Robert J Fox1, Christopher S Coffey1, Robin Conwit1, Merit E Cudkowicz1, Trevis Gleason1, Andrew Goodman1, Eric C Klawiter1, Kazuko Matsuda1, Michelle McGovern1, Robert T Naismith1, Akshata Ashokkumar1, Janel Barnes1, Dixie Ecklund1, Elizabeth Klingner1, Maxine Koepp1, Jeffrey D Long1, Sneha Natarajan1, Brenda Thornell1, Jon Yankey1, Robert A Bermel1, Josef P Debbins1, Xuemei Huang1, Patricia Jagodnik1, Mark J Lowe1, Kunio Nakamura1, Sridar Narayanan1, Ken E Sakaie1, Bhaskar Thoomukuntla1, Xiaopeng Zhou1, Stephen Krieger1, Enrique Alvarez1, Michelle Apperson1, Khurram Bashir1, Bruce A Cohen1, Patricia K Coyle1, Silvia Delgado1, L Dana Dewitt1, Angela Flores1, Barbara S Giesser1, Myla D Goldman1, Burk Jubelt1, Neil Lava1, Sharon G Lynch1, Harold Moses1, Daniel Ontaneda1, Jai S Perumal1, Michael Racke1, Pavle Repovic1, Claire S Riley1, Christopher Severson1, Shlomo Shinnar1, Valerie Suski1, Bianca Weinstock-Guttman1, Vijayshree Yadav1, Aram Zabeti1. 1. 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.).
Abstract
BACKGROUND: There 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. METHODS: We 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. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 toplacebo. 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. CONCLUSIONS: In 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 .).
RCT Entities:
BACKGROUND: There 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. METHODS: We 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. RESULTS: Of 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. CONCLUSIONS: In 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 .).
Authors: Yoonsang Cho; Gregg V Crichlow; Jon J Vermeire; Lin Leng; Xin Du; Michael E Hodsdon; Richard Bucala; Michael Cappello; Matt Gross; Federico Gaeta; Kirk Johnson; Elias J Lolis Journal: Proc Natl Acad Sci U S A Date: 2010-06-08 Impact factor: 11.205
Authors: Xavier Montalban; Stephen L Hauser; Ludwig Kappos; Douglas L Arnold; Amit Bar-Or; Giancarlo Comi; Jérôme de Seze; Gavin Giovannoni; Hans-Peter Hartung; Bernhard Hemmer; Fred Lublin; Kottil W Rammohan; Krzysztof Selmaj; Anthony Traboulsee; Annette Sauter; Donna Masterman; Paulo Fontoura; Shibeshih Belachew; Hideki Garren; Nicole Mairon; Peter Chin; Jerry S Wolinsky Journal: N Engl J Med Date: 2016-12-21 Impact factor: 91.245
Authors: R J Fox; T Cronin; J Lin; X Wang; K Sakaie; D Ontaneda; S Y Mahmoud; M J Lowe; M D Phillips Journal: AJNR Am J Neuroradiol Date: 2010-10-14 Impact factor: 3.825
Authors: Robert J Fox; Christopher S Coffey; Merit E Cudkowicz; Trevis Gleason; Andrew Goodman; Eric C Klawiter; Kazuko Matsuda; Michelle McGovern; Robin Conwit; Robert Naismith; Akshata Ashokkumar; Robert Bermel; Dixie Ecklund; Maxine Koepp; Jeffrey Long; Sneha Natarajan; Srividya Ramachandran; Thomai Skaramagas; Brenda Thornell; Jon Yankey; Mark Agius; Khurram Bashir; Bruce Cohen; Patricia Coyle; Silvia Delgado; Dana Dewitt; Angela Flores; Barbara Giesser; Myla Goldman; Burk Jubelt; Neil Lava; Sharon Lynch; Augusto Miravalle; Harold Moses; Daniel Ontaneda; Jai Perumal; Michael Racke; Pavle Repovic; Claire Riley; Christopher Severson; Shlomo Shinnar; Valerie Suski; Bianca Weinstock-Gutman; Vijayshree Yadav; Aram Zabeti Journal: Contemp Clin Trials Date: 2016-08-10 Impact factor: 2.226
