Effect of MD1003 in Progressive Multiple Sclerosis (SPI2)

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the disability of patients suffering from progressive multiple sclerosis and especially those with gait impairment.

Official Title
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Effect of MD1003 in Progressive Multiple Sclerosis: a Randomized Double Blind Placebo Controlled Study

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: MD1003 100mg capsule
* Drug: PLACEBO


Participation Criteria
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Eligibility Criteria
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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 to inclusion, i.e. a) progression of EDSS during the past two years of at least 1 point sustained for at least 6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5 point increase sustained for at least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of TW25 by at least 20% in the last two years sustained for at least 6 months or c) other well-documented objective worsening validated by the Adjudication Committee EDSS at inclusion from 3.5 to 6.5 TW25 < 40 seconds at inclusion visit Kurtzke pyramidal functional subscore ≥2 defined as minimal disability: patient complains of motor-fatigability or reduced performance in strenuous motor tasks (motor performance 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 months prior to inclusion (multivitamin supplementation authorized if biotin < 1mg per day) Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to inclusion Treatment with botulinum toxin (except for cosmetic purpose) initiated within 6 months prior to inclusion In-patient rehabilitation program within the 3 months prior to inclusion Pregnancy, breastfeeding or women with childbearing potential without acceptable form of 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 using biotinylated antibodies or substrates Past history of rhabdomyolysis/metabolic myopathy Known fatty acids beta oxidation defect Known hypersensitivity or intolerance to biotin, analogues or excipients, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Patients with hypersensitivity or any contra-indication to Gadolinium Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer Laboratory tests out of normal ranges considered by the investigator as clinically significant 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 by Columbia-Suicide Severity Rating Scale (C-SSRS) Participation in another research study involving an investigational product (IP) in the 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-term follow-up seems to be difficult to achieve Relapse that occurs between inclusion and randomization visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: PART 1: Total duration of Part 1 is 27 months. The randomized double-blind placebo-controlled period ranges from 15 to 27 months depending upon the randomization date of an individual patient. Once the last month 15 evaluation of the study has been completed, patients will switch to the active drug at the next planned visit. Participants and study personnel will remain blinded as to the original treatment assignment. Maximum duration of double-blind period per patient will be no longer than 27 months. PART 2: At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be offered active treatment in an open label extension for 39 additional months (From V11/M27 to V18/M66). The purpose of the active drug extension is to further define the safety of MD1003.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: GROUP 1<br>Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. | Drug: PLACEBO<br>* an inactive substance<br>|
| Experimental: GROUP 2<br>MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. | Drug: MD1003 100mg capsule<br> <br> * Other names: high dose biotin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25) | Proportion of patients improved on either Expanded Disability Status Scale (EDSS) or time to walk 25 feet (TW25) : - with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5) or - with improved TW25 of at least 20% at Month 12 and Month15 compared to the lowest of the two EDSS and TW25* scores among inclusion and randomization visits. *The lowest TW25 value recorded among the four values obtained during the inclusion and randomization visits will be considered as the baseline TW25 value. | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 12-Weeks Confirmed EDSS Progression | 12-weeks EDSS progression is defined by an increase of at least 1 point for baseline EDSS 3.5 to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 12 weeks later. Date of 12-weeks confirmed EDSS progression will be the first date of an EDSS progression (as defined above) that is confirmed 12 weeks later. | 3 to 27 months | 
| CGI-I Score (Clinical Global Impression of Change - Improvement), Evaluated Both by the Patient (SGI) and by the Evaluating Physician (CGI) |  | 15 months | 
| Mean Change in TW25 Between M0 and M15 |  | 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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progressive multiple sclerosis, MS, EDSS, TW25, multiple sclerosis