• Robert J Fox, Christopher S Coffey, Robin Conwit, Merit E Cudkowicz, Trevis Gleason, Andrew Goodman, Eric C Klawiter, Kazuko Matsuda, Michelle McGovern, Robert T Naismith, Akshata Ashokkumar, Janel Barnes, Dixie Ecklund, Elizabeth Klingner, Maxine Koepp, Jeffrey D Long, Sneha Natarajan, Brenda Thornell, Jon Yankey, Robert A Bermel, Josef P Debbins, Xuemei Huang, Patricia Jagodnik, Mark J Lowe, Kunio Nakamura, Sridar Narayanan, Ken E Sakaie, Bhaskar Thoomukuntla, Xiaopeng Zhou, Stephen Krieger, Enrique Alvarez, Michelle Apperson, Khurram Bashir, Bruce A Cohen, Patricia K Coyle, Silvia Delgado, L Dana Dewitt, Angela Flores, Barbara S Giesser, Myla D Goldman, Burk Jubelt, Neil Lava, Sharon G Lynch, Harold Moses, Daniel Ontaneda, Jai S Perumal, Michael Racke, Pavle Repovic, Claire S Riley, Christopher Severson, Shlomo Shinnar, Valerie Suski, Bianca Weinstock-Guttman, Vijayshree Yadav, Aram Zabeti, and NN102/SPRINT-MS Trial Investigators.
• From the Mellen Center for Multiple Sclerosis, Neurological Institute (R.J.F., S. Natarajan, R.A.B., D.O.), the Imaging Institute (X.H., M.J.L., K.E.S., X.Z.), and the Department of Biomedical Engineering (P.J., K.N., B. Thoomukuntla), Cleveland Clinic, Cleveland, Ohio State University, Columbus (M.R.), and University of Cincinnati, Cincinnati (A.Z.) - all in Ohio; the Data Coordinating Center, Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), University of Iowa, Iowa City (C.S.C., J.B., D.E., E.K., M.K., J.D.L., J.Y.); the National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); the Clinical Coordinating Center, NeuroNEXT, Massachusetts General Hospital, Neurological Clinical Research Institute, Harvard Partners (M.E.C., M.M., A.A., B. Thornell), the Department of Neurology, Massachusetts General Hospital, Harvard Medical School (E.C.K.), and Brigham and Women's Hospital (C.S.), Boston; patient advocate (T.G.) and Swedish Medical Center at Seattle (P.R.), Seattle; University of Rochester Medical Center, Rochester (A.G.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center (S.K.), Weill Cornell Medical College (J.S.P.), Columbia University Medical Center (C.S.R.), and Montefiore Medical Center, Albert Einstein College of Medicine (S.S.), New York, State University of New York (SUNY) at Stony Brook, Stony Brook (P.K.C.), SUNY Upstate Medical University, Syracuse (B.J.), and SUNY at Buffalo, Buffalo (B.W.-G.) - all in New York; MediciNova, La Jolla (K.M.), University of California at Davis, Sacramento (M.A.), and University of California at Los Angeles, Los Angeles (B.S.G.) - all in California; Washington University School of Medicine, St. Louis (R.T.N.); Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (J.P.D.); NeuroRx Research, Montreal (S. Narayanan); the School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN (X.Z.); University of Colorado Denver, Aurora (E.A.); University of Alabama at Birmingham, Birmingham (K.B.); Feinberg School of Medicine, Northwestern University, Chicago (B.A.C.); University of Miami Miller School of Medicine, Miami (S.D.); University of Utah, Salt Lake City (L.D.D.); University of Texas Southwestern Medical Center, Dallas (A.F.); University of Virginia at Charlottesville, Charlottesville (M.D.G.); Emory University, Atlanta (N.L.); University of Kansas Medical Center, Kansas City (S.G.L.); Vanderbilt University, Nashville (H.M.); University of Pittsburgh Medical Center, Pittsburgh (V.S.); and Oregon Health and Science University, Portland (V.Y.).
• N. Engl. J. Med. 2018 Aug 30; 379 (9): 846855846-855.

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

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