| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing Multiple Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsing Multiple Sclerosis |
|
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048393 |
| E.1.2 | Term | Multiple sclerosis relapse |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
The primary objective is to evaluate the efficacy and dose-response of M2951 on the number of gadolinium-positive (Gd+) T1 MRI lesions versus placebo after 24 weeks of treatment.
The primary objective of the open-label extension period is to evaluate
the long-term safety, efficacy, and HRQoL of M2951 for an additional 2 years at an initial dose of
75 mg once daily which is eventually switched to 75mg twice daily. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are as follows:
- To evaluate the efficacy and dose-response of M2951 on clinical endpoints over 24 weeks versus placebo
- To evaluate the safety of M2951
Additional secondary objectives are as follows:
- To evaluate the efficacy of M2951 on additional MRI parameters over 24 weeks versus placebo
- To evaluate the efficacy of M2951 on clinical and MRI endpoints from Week 24 to 48
- To evaluate the efficacy of Tecfidera on clinical and MRI endpoints over 24 weeks
- To evaluate the efficacy of Tecfidera on clinical and MRI endpoints from Week 24 to 48
- To evaluate the safety of Tecfidera |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacodynamics Bruton’s tyrosine kinase (BTK) occupancy (version and date as per current protocol).
Bruton’s tyrosine kinase (BTK) occupancy samples will be taken from a subset of approximately 30 evaluable subjects treated with M2951 or placebo from selected sites capable of providing samples.
Objective: To determine the Change from Baseline in percent BTK occupancy to predose on Days 28, 84 and 168 and 2 hours postdose on Days 1, 28, 84 and 168. |
|
| E.3 | Principal inclusion criteria |
1. Subjects with a diagnosis of relapsing multiple sclerosis (may include subjects with Secondary PMS [SPMS] with superimposed relapses provided they meet the other criteria) in accordance with revised McDonald criteria for MS and Lublin and Reingold
2. Male or female aged 18 to 65 years
3. One or more documented relapses within the 2 years before Screening with either: a) One relapse which occurred within the last year prior to randomization or b) the presence of at least 1 Gd+ T1 lesion within 6 months prior to randomization would make the patient eligible.
4. Expanded Disability Status Scale score of 0 to 6 at Baseline
5. Women of childbearing potential must use a supplementary barrier method together with a highly effective method of contraception for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. Male subjects and their female partners must also use the above.
6. Signed and dated informed consent (subject must be able to understand the informed consent) indicating that the subject has been informed of all the pertinent aspects of the trial prior to enrolment and will comply with the requirements of the protocol.
For the open-label extension period;
Subjects who have withdrawn after randomization (eg, due to AEs or
lack of efficacy) will not be replaced and will not be eligible to
participate in the OLE Period. Only subjects who have completed the 48-
week main study are eligible to participate. |
|
| E.4 | Principal exclusion criteria |
• Progressive MS
• Disease duration > 15 years in subjects with EDSS of 2 or less
• Use of the following, as determined in the protocol ; rituximab, ocrelizumab, mitoxantrone, or lymphocyte-depleting therapies, lymphocyte trafficking blockers (eg, natalizumab, fingolimod), intravenous (IV) immunoglobulins (Ig), plasmapheresis, immunosuppressive treatments, B-interferons or glatiramer acetate, Systemic glucocorticoids, teriflunomide, daclizumab
• Exposure to Tecfidera within 6 months prior to randomization
• Any allergy, contraindication, or inability to tolerate Tecfidera
• Treatment with dalfampridine (fampridine, Ampyra) unless on a stable dose for ≥ 30 days prior to randomization
• Inability to comply with MRI scanning
• Immunologic disorder other than MS, with the exception of secondary well-controlled diabetes or thyroid disorder, or any other condition requiring oral, IV, intramuscular, or intra-articular corticosteroid therapy
• Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
• Severe drug allergy or history of anaphylaxis, or allergy to the IMP or any of its incipients
• Active, clinically significant viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary.
• History of or positive testing for human immunodeficiency virus (HIV), hepatitis C (HCV) antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or IgM antibody (+) at Screening.
• The subject: • Has a history of or current diagnosis of active tuberculosis (TB) or • Is currently undergoing treatment for latent TB infection (LTBI) or • Has an untreated LTBI or • Has a positive QuantiFERON®-TB test at Screening.
• Indeterminate QuantiFERON
• Subjects with current household contacts with active TB will also be excluded
• History of splenectomy or any major surgery within 2 months prior to Screening
• History of myocardial infarction or cerebrovascular event as per the protocol
• History of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS)
• An episode of major depression within the last 6 months prior to Screening
• On anticoagulation, fish oil supplements, or antiplatelet therapy other than daily aspirin for cardioprotection and treatment of Tecfidera induced flushing
• History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin
• Breastfeeding/lactating or pregnant women
• Participation in any investigational drug trial within 1 month or 5 half-lives of the investigational drug, whichever is longest, prior to Screening
• Subjects currently receiving (or unable to stop using prior to receiving the first dose of IMP) medications or herbal supplements known to be potent inhibitors of cytochrome P450 3A (CYP3A)
• History of or current alcohol or substance abuse
• Clinically significant abnormality on electrocardiogram or screening chest X-ray
• Clinically significant laboratory abnormality
Note: for subjects participating in the OLE Period after receiving
Tecfidera during the 48-week main study, absolute lymphocyte count <
800/mm^3 is considered an exclusion criterion. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Main Study
Total number of gadolinium-enhancing T1 lesions at Weeks 12, 16, 20, and 24
OLE Period
•Efficacy and HRQoL endpoints at Week 48 and 96.
•Safety as assessed by the nature, severity, and occurrence of AEs; vital
signs; ECGs; absolute concentrations and change from Baseline in Ig
levels; absolute numbers and change from Baseline in B cells; and
clinical laboratory safety parameters. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 12, 16, 20 and 24
Week 48 and 96
AEs are evaluated throughout the study |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints to evaluate the efficacy and safety of M2951 compared to placebo:
• Annualized relapse rate (ARR), based on protocol-defined qualified relapses, at Week 24
• Qualified relapse-free status at Week 24
• Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 24
• Safety as assessed by the nature, severity, and of AEs; vital signs;
ECGs; absolute concentrations and change from Baseline in Ig levels;
absolute numbers and change from Baseline in B cells; and clinical
laboratory safety parameters (duration of placebo treatment
group limited to 24 weeks). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 24 for the key secondary endpoints
AEs are evaluated throughout the study |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability; determine the potential correlation between gene expression signatures and PD/efficacy |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Russian Federation |
| Serbia |
| Turkey |
| Ukraine |
| United States |
| Bulgaria |
| Croatia |
| Czechia |
| Poland |
| Slovakia |
| Spain |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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