (FA), mean (MD), axial (AD), and radial (AD) diffusivities. These were statistically analyzed for associations with CI after adjusting for the confounders. RESULTS Fornix FA and RD, left cingulum FA, MD, and RD, right cingulum FA, MD, and RD, and left UF FA showed significant differences between MSNI and MSCI (P < .001). Fornix FA (r = −.6) and RD (r = .52), and right cingulum FA (r = −.54) and RD (r = .5) correlated significantly with CI in regression analyses. CONCLUSIONS The extent of disruption of microstructural disorganization in the main limbic pathways using DTI impacts the extent of CI seen in subjects with MS.