1. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2) : a randomised, double-blind, placebo-controlled, phase 3 trial
- Author
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Jennifer Graves, Adrian Pace, Maria Pia Sormani, Devon S. Conway, Bianca Weinstock-Guttman, Frederick E. Munschauer, Corey C. Ford, Vernon Rowe, Jana Lizrova Preiningerova, Shiv Saidha, Radek Ampapa, Jens Kuhle, Harold L. Moses, Claire S Riley, Tobias Derfuss, Lilyana Amezcua, Joshua Barton, Kottil Rammohan, Pierre Duquette, Thomas Leist, Alexander Rae-Grant, Evanthia Bernitsas, Myla D. Goldman, R. Talab, Jerry S. Wolinsky, Nina De Klippel, Guillermo Izquierdo Ayuso, Bridget Bagert, Virginia Devonshire, Mariko Kita, Hayrettin Tumani, Bhatia Perminder, Scott D. Newsome, Paul S. Giacomini, Frédéric Sedel, Jan Lycke, M. S. Freedman, Stewart Webb, Sanjay Yathiraj, Agata Klosek, Stephen Krieger, Edward Fox, Malgorzata Zajda, Eva Meluzinova, Valerie J Block, Lluís Ramió-Torrentà, John R. Corboy, Aaron E. Miller, Xavier Montalban, Mark A. Agius, Michelle L Apperson, Patricia K. Coyle, Giancarlo Comi, Jose Enrique Martinez Rodriguez, Daniela Rau, Derrick Robertson, Elias Hamp Birte, Douglas L. Arnold, Fred D. Lublin, Galina Vorobeychik, Benjamin Greenberg, Mathias Buttmann, Daniel Bandari, Ludivine Witkowski, Sharon G. Lynch, Victoria Fernandez Sanchez, Jonathan Calkwood, Maria Satori, Tania Kuempfel, Rana K. Zabad, J. Marc Girard, Bruce A.C. Cree, Ahmed T. Toosy, Don J. Mahad, Bruce A. Cohen, Jozef Koscielniak, Jonathan Carter, Daniel Selchen, Paul Friedemann, Sharon Stoll, Fryze Waldemar, Gerd Reifschneider, Mark S. Freedman, Gary Cutter, Franz Fazekas, Robert T. Naismith, Marta Vachova, Richard MacDonell, Mary Ann Picone, Gavin Giovannoni, Randall Trudell, Barbara Willekens, Orhan Aktas, Mark Marriott, Roger McKelvey, Bruce C.A. Cree, Christopher Severson, Rafael Arroyo Gonzalez, Kyle Smoot, Murat Terzi, Joanna Cooper, Lou Brundin, Hans-Peter Hartung, Piotr Sokolowski, Joe Guadagno, Stephen C. Reingold, Klaus Schmierer, Guy Laureys, Robert P. Lisak, Lawrence Samkoff, Carlo Pozzilli, Celia Oreja Guevara, Mitchel Freedman, Anthony T. Reder, and SPI2 investigative teams
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Biotin ,Placebo ,Severity of Illness Index ,law.invention ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Outcome Assessment, Health Care ,Severity of illness ,Aged ,Disease Progression ,Female ,Humans ,Middle Aged ,Multiple Sclerosis, Chronic Progressive ,Vitamin B Complex ,Walking Speed ,Clinical endpoint ,Medicine ,Expanded Disability Status Scale ,business.industry ,Multiple sclerosis ,medicine.disease ,Clinical trial ,030104 developmental biology ,Cohort ,Neurology (clinical) ,Human medicine ,business ,030217 neurology & neurosurgery - Abstract
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 (
- Published
- 2020