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

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.

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 Overview

• Status: Terminated
• Conditions: Relapsing-remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Evobrutinib; Drug: Evobrutinib; Drug: Tecfidera; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Research Site
  • Dupnitsa, Bulgaria, 2600
    • Research Site
  • Pleven, Bulgaria, 5800
    • Research Site 1
  • Pleven, Bulgaria, 5800
    • Research Site 2
  • Ruse, Bulgaria, 7002
    • Research Site
  • Sofia, Bulgaria, 1431
    • Research Site
  • Sofia, Bulgaria, 1407
    • Research Site
  • Sofia, Bulgaria, 1336
    • Research Site
  • Sofia, Bulgaria, 1142
    • Research Site
  • Sofia, Bulgaria, 1309
    • Research Site
  • Sofia, Bulgaria, 1606
    • Research Site
  • Sofia, Bulgaria, 1797
    • Research Site
• Czechia
  • Brno, Czechia, 656 91
    • Research Site
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Hradec Kralove, Czechia, 50003
    • Research Site
  • Jihlava, Czechia, 58633
    • Research Site
  • Prague 5, Czechia, 150 06
    • Research Site
  • Teplice, Czechia, 41529
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-654
    • Research Site
  • Katowice, Poland, 40-595
    • Research Site
  • Katowice, Poland, 40-650
    • Research Site
  • Lodz, Poland, 90-324
    • Research Site
  • Lublin, Poland, 20-605
    • Research Site
  • Oswiecim, Poland, 32-600
    • Research Site
  • Plewiska, Poland, 62-064
    • Research Site
  • Poznan, Poland, 61-853
    • Research Site
  • Rzeszow, Poland, 35-055
    • Research Site
  • Warszawa, Poland, 01-697
    • Research Site
• Russian Federation
  • Kazan, Russian Federation, 420021
    • Research Site
  • Krasnoyarsk, Russian Federation, 660049
    • Research Site
  • Krasnoyarsk, Russian Federation, 660037
    • Research Site
  • Moscow, Russian Federation, 129128
    • Research Site
  • Novosibirsk, Russian Federation, 630102
    • Research Site
  • Perm, Russian Federation, 614000
    • Research Site
  • Saransk, Russian Federation, 430032
    • Research Site
• Serbia
  • Belgrade, Serbia, 11000
    • Research Site
  • Kragujevac, Serbia, 34000
    • Research Site
  • Nis, Serbia, 18000
    • Research Site
  • Uzice, Serbia, 31000
    • Research Site
• Slovakia
  • Banska Bystrica, Slovakia, 97404
    • Research Site
  • Bratislava, Slovakia, 85101
    • Research Site
  • Dubnica nad Vahom, Slovakia, 01841
    • Research Site
• Spain
  • A Coruña, Spain, 15006
    • Research Site
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08003
    • Research Site
• Ukraine
  • Chernivtsi, Ukraine, 58018
    • Research Site
  • Ivano-Frankivsk, Ukraine, 76008
    • Research Site
  • Kharkiv, Ukraine, 61058
    • Research Site
  • Kharkiv, Ukraine, 61103
    • Research Site
  • Kharkiv, Ukraine, 61068
    • Research Site
  • Kyiv, Ukraine, 01601
    • Research Site
  • Kyiv, Ukraine, 03110
    • Research Site
  • Lviv, Ukraine, 79010
    • Research Site
  • Poltava, Ukraine, 36011
    • Research Site
  • Zaporizhzhia, Ukraine, 69600
    • Research Site
  • Zaporizhzhia, Ukraine, 69035
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1.	Drug: Placebo; Placebo were administered for 24 weeks in active treatment period.
Experimental: Placebo then Evobrutinib 25 mg QD (Period 2); 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: Evobrutinib; 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.; Other Names: M2951; Drug: Evobrutinib; 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.; Other Names: M2951
Experimental: Evobrutinib 25 mg QD (Period 1, 2 and 3); 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.	Drug: Evobrutinib; 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.; Other Names: M2951; Drug: Evobrutinib; 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.; Other Names: M2951
Experimental: Evobrutinib 75 mg QD (Period 1, 2 and 3); 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.	Drug: Evobrutinib; 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.; Other Names: M2951; Drug: Evobrutinib; 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.; Other Names: M2951
Experimental: Evobrutinib 75 mg BID (Period 1, 2 and 3); Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period received Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.	Drug: Evobrutinib; 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.; Other Names: M2951; Drug: Evobrutinib; 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.; Other Names: M2951
Active Comparator: Tecfidera (Period 1, 2 and 3); 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.	Drug: Tecfidera; 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.
Experimental: Placebo + Evobrutinib 25 mg QD (Period 3); Participants who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 mg orally, QD from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.	Drug: Evobrutinib; 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.; Other Names: M2951; Drug: Evobrutinib; 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.; Other Names: M2951

What is the study measuring?

