A Study of Efficacy and Safety of M2951 in Participants With Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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The aim of this protocol is to find out about the safety and effectiveness of M2951 in participants with relapsing multiple sclerosis. Participants were placed into 1 of 3 groups to receive M2951, placebo or tecfidera for 24 weeks. After 24 weeks, the participants on placebo were given M2951.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase II Study of M2951 With a Parallel, Open-Label, Active Control Group (Tecfidera), in Patients With Relapsing Multiple Sclerosis to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, and Biological Activity.

Conditions
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Relapsing-remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Evobrutinib
* Drug: Evobrutinib
* Drug: Evobrutinib
* Drug: Placebo
* Drug: Tecfidera
* Drug: Evobrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with a diagnosis of relapsing multiple sclerosis (may include participants with Secondary Progressive Multiple Sclerosis (SPMS) with superimposed relapses provided they meet the other criteria) in accordance with revised McDonald criteria for MS and Lublin and Reingold Male or female aged 18 to 65 years 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 gadolinium-positive (Gd+) T1 lesion within 6 months prior to randomization would make the patient eligible. Expanded Disability Status Scale score of 0 to 6 at Baseline Women of childbearing potential must use a supplementary barrier method together with a highly effective method of contraception (according to International Council for Harmonisation [ICH] guidance M3[R2]) for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. 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. 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), intravenous (IV) immunoglobulins (Ig), plasmapheresis, immunosuppressive treatments, B-interferons or glatiramer acetate, Systemic glucocorticoids, teriflunomide 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 immunoglobulin M (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 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 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 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

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo then Evobrutinib 25 mg QD<br>Participants who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 milligram (mg) orally, once daily (QD) in blinded extension (BE) period from week 25 to week 48. | Drug: Placebo<br>* Placebo were administered for 24 weeks<br>Drug: Evobrutinib<br>* Following Placebo for 24 weeks, participants received Evobrutinib 25 milligram (mg) orally, once daily (QD) from Week 24 to 48 weeks.<br>* Other names: M2951;|
| Experimental: Evobrutinib 25 mg QD<br>Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. | Drug: Evobrutinib<br>* Participants received Evobrutinib 25 mg orally, once daily (QD) up to Week 48<br>* Other names: M2951;|
| Experimental: Evobrutinib 75 mg QD<br>Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. | Drug: Evobrutinib<br>* Participants received Evobrutinib 75 mg orally, QD up to Week 48<br>* Other names: M2951;|
| Experimental: Evobrutinib 75 mg BID<br>Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. | Drug: Evobrutinib<br>* Participants received Evobrutinib 75 milligrams (mg) orally, twice daily (BID) up to Week 48<br>* Other names: M2951;|
| Active Comparator: Tecfidera<br>Participants received Tecfidera 120 mg twice daily (BID) for first 7 days followed by 240 mg orally, BID up to Week 48 in active treatment period 1 and BE period. | Drug: Tecfidera<br>* Tecfidera; 120 mg hard capsule BID for 7 days then 240 mg hard capsule BID for duration of treatment (48 weeks).<br>|
| Placebo Comparator: Placebo<br>Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. | Drug: Placebo<br>* Placebo were administered for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Gadolinium-Enhancing T1 Lesions | Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 12 to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate (ARR) at Week 24 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 24 | 
| Qualified Relapse-Free Status at Week 24 | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status at week 24 were reported. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 24 | 
| Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 | The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis [MS]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Baseline, Week 24 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent adverse events are defined as any adverse event with a start date on or after the date of first dose and within 28 days after the date of last dose in the study. TEAEs include both Serious TEAEs and non-serious TEAEs. | Baseline up to Safety Follow-up (Week 52) | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) | Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator. | Baseline up to Safety Follow-up (Week 52) | 
| Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values | Hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). For the hematology and biochemistry parameters, participants with a value grade 3 or higher were reported. For the urinalysis parameters, participants with a value grade 3 or higher, or a value >= 2 upper limit of normal (ULN), or a value classified as ++ Increasing were reported. | Baseline up to Safety Follow-up (Week 52) | 
| Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) | Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. | Baseline (Day 1), Weeks 4, 16, and 24 | 
| Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) | Absolute Concentrations serum levels of IgG, IgA, IgM were to be assessed. | Weeks 48 | 
| Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) | Change in the serum levels of IgG, IgA, IgM were assessed. | Baseline (Day 1), Weeks 4, 16, and 24 | 
| Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) | Change in the serum levels of IgG, IgA, IgM were to be assessed. | Baseline (Day 1), Week 48 | 
| Absolute Numbers of B Cells (Active Treatment Period) | Absolute Numbers of B Cells are reported. | Baseline (Day 1), Weeks 4, and 24 | 
| Absolute Numbers of B Cells (Blinded Extension Period) | Absolute Numbers of B Cells to be reported. | Weeks 48 and 52 | 
| Change From Baseline in Absolute B Cells (Active Treatment Period) | Change from baseline in absolute B cells are reported. | Baseline (Day 1), Weeks 4, and 24 | 
| Change From Baseline in Absolute B Cells (Blinded Extension Period) | Change from baseline in absolute B cells to be reported. | Weeks 48 and 52 | 
| Total Number of New Gadolinium-positive (Gd+) T1 Lesions | Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 12 to 24 | 
| Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions | Analysis of Gadolinium-positive T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 12 to Week 24 | 
| Total Number of New or Enlarging T2 Lesions | Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Week 12 to Week 24 | 
| Change From Baseline in Volume of T2 Lesions at Week 24 | Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. Tecfidera treatment group was not included in inferential analysis. | Baseline, Week 24 | 
| Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 | Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. | Baseline, Week 24 | 
| Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. | Week 48 | 
| Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. | Week 48 | 
| Annualized Relapse Rate (ARR) | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. | Week 0 to Week 48 | 
| Qualified Relapse-free Status | A qualifying relapse is defined as new, worsening or recurrent neurological symptoms attributed to Multiple Sclerosis (MS) that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Percentage of participants with qualified relapse-free status were reported. | Week 25 to Week 48 | 
| Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48 | The EDSS is an ordinal clinical rating scale in half-point increments. It assesses the following eight functional systems, areas of the central nervous system that control bodily functions: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, Visual, Mental, Other (includes any other neurological findings due to Multiple Sclerosis [MS]). EDSS overall score ranging from 0 (normal) to 10 (death due to MS). | Week 24, Week 48 | 
| Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 | Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. | Week 24 to Week 48 | 
| Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 | Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. | Week 24, Week 48 | 
| Change From Week 24 in Volume of T2 Lesions at Week 48 | Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. | Week 24, Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M2951, Relapsing Multiple Sclerosis, Bruton's Tyrosine Kinase inhibitor