Effect of MD1003 in Progressive Multiple Sclerosis (SPI2)

Inclusion Criteria:

• Patient aged 18-65 years old
• Signed and dated written informed consent form in accordance with local regulations:having freely given their written informed consent to participate in the study
• Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) and Lublin criteria (2014)
• Documented evidence of clinical disability progression within the 2 years prior toinclusion, i.e. a) progression of EDSS during the past two years of at least 1 pointsustained for at least 6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5point increase sustained for at least 6 months if inclusion EDSS is from 6 to 6.5 orb) increase of TW25 by at least 20% in the last two years sustained for at least 6months or c) other well-documented objective worsening validated by the AdjudicationCommittee
• EDSS at inclusion from 3.5 to 6.5
• TW25 < 40 seconds at inclusion visit
• Kurtzke pyramidal functional subscore ≥2 defined as "minimal disability: patientcomplains of motor-fatigability or reduced performance in strenuous motor tasks (motorperformance grade 1) and/or BMRC grade 4 in one or two muscle groups"

Exclusion Criteria:

• Clinical evidence of a relapse in 24 months prior to inclusion
• Treatment with any product containing biotin as single ingredient within six monthsprior to inclusion (multivitamin supplementation authorized if biotin < 1mg per day)
• Concomitant treatment with fampridine at inclusion or in the 30 days prior toinclusion
• New immunosuppressive/immunomodulatory drug initiated less than 90 days prior toinclusion
• Treatment with botulinum toxin (except for cosmetic purpose) initiated within 6 monthsprior to inclusion
• In-patient rehabilitation program within the 3 months prior to inclusion
• Pregnancy, breastfeeding or women with childbearing potential without acceptable formof contraception
• Men unwilling to use an acceptable form of contraception
• Any general chronic handicapping/incapacitating disease other than MS
• Any serious disease necessitating biological follow-up with biological tests usingbiotinylated antibodies or substrates
• Past history of rhabdomyolysis/metabolic myopathy
• Known fatty acids beta oxidation defect
• Known hypersensitivity or intolerance to biotin, analogues or excipients, patientswith rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption
• Patients with hypersensitivity or any contra-indication to Gadolinium
• Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, orcancer
• Laboratory tests out of normal ranges considered by the investigator as clinicallysignificant with regards to the study continuation
• Patients with history or presence of alcohol abuse or drug addiction
• Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed byColumbia-Suicide Severity Rating Scale (C-SSRS)
• Participation in another research study involving an investigational product (IP) inthe 90 days prior to inclusion, or planned use during the study duration
• Patients likely to be non-compliant to the study procedures or for whom a long-termfollow-up seems to be difficult to achieve
• Relapse that occurs between inclusion and randomization visit