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
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
Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)	Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.	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.	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.	Baseline (Week 25), Week 48
Absolute Concentration of B Cells (Active Treatment Period)	Absolute concentration of B Cells are reported.	Baseline (Day 1), Weeks 4, and 24
Absolute Concentration of B Cells (Blinded Extension Period)	Absolute concentration of B Cells were 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 are reported.	Baseline (Week 25), Weeks 48 and 52
OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions	Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans.	OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
OLE Period: 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.	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.	OLE Baseline (BE period Week 48) up to OLE Week 336
OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336	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).	OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	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.	OLE Baseline (BE period Week 48) up to OLE Week 336
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Number of participants with clinically significant change from baseline in vital signs were reported. Clinical Significance was decided by the investigator.	OLE Baseline (BE period Week 48) up to OLE Week 336
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters	Laboratory parameters included hematology, biochemistry, and urinalysis. Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator.	OLE Baseline (BE period Week 48) up to OLE Week 336
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)	ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of participants with clinically significant change from baseline in ECG were reported. Clinical Significance was decided by the investigator.	OLE Baseline (BE period Week 48) up to OLE Week 336
OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels	Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.	OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels	Change from baseline in the serum levels of IgG, IgA, IgM were assessed.	OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS; Evobrutinib Phase 2 Study Group. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019 Jun 20;380(25):2406-2417. doi: 10.1056/NEJMoa1901981. Epub 2019 May 10.
• Arnold DL, Elliott C, Martin EC, Hyvert Y, Tomic D, Montalban X. Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial. Neurology. 2024 Mar 12;102(5):e208058. doi: 10.1212/WNL.0000000000208058. Epub 2024 Feb 9.
• Papasouliotis O, Mitchell D, Girard P, Dangond F, Dyroff M. Determination of a clinically effective evobrutinib dose: Exposure-response analyses of a phase II relapsing multiple sclerosis study. Clin Transl Sci. 2022 Dec;15(12):2888-2898. doi: 10.1111/cts.13407. Epub 2022 Sep 30.
• Montalban X, Wallace D, Genovese MC, Tomic D, Parsons-Rich D, Le Bolay C, Kao AH, Guehring H. Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):1-9. doi: 10.1136/jnnp-2022-328799. Epub 2022 Nov 23.
• Bar-Or A, Cross AH, Cunningham AL, Hyvert Y, Seitzinger A, Guhring H, Drouin EE, Alexandri N, Tomic D, Montalban X. Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor. Mult Scler. 2023 Oct;29(11-12):1471-1481. doi: 10.1177/13524585231192460. Epub 2023 Aug 25.

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Actual): January 24, 2018
• Study Completion (Actual): April 2, 2024

Study Registration Dates

• First Submitted: November 23, 2016
• First Submitted That Met QC Criteria: November 23, 2016
• First Posted (Estimated): November 29, 2016

Study Record Updates

• Last Update Posted (Actual): May 14, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Relapsing Multiple Sclerosis; M2951; Bruton's Tyrosine Kinase inhibitor
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: MS200527-0086; 2016-001448-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Per company policy and with respect to the principles set forth by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Pharmaceutical Research and Manufacturers of America (PhRMA), the Declaration of Helsinki, and applicable laws and regulations , we inform the public about the designs and results of our clinical trials in a timely and balanced manner, regardless of the outcome. We are committed to enhancing public health through responsible sharing of clinical trial data in a manner that is consistent with: safeguarding the privacy of patients; respecting the integrity of national regulatory systems; and maintaining incentives for investment in biomedical research.
• IPD Sharing Time Frame: Within six months after the occurrence of an approval of a new product or a new indication for an approved product in both the European Union and the United States after January 1, 2014 If approval of a product is not sought, Merck shall make publicly available such data within eighteen months after the trial completion date. Data will not be shared for products and indications approved prior to January 1, 2014
• IPD Sharing Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researcher qualifications and legitimacy of the research purpose.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No