Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial

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 survi...

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Published in:Lancet neurology 2020-12, Vol.19 (12), p.988-997
Main Authors: Cree, Bruce A C, Cutter, Gary, Wolinsky, Jerry S, Freedman, Mark S, Comi, Giancarlo, Giovannoni, Gavin, Hartung, Hans-Peter, Arnold, Douglas, Kuhle, Jens, Munschauer, Frederick E, Sedel, Frédéric, Lublin, Fred D, Reingold, Stephen, Duquette, Pierre, Derfuss, Tobias, Sormani, Maria Pia, Lisak, Robert P., Graves, Jennifer, Krieger, Stephen, Zabad, Rana K., Newsome, Scott, MacDonell, Richard, Marriott, Mark, De Klippel, Nina, Willekens, Barbara, Devonshire, Virginia, Freedman, Mark, Girard, J Marc, Giacomini, Paul, McKelvey, Roger, Witkowski, Ludivine, Ampapa, Radek, Preiningerova, Jana Lizrova, Meluzinova, Eva, Talab, Radomir, Vachova, Marta, Aktas, Orhan, Buttmann, Mathias, Birte, Elias-Hamp, Kuempfel, Tania, Friedemann, Paul, Rau, Daniela, Reifschneider, Gerd, Sokolowski, Piotr, Tumani, Hayrettin, Pozzilli, Carlo, Klosek, Agata, Koscielniak, Jozef, Waldemar, Fryze, Zajda, Malgorzata, Gonzalez, Rafael Arroyo, Ayuso, Guillermo Izquierdo, Sanchez, Victoria Fernandez, Guevara, Celia Oreja, Rodriguez, Jose Enrique Martinez, Montalban, Xavier, Ramio-Torrenta, Lluis, Brundin, Lou, Lycke, Jan, Guadagno, Joe, Mahad, Don, Pace, Adrian, Schmierer, Klaus, Toosy, Ahmed, Webb, Stewart, Agius, Mark, Apperson, Michelle, Bagert, Bridget, Bandari, Daniel, Bernitsas, Evanthia, Calkwood, Jonathan, Carter, Jonathan, Conway, Devon, Cooper, Joanna, Corboy, John, Cree, Bruce, Freedman, Mitchel, Ford, Corey, Fox, Edward, Goldman, Myla, Kita, Mariko, Lynch, Sharon, Miller, Aaron, Moses, Harold, Naismith, Robert, Picone, Mary Ann, Perminder, Bhatia, Rae-Grant, Alexander, Rammohan, Kottil, Reder, Anthony, Riley, Claire, Robertson, Derrick, Rowe, Vernon, Saidha, Shiv, Samkoff, Lawrence, Severson, Christopher, Smoot, Kyle, Stoll, Sharon, Weinstock-Guttman, Bianca, Yathiraj, Sanjay
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Biotin
Biotin - administration & dosage
Biotin - adverse effects
Biotin - pharmacology
Cell survival
Clinical trials
Disease Progression
Double-Blind Method
Double-blind studies
Female
Humans
Laboratories
Male
Middle Aged
Multiple sclerosis
Multiple Sclerosis, Chronic Progressive - drug therapy
Multiple Sclerosis, Chronic Progressive - physiopathology
Neurodegeneration
Outcome Assessment, Health Care
Patients
Pharmaceuticals
Physicians
Quality of life
Safety
Severity of Illness Index
Therapeutic applications
Vitamin B Complex - administration & dosage
Vitamin B Complex - adverse effects
Vitamin B Complex - pharmacology
Walking
Walking Speed - drug effects
Young Adult
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Summary: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. 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). 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%)
ISSN:1474-4422
1474-4465
DOI:10.1016/S1474-4422(20)30347-1