E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superiority of MD1003, 300 mg/day, over placebo to clinically improve patients with not active progressive multiple sclerosis (MS). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of MD1003
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient aged 18-65 years old
2. Signed and dated written informed consent form in accordance with local regulations: having freely given their written informed consent to participate in the study
3. Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) and Lublin criteria (2014)
4. 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
5. EDSS at inclusion from 3.5 to 6.5
6. TW25 < 40 seconds
7. 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”
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E.4 | Principal exclusion criteria |
1. Clinical evidence of a relapse in 24 months prior to inclusion
2. Treatment with any product containing biotin as single ingredient within six months prior to inclusion (multivitamin supplementation authorized if biotin < 1mg per day)
3. Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion
4. New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to inclusion
5. Treatment with botulinium toxin (except for cosmetic purpose) initiated within 6 months prior to inclusion
6. In-patient rehabilitation program within the 3 months prior to inclusion
7. Pregnancy, breastfeeding or women with childbearing potential without acceptable form of contraception
8. Men unwilling to use an acceptable form of contraception
9. Any general chronic handicapping/incapacitating disease other than MS
10. Any serious disease necessitating biological follow-up with biological tests using biotinylated antibodies or substrates
11. Past history of rhabdomyolysis/metabolic myopathy
12. Known fatty acids beta oxidation defect
13. 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
14. Patients with hypersensitivity or any contra-indication to Gadolinium
15. Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer
16. Laboratory tests out of normal ranges considered by the investigator as clinically significant with regards to the study continuation
17. Patients with history or presence of alcohol abuse or drug addiction
18. Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
19. Participation in another research study involving an investigational product (IP) in the 90 days prior to inclusion, or planned use during the study duration
20. Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve
21. Relapse that occurs between inclusion and randomization visit |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
Proportions of patients:
- 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 M12 and M15
The baseline score for EDSS will be the lowest (best) value obtained during either the inclusion or randomization visit.
The baseline value for TW25 will be the best mean of the 2 scores obtained at either the inclusion or randomization visit (the lowest mean between the 2 visits).
The TW 25 value at visit M12 and M15 is defined as the mean of the two TW25 attempts at each visit. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints
1. Time to EDSS progression confirmed at 12 weeks
2. Mean difference between treatment arms in CGI at M15;
3. Mean difference between treatment arms in SGI at M15;
4. Mean change in TW25 score between M0 and M15;
5. Mean change in TW25 score between M0 and the last visit in doubleblind
phase of any particular patient (M15, M18, M21, M24 or M27 or
Early Termination).
- Exploratory endpoints
1. Brain MRI measurements will assess the following endpoints between
M0 and M15 (and between M0 and M27 and every year until the end of
the study)
a. Percent whole brain volume
b. Percent thalamic volume
c. Percent cortical grey matter volume
d. Brain water content evaluated by Pseudo T2 relaxation time
e. NAA/Cr in a subset of sites acquiring MRS
2. Remote monitoring of ambulation
3. Multiple Sclerosis Quality of Life-54 (MSQOL54) and Caregiver healthrelated
quality of life in Multiple Sclerosis (CAREQOL-MS) subscores and
composite scores
4. Subscores of the Kurtzke functional score
5. Symbol digit modalities test (SDMT)
- Safety evaluation
a. Recording of AEs
b. Laboratory testing (standard haematology and biochemistry panel)
c. ECG : PR, QRS, QT and RR interval, HR and QTcF, wave morphology,
rhythm and conduction
d. Brain MRI: new or enlarging T2 lesions and Gd+ lesions
e. Columbia-Suicide Severity Rating Scale |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 12, Month 15, Month 27, the last visit in double-blind phase (M15, M18, M21, M24 or M27 or Early Termination) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
Czech Republic |
Germany |
Hungary |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |