| 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 of the main study is to evaluate the efficacy and dose-response of M2951 on the number of 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 up to 8 additional
years, at an initial dose of 75 mg once daily which is eventually switched
to 75 mg 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. Participants with a diagnosis of RMS (may include participants with
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. EDSS 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 (participant must be able to
understand the informed consent) indicating that the participant 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;
Participants 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 participants who have completed the
48-week main study are eligible to participate. |
|
| E.4 | Principal exclusion criteria |
• Progressive MS
• Disease duration > 15 years in participants 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), IV Igs,
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
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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 HIV, HCV antibody and/or polymerase
chain reaction,HBsAg (+) and/or hepatitis B core total, and/or IgM
antibody (+) at Screening.
• The participant: • 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
• Participants 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 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 halflives
of the investigational drug, whichever is longest, prior to Screening
• Participants 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 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 participants 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, 96, 144, 192, 240, 288 and 336.
•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, 96, 144, 192, 240, 288 and 336.
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:
• ARR, based on protocol-defined qualified relapses, at Week 24
• Qualified relapse-free status at Week 24
• Change from Baseline in 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 |
| Ukraine |
| Russian Federation |
| Serbia |
| Turkey |
| United States |
| Bulgaria |
| Croatia |
| Czechia |
| Poland |
| Slovakia |
| Spain |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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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