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Background: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF., Objective: To report final outcomes from EVOLVE-MS-1., Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory., Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15)., Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BAS: research grant support from AbbVie, Biogen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, and Sanofi and consulting and/or speaking fees from Alexion, Biogen, Bristol Myers Squibb, Cigna, Cycle, EMD Serono, Genentech, Horizon, Janssen, Novartis, Octave Bioscience, Roche, Sanofi, and TG Therapeutics.DLA: consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi-Aventis; grants from Biogen, Immunotec, and Novartis; and equity interest in NeuroRx.JD: advisory boards for Amicus, Biogen, Janssen, Medis, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; speaker bureaus for Biogen, Bayer, Hemofarm, Janssen, Medis, Medtronic, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, and Zentiva; and research grant from Roche.MSF: research/educational grants from Sanofi-Genzyme; honoraria/consultation fees from Alexion/AstraZeneca, BMS (Celgene), EMD Serono, Hoffman La-Roche, Actelion/Janssen (J&J), Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation; advisory boards/boards of directors for Alexion/AstraZeneca, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, Hoffman La-Roche, Actelion/Janssen (J&J), EMD Serono/Merck Serono, Novartis, and Sanofi-Genzyme; and participated in speakers bureau for Sanofi-Genzyme and EMD Serono.RG: research support and speaker’s honoraria from Bayer-Schering, Biogen Idec, BMS, Chugai, Eisai, Genesis, Janssen, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme, Sandoz, and Teva; consulting honoraria from ZLB Behring, Baxter, Roche, and Talecris; and personal stock options in Bayer, Merck, and Roche.MG: consulting fees from Biogen, EMD Serono, Novartis, and Sanofi-Genzyme; research support from Alkermes; and speaker bureaus for Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme.EJ: advisory boards for Biogen and speaker fees from Biogen, Novartis, Roche, and Sanofi.CLG: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.RTN: consultant for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics.DN: research support from and consultant/advisory boards/speaker bureaus for Adamas, Alkermes, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono, Janssen, Novartis, Roche-Genentech, and Sanofi-Genzyme.JO: research support from Biogen Idec, EMD Serono, and Roche and personal compensation for consulting/speaking from Biogen Idec, BMS, EMD Serono, Eli Lilly, Roche, Sanofi-Genzyme, and Novartis.MAHP: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.KS: research support from Merck; advisory boards for Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi, and TG Therapeutics.FTB: research support and travel grants, through his institution, from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Merck, Novartis, Pfizer, Roche, Sanofi, and Teva and speaker fees from and advisory boards for Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva.AW: adviser fees from AbbVie and research support from AbbVie, Alkermes, and Biogen.TZ: personal compensation for consulting services and speaker honoraria from Bayer, Biogen Idec, Novartis, Sanofi, Synthon, and Teva and financial support for research activities from Bayer, Biogen Idec, Novartis, Sanofi-Aventis, and Teva.WC-B, HC, SL, MS, SLS, and TW: employees of and hold stock/stock options in Biogen.SW: consulting fees from and advisory boards for Biogen, Celgene, and EMD Serono; speaker bureaus for Biogen, Celgene, EMD Serono, Roche-Genentech, and Sanofi-Genzyme; and research support from Biogen, Celgene, EMD Serono, Novartis, Receptos, Roche-Genentech, Sanofi-Genzyme, and TG.

Introduction: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated., Methods: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1., Results: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%)., Conclusion: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs., Trial Registration: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC., (© 2022. The Author(s).)

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice.

