A Phase II Trial of Ibudilast in Progressive Multiple Sclerosis

Objective: To assess efficacy, safety, and tolerability of ibudilast in progressive MS. Background: Ibudilast, a phosphodiesterase- and macrophage migration inhibitory factor-inhibitor, was suggested to have a neuroprotective effect in relapsing-remitting MS in a prior phase II study. We conducted a phase II trial to further evaluate ibudilast in progressive MS, for which there are limited treatment options. Design/Methods: 255 subjects with primary or secondary progressive MS and evidence for disability progression in the prior two years were randomized to receive either ibudilast up to 100 mg/d or matching placebo. Over this 96 week study, clinical and imaging outcomes were assessed every 24 weeks. Primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography and cortical atrophy. Analysis was based on modified intention-to-treat (mITT). Linear mixed effects modeling was used to estimate the rate of change of each imaging measure; the difference in rates between groups was used to assess efficacy. Results: 244 subjects (96%) were included in the mITT analysis; 220 (86%) completed 96 weeks follow-up. Ibudilast was associated with a 48% reduction in the rate of brain atrophy progression (p=0.04). The adverse events reported more commonly (p Conclusions: Ibudilast met its primary outcome of brain atrophy. Safety and tolerability were also favorable. These results support further investigation of ibudilast as a potential treatment for progressive MS. Study Supported by: Support by National Institutes of Health (U01NS082329), National Multiple Sclerosis Society (RG-5184-A-6), National Institute of Neurological Disorders and Stroke for the NeuroNEXT Clinical Coordinating Center (U01NS077179) and Data Coordinating Center (U01NS077352) and Medicinova. Disclosure: Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for serving as consultant or speaker from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva Pharmaceutical Industries. Dr. Fox has received research support from Biogen (clinical trial contracts) and Novartis (research study support). Dr. Ashokkumar has nothing to disclose. Dr. Barnes has nothing to disclose. Dr. Kearney has nothing to disclose. Dr. Coffey has nothing to disclose. Dr. Conwit has nothing to disclose. Dr. Cudkowicz has nothing to disclose. Dr. Ecklund has nothing to disclose. Dr. Gleason has nothing to disclose. Dr. Goodman has nothing to disclose. Dr. Klawiter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Atlas5d, and Celgene. Dr. Klinger has nothing to disclose. Dr. Koepp has nothing to disclose. Dr. Matsuda has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Medicinova Inc. Dr. McGovern has nothing to disclose. Dr. Naismith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genzyme, Novartis, Teva. Dr. Yankey has nothing to disclose. Dr. NN102 SPRINT MS Investigators has nothing to disclose.