Authors: Asa Andersson; Ruxandra Covacu; Dan Sunnemark; Alexandre I Danilov; Assunta Dal Bianco; Mohsen Khademi; Erik Wallström; Anna Lobell; Lou Brundin; Hans Lassmann; Robert A Harris Journal: J Leukoc Biol Date: 2008-07-21 Impact factor: 4.962
Authors: Chris H Polman; Stephen C Reingold; Brenda Banwell; Michel Clanet; Jeffrey A Cohen; Massimo Filippi; Kazuo Fujihara; Eva Havrdova; Michael Hutchinson; Ludwig Kappos; Fred D Lublin; Xavier Montalban; Paul O'Connor; Magnhild Sandberg-Wollheim; Alan J Thompson; Emmanuelle Waubant; Brian Weinshenker; Jerry S Wolinsky Journal: Ann Neurol Date: 2011-02 Impact factor: 10.422
Authors: Lien D Nguyen; Tom T Fischer; Damien Abreu; Alfredo Arroyo; Fumihiko Urano; Barbara E Ehrlich Journal: Proc Natl Acad Sci U S A Date: 2020-07-06 Impact factor: 11.205
Authors: Michael J Li; Marisa S Briones; Keith G Heinzerling; Mariah M Kalmin; Steven J Shoptaw Journal: Drug Alcohol Depend Date: 2019-11-26 Impact factor: 4.492
Authors: Merit Cudkowicz; Marianne K Chase; Christopher S Coffey; Dixie J Ecklund; Brenda J Thornell; Codrin Lungu; Katy Mahoney; Laurie Gutmann; Jeremy M Shefner; Kevin J Staley; Michael Bosch; Eric Foster; Jeffrey D Long; Emine O Bayman; James Torner; Jon Yankey; Richard Peters; Trevis Huff; Robin A Conwit; Shlomo Shinnar; Donna Patch; Basil T Darras; Audrey Ellis; Roger J Packer; Karen S Marder; Claudia A Chiriboga; Claire Henchcliffe; Joyce Ann Moran; Blagovest Nikolov; Stewart A Factor; Carole Seeley; Steven M Greenberg; Anthony A Amato; Sara DeGregorio; Tanya Simuni; Tina Ward; John T Kissel; Stephen J Kolb; Amy Bartlett; Joseph F Quinn; Kellie Keith; Steven R Levine; Nadege Gilles; Patricia K Coyle; Jessica Lamb; Gil I Wolfe; Annemarie Crumlish; Luis Mejico; Muhammad Maaz Iqbal; James D Bowen; Caryl Tongco; Louis B Nabors; Khurram Bashir; Melanie Benge; Craig M McDonald; Erik K Henricson; Björn Oskarsson; Bruce H Dobkin; Catherine Canamar; Tracy A Glauser; Daniel Woo; Angela Molloy; Peggy Clark; Timothy L Vollmer; Alexander J Stein; Richard J Barohn; Mazen M Dimachkie; Jean-Baptiste Le Pichon; Michael G Benatar; Julie Steele; Lawrence Wechsler; Paula R Clemens; Christine Amity; Robert G Holloway; Christine Annis; Mark P Goldberg; Mariam Andersen; Susan T Iannaccone; A Gordon Smith; J Robinson Singleton; Mariana Doudova; E Clarke Haley; Mark S Quigg; Stephanie Lowenhaupt; Beth A Malow; Karen Adkins; David B Clifford; Mengesha A Teshome; Noreen Connolly Journal: JAMA Neurol Date: 2020-06-01 Impact factor: 18.302
Authors: Robert A Bermel; Janel K Fedler; Peter Kaiser; Cindy Novalis; Jeff Schneebaum; Elizabeth A Klingner; Dawn Williams; Jon W Yankey; Dixie J Ecklund; Marianne Chase; Robert T Naismith; Eric C Klawiter; Andrew D Goodman; Christopher S Coffey; Robert J Fox Journal: Mult Scler Date: 2020-10-15 Impact factor: 6.312