Objective: The aim of this study is to assess the impact of interferon (IFN) beta treatment on the development of worsening disability in relapsing-remitting (RR) multiple sclerosis (MS) patients in the single-center observation cohort., Method: This is a prospective study of 236 IFN-beta-treated and 183 untreated RRMS patients recruited consecutively at the Clinic of Neurology in Belgrade (Serbia). Out of this original cohort, 10-year follow-up data were available for 233 IFN-beta-treated and 131 untreated subjects. The median time since recruitment was 9.7 years., Results: IFN-beta treatment significantly delayed (p < 0.001) the time to reach each of the clinical outcomes (secondary progression-SP, EDSS scores 4 and 6) since recruitment. Time from the first visit to SP was reached after 9.7 years for IFN-beta-treated vs. 7.8 years for untreated patients. The delay for the development of EDSS score ≥ 4 from the first visit was 1.6 years (8.7 years for IFN-beta-treated vs. 7.1 years for untreated patients). Time from the first visit to EDSS score of 6 was reached after 9.8 years for IFN-beta-treated vs. 8.8 years for untreated patients. The IFN-beta-treated group showed significant reduction (p < 0.001) in the risk of conversion to SP when compared with untreated patients (HR = 0.22). There was also a significant difference in reaching EDSS scores 4 and 6 (p < 0.001), in favor of the IFN-beta-treated group (HR = 0.40 and HR = 0.27, respectively)., Conclusion: Comparison of outcomes in our IFN-beta-treated vs. untreated RRMS patients suggests that this treatment may delay development of long-term disability in MS.

Background: Adequate disease and treatment-related risk knowledge of people with Multiple Sclerosis (pwMS) is a prerequisite for informed choices in medical encounters. Previous work showed that MS risk knowledge is low among pwMS and role preferences are different in Italy and Germany., Objective: We investigated the level of risk knowledge and role preferences in 8 countries and assessed putative variables associated with risk knowledge., Methods: An online-survey was performed based on the Risk knowledge questionnaire for people with relapsing-remitting MS (RIKNO 2.0), the electronic Control Preference Scale (eCPS), and other patient questionnaires. Inclusion criteria of participants were: (1) age ≥18 years, (2) a diagnosis of relapsing-remitting MS (RRMS), (3) being in a decision making process for a disease modifying drug., Results: Of 1939 participants from Germany, Italy, the Netherlands, Serbia, Spain and Turkey, 986 (51%) (mean age 38.6 years [range 18-67], 77% women, 7.8 years of disease duration) completed the RIKNO 2.0, with a mean of 41% correct answers. There were less than 50 participants in the UK and Estonia and data were not analysed. Risk knowledge differed across countries (p < 0.001). Variables significantly associated with higher risk knowledge were higher education (p < 0.001), previous experience with disease modifying drugs (p = 0.001), correct answer to a medical data interpretation question (p < 0.001), while higher fear for wheelchair dependency was negatively associated to risk knowledge (p = 0.001)., Conclusion: MS risk knowledge was overall low and differed across participating countries. These data indicate that information is an unmet need of most pwMS., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: K. Liethmann was partly financed by a grant on adherence factors in MS (ADEPT) by Genzyme Sanofi-Aventis. J. Drulovic has received honoraria as speaker and for participation in Advisory Boards from Merck Serono, Teva, Bayer Schering, Sanofi Genzyme, and Medis. J. Sastre-Garriga has received compensation for participating on Advisory Boards, speaking honoraria and travel expenses for scientific meetings, consulting services or research support from Celgene, Novartis, Biogen, Teva, Merck, Almirall, and Genzyme. I. Galea has received funding for travel and conference attendance from Teva and research funding from Merck Serono; he has served as a scientific advisor to Evgen. A. Solari has been a board member of Merck Serono and Novartis. She has received speaker honoraria from Almirall, Excemed, Genzyme, Merck Serono, and Teva. C. Heesen has received speaker honoraria and travel grants from Biogen, Genzyme, Sanofi Aventis, Merck, Novartis and Roche. All other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Risk knowledge is relevant to make informed decisions in multiple sclerosis (MS). The risk knowledge questionnaire for relapsing-remitting MS (RIKNO 1.0) was developed and piloted in Germany., Objective: To produce a revised RIKNO 2.0 questionnaire using mixed methodology in a European setting., Methods: The questionnaire was translated in seven languages. MS patient and health professional (HP) expert feedback was obtained from Germany, Italy, Estonia, Serbia, and the UK. A German web-based survey of RIKNO 2.0 compared the tool with the MS Knowledge Questionnaire (MSKQ), each one used with two versions (with/without a "don't know" DN option)., Results: While RIKNO 2.0 was considered difficult, it was rated as highly educational. One item was reframed, and two new items were added. The web-based German survey (n = 708 completers) showed that the DN version did not increase participation rate and did not produce significantly higher scores. Internal consistency (Cronbach alpha) without SN response was 0.73. RIKNO 2.0 scores showed normality distribution irrespective of the answering format. Item difficulty was high ranging from 0.07 to 0.79. Less than 50% of questions were answered correctly (mean 8.9) compared to 80.4% in the MSKQ (mean 20.1). Higher numeracy competency and education were significantly, albeit weakly, associated to higher scores for both RIKNO 2.0 and MSKQ., Conclusion: Including "don't know" options in knowledge questionnaires does not increase percentage of correct replies. RIKNO 2.0 is a complex questionnaire to be used in an educational context and studies on patient information. The tool is now available in seven languages., (Copyright © 2017. Published by Elsevier B.V.)

