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Randomized Controlled Trial
. 2016 Nov;22(13):1719-1731.
doi: 10.1177/1352458516667568. Epub 2016 Sep 1.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study

Ayman Tourbah  1 , Christine Lebrun-Frenay  2 , Gilles Edan  3 , Michel Clanet  4 , Caroline Papeix  5 , Sandra Vukusic  6 , Jerome De Sèze  7 , Marc Debouverie  8 , Olivier Gout  9 , Pierre Clavelou  10 , Gilles Defer  11 , David-Axel Laplaud  12 , Thibault Moreau  13 , Pierre Labauge  14 , Bruno Brochet  15 , Frédéric Sedel  16 , Jean Pelletier  17 ; MS-SPI study group
Affiliations
Randomized Controlled Trial

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study

Ayman Tourbah et al. Mult Scler. 2016 Nov.

Abstract

Background: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.

Objective: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.

Methods: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits.

Results: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo.

Conclusion: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.

Keywords: MD1003; Multiple sclerosis; clinical trial; disability progression; high-dose biotin; primary progressive multiple sclerosis; secondary progressive multiple sclerosis.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Prof. Ayman Tourbah has received consulting fees, travel grants and reports institutional financial compensation for patient visits during the trial from MedDay Pharmaceuticals and consulting and lecturing fees, travel grants and research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono, Teva Pharmaceuticals and Roche. Prof. Gilles Edan reports personal fees from Biogen Idec and Novartis and grants and personal fees from Merck Serono, Teva, Sanofi and Bayer, outside the submitted work. Prof. Sandra Vukusic reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis and Teva Pharmaceuticals; and invited congress support from Biogen Idec, Merck Serono, Novartis and Genzyme. Prof. Jérôme De Sèze reports clinical trial support from MedDay Pharmaceuticals, Biogen Idec, Merck Serono, Bayer, LFB, UCB, AB Sciences, Sanofi-Aventis, Teva Pharmaceuticals and Genzyme; advisory or consultancy fees from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Almirall and Allergan; and invited congress support from Biogen Idec, Merck Serono, Bayer, LFB, Sanofi-Aventis, Teva Pharmaceuticals, Genzyme and Allergan. Dr Olivier Gout reports personal fees and non-financial support from Biogen Idec, Teva Pharmaceuticals, Genzyme and Novartis and personal fees from Merck, outside the submitted work. Prof. Gilles Defer reports personal fees from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme and Teva Pharmaceuticals; grants from Novartis, Merck Serono and Teva Pharmaceuticals; and funding for travel from Merck Serono, Biogen Idec, Guerbet, Sanofi-Aventis, Novartis, Genzyme and Teva Pharmaceuticals, outside the submitted work. Prof. David-Axel Laplaud reports personal fees from Biogen and Teva Pharmaceuticals and grants and personal fees from Novartis and Genzyme, outside the submitted work. Prof. Thibault Moreau reports personal fees and non-financial support from Biogen, Novartis, Sanofi-Genzyme, Bayer, Merck, Teva Pharmaceuticals and Almirall, outside the submitted work. Prof. Bruno Brochet received grants from MedDay Pharmaceuticals during the conduct of the study; personal fees and non-financial support from Biogen Idec, Novartis and Genzyme; grants from Merck Serono; grants, personal fees and non-financial support from Teva Pharmaceuticals; and grants and non-financial support from Bayer, outside the submitted work. Dr Frédéric Sedel is CEO and a shareholder at MedDay Pharmaceuticals (the study sponsor). Prof. Jean Pelletier has received consulting and lecturing fees, travel grants and unconditional research support from Biogen Idec, Sanofi-Genzyme, Novartis, Merck Serono and Teva Pharmaceuticals. Dr Christine Lebrun-Frenay, Prof. Michel Clanet, Dr Caroline Papeix, Prof. Marc Debouverie, Prof. Pierre Clavelou and Prof. Pierre Labauge have nothing to disclose.

Figures

Figure 1.
Figure 1.
Screening, enrolment, randomisation and follow-up of study patients. The ITT population was defined as all patients who were assigned to a treatment arm. The per-protocol population was defined as all patients of the ITT population with assessments of EDSS or TW25 at screening, baseline, month 9 and month 12 without major protocol deviations. EDSS: Expanded Disability Status Scale; ITT: intention to treat; TW25: timed 25-foot walk.
Figure 2.
Figure 2.
Proportion of patients with reversal of MS-related disability. Reversal of disability was defined as improvement of EDSS or TW25 values confirmed at the next visit (except for month 24 where no subsequent visit was available) compared with best respective values recorded at either the screening or the randomisation visits. EDSS: Expanded Disability Status Scale; TW25: timed 25-foot walk.
Figure 3.
Figure 3.
Mean change from baseline in EDSS during the 12-month double-blind placebo-controlled phase and 12-month extension phase. This figure also shows the mean change from baseline in EDSS (represented as the mean of means) as reported in other published placebo-controlled studies of pharmacological agents in PPMS or SPMS (>6000 patients in total).,,– EDSS: Expanded Disability Status Scale; DR 2/4 (+ or −): human leukocyte antigen haplotype (positive or negative); GA: glatiramer acetate; IFNb: interferon beta; PPMS: primary progressive multiple sclerosis; SEM: standard error of the mean; SPMS: secondary progressive multiple sclerosis; TW25: timed 25-foot walk.
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