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

Phase 2TerminatedNCT02975349

EMD Serono Research & Development Institute, Inc.267 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

267

Conditions

Relapsing-remitting Multiple Sclerosis

Interventions

EvobrutinibDRUG

Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

EvobrutinibDRUG

Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

EvobrutinibDRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (56)

Outcomes

Primary Outcomes

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.

Time frame: Week 12 to Week 24

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Placebo were administered for 24 weeks in active treatment period.

TecfideraDRUG

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 received Tecfidera 120 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Research Site

Blagoevgrad, Bulgaria

Research Site

Dupnitsa, Bulgaria

Research Site 1

Pleven, Bulgaria

Research Site 2

Pleven, Bulgaria

Research Site

Rousse, Bulgaria

Research Site

Sofia, Bulgaria

Research Site

Sofia, Bulgaria

Research Site

Sofia, Bulgaria

Research Site

Sofia, Bulgaria

Research Site

Sofia, Bulgaria

...and 46 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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 assessed.

Time frame: Week 48

Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)

Change from baseline in the serum levels of IgG, IgA, IgM were assessed.

Time frame: Baseline (Day 1), Weeks 4, 16, and 24

Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)

Change from baseline in the serum levels of IgG, IgA, IgM were assessed.

Time frame: Baseline (Week 25), Week 48

Absolute Concentration of B Cells (Active Treatment Period)

Absolute concentration of B Cells are reported.

Time frame: Baseline (Day 1), Weeks 4, and 24

Absolute Concentration of B Cells (Blinded Extension Period)

Absolute concentration of B Cells were reported.

Time frame: Weeks 48 and 52

Change From Baseline in Absolute B Cells (Active Treatment Period)

Change from baseline in absolute B cells are reported.

Time frame: Baseline (Day 1), Weeks 4 and 24

Change From Baseline in Absolute B Cells (Blinded Extension Period)

Change from baseline in absolute B cells are reported.

Time frame: Baseline (Week 25), 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Week 48

Annualized Relapse Rate (ARR)

Time frame: 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.

Time frame: Week 25 to Week 48

Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Week 24, Week 48

OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions

Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.

Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336

OLE Period: Annualized Relapse Rate (ARR)

Time frame: OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336

OLE Period: Percentage of Participants With 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 from OLE Baseline (BE period Week 48) up to Week 336 were reported.