Cytokines produced by helper T (Th)1 cells, Th17 and regulatory T cells (Treg) are involved in multiple sclerosis (MS) immunopathogenesis. Interferon (IFN)-β alters the numerous genes' expression, but how this alteration affects the treatment response is still elusive. We assessed relative gene expression of nineteen Th1/Th17/Treg-associated mediators in peripheral blood mononuclear cells and plasma levels of GM-CSF, IL-17A and IL-17F, in relapsing-remitting MS (RRMS) patients before IFN-β1b treatment initiation and at 6, 12, 24 and 36 months of therapy. All mRNA levels changed significantly during the IFN-β1b therapy. Higher IL-12Rβ2 mRNA levels were associated with lower risk of relapse. Despite recent reports regarding role of GM-CSF in MS, our study failed to demonstrate its significance as therapy response biomarker, both on the mRNA and protein level., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Adequate risk knowledge of patients is a prerequisite for shared decision making but few attempts have been made to develop assessment tools. Multiple Sclerosis (MS) is a chronic inflammatory disease of young adults with an increasing number of partially effective immunotherapies and therefore a paradigmatic disease to study patient involvement., Objective/methods: Based on an item bank of MS risk knowledge items and patient feedback including perceived relevance we developed a risk knowledge questionnaire for relapsing remitting (RR) MS (RIKNO 1.0) which was a primary outcome measure in a patient education trial (192 early RRMS patients)., Results: Fourteen of the RIKNO 1.0 multiple-choice items were selected based on patient perceived relevance and item difficulty indices, and five on expert opinion. Mean item difficulty was 0.58, ranging from 0.14 to 0.79. Mean RIKNO 1.0 score increased after the educational intervention from 10.6 to 12.4 (p = 0.0003). Selected items were particularly difficult (e.g. those on absolute risk reductions of having a second relapse) and were answered correctly in only 30% of the patients, even after the intervention., Conclusion: Despite its high difficulty, RIKNO 1.0 is a responsive instrument to assess risk knowledge in RRMS patients participating in educational interventions.

Clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) is the earliest clinically evident phase of the disease, which may provide valuable insight into the molecular mechanisms of the initiation of the autoimmune response in MS. Our results introduce IL-11 as a new cytokine that plays a role in the autoimmune response in the early phase of the disease. IL-11 is the highest upregulated cytokine in the sera and cerebrospinal fluid from CIS patients, which is also increased in patients with clinically definitive relapsing-remitting MS in comparison with healthy control subjects. Serum IL-11 levels are significantly increased during clinical exacerbations in comparison with remissions in the same patients. CD4(+) cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11(+)CD4(+) cells is significantly increased in CIS patients in comparison with healthy control subjects. Furthermore, we have identified IL-11 as a new Th17-promoting cytokine, because it induces a differentiation of naive CD4(+) T cells into Th17 cells, as well as expansion of Th17 memory cells. Because the Th17 cytokines IL-17F, IL-21 and TNF-α, and TGF-β induce differentiation of naive cells in the IL-11-secreting CD4(+) cells, we propose that cross-talk between IL-11(+)CD4(+) and Th17 cells may play a role in the inflammatory response in relapsing-remitting MS., (Copyright © 2015 by The American Association of Immunologists, Inc.)

In an important article published in Nature Medicine, Liu and colleagues described a novel CD4(+) FoxA1(+) regulatory T (Treg) cell population as distinct regulators of relapsing-remitting multiple sclerosis (RRMS) and experimental autoimmune encephalomyelitis (EAE). CD4(+) FoxA1(+) Treg cells appear as key regulators of responsiveness to therapy with interferon beta (IFN-β) in RRMS patients. Data indicate that CD4(+)FoxA1(+) FOXP3(-) Treg cells develop within the central nervous system (CNS), and a potential of cerebellar granule neurons (CGN) in generation of CD4(+)FoxA1(+)PD-L1(hi)FOXP3(-) Treg cells from encephalitogenic CD4(+) T cells. A CD4 co-receptor specific ligand, IL-16, governs trafficking and biological properties of CD4(+) T cells irrespective of their activation state. Functions of IL-16, relevant to Treg cells, include expansion of CD4(+)CD25(+) T cells in long-term cultures with IL-2, de novo induction of FOXP-3 and migration of FOXP-3(+) T cells. IL-16 is highly conserved across species including human and mouse. CGN and neurons in hippocampus contain neuronal-IL-16 (NIL-16), splice variant of immune IL-16, and express CD4 molecule. In a CD4-dependent manner, IL-16 supports cultured CGN survival. Concomitant studies of RRMS lesions and corresponding MOG35-55-induced relapsing EAE in (B6 × JL)F1 (H-2(b/s)) mice discovered similar roles of IL-16 in regulation of relapsing disease. In RRMS and EAE relapse, peak levels of IL-16 and active caspase-3 correlated with CD4(+) T cell infiltration and levels of T-bet, Stat-1(Tyr(701)), and phosphorylated neurofilaments of axonal cytoskeleton [NF (M + H) P], suggesting a role of locally produced IL-16 in regulation of CD4(+) Th1 inflammation and axonal damage, respectively. IL-16 was abundantly present in CD4(+) T cells, followed by CD20(+) B, CD8(+) T, CD83(+) dendritic cells, and Mac-1(+) microglia. Apart from lesions, bioactive IL-16 was located in normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in RRMS brain and spinal cord. A cytokine IL-16 emerges as an important regulator of relapsing MS and EAE. Better understanding of immune cell-neuron interactions mediated by IL-16 will foster development of more specific CD4(+) T cell subset-targeted therapies to prevent or ameliorate progression of neuroinflammation and axonal and neuronal damage. Translational studies necessitate corresponding EAE models.

Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS)., Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed., Results: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions., Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS., Classification of Evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.

Objective: To assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study., Methods: A cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable., Results: The IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19-0.61, p<0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR=0.45, 95%CI 0.28-0.73, p=0.001) and EDSS score of 6 (HR=0.34, 95%CI 0.16-0.75, p=0.007)., Conclusion: This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-beta1a in relapsing-remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-beta1a or placebo for 16 weeks; all patients then received IFN-beta1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-beta1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-beta1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-beta1a has rapid beneficial effects on MRI outcomes in RRMS.

Background: Ibudilast is a phosphodiesterase inhibitor influencing inflammation and neurodegeneration in multiple sclerosis (MS). This study evaluated the safety, tolerability, and effects on MRI parameters of 2 different doses of ibudilast in relapsing forms of MS., Methods: In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1-hypointense lesion volumes, and percent brain volume change (PBVC)., Results: A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated., Conclusion: Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression., Classification of Evidence: This interventional study provides Class III evidence on the effect of ibudilast on disease activity.