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TerminatedNCT02975349Updated May 14, 2025Results posted

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

A Phase 2 interventional study of Evobrutinib and Evobrutinib in Relapsing-remitting Multiple Sclerosis, sponsored by EMD Serono Research & Development Institute, Inc.. Terminated at 56 sites in 8 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-05-14.

Sponsored by EMD Serono Research & Development Institute, Inc. · Phase 2, Interventional, and Treatment

Why this study was terminated
Results from the EVOLUTION clinical trials showed evobrutinib did not meet its primary endpoint of annualized relapse rate for up to 156 weeks compared to oral teriflunomide in both studies.
Phase
Phase 2
Study type
Interventional
Enrollment
267
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study summary

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.

02

Conditions studied

  • Relapsing-remitting Multiple Sclerosis

Keywords

  • M2951
  • Relapsing Multiple Sclerosis
  • Bruton's Tyrosine Kinase inhibitor
03

In context

Multiple Sclerosis

3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.

This study's enrollment of 267 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.

Browse Multiple Sclerosis studies →

Lead sponsor

EMD Serono Research & Development Institute, Inc. is the lead sponsor of 85 studies on the registry; 8 are open to participants now.

Of its 46 completed or terminated interventional studies of FDA-regulated products, 38 (83%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Investigator, Outcomes assessor)
Enrollment
267 participants (actual)

Study arms

  • 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

  • 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

  • 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

  • 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

  • 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

  • Placebo comparator
    Placebo

    Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1.

    Drug: Placebo

  • 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

Interventions

  • DrugEvobrutinib

    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.

    Also known as: M2951

  • DrugEvobrutinib

    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.

    Also known as: M2951

  • DrugEvobrutinib

    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.

    Also known as: M2951

  • DrugPlacebo

    Placebo were administered for 24 weeks in active treatment period.

  • DrugTecfidera

    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.

06

What researchers measure

Primary outcomes

  1. 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

  1. 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

  2. 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

  3. 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.

    Time frame: Baseline, Week 24

  4. 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)

  5. 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)

  6. 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)

  7. 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

  8. Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)

    Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.

    Time frame: Week 48

  9. 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

  10. 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

  11. Absolute Concentration of B Cells (Active Treatment Period)

    Absolute concentration of B Cells are reported.

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

  12. Absolute Concentration of B Cells (Blinded Extension Period)

    Absolute concentration of B Cells were reported.

    Time frame: Weeks 48 and 52

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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.

    Time frame: Week 0 to Week 48

  23. 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

  24. 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).

    Time frame: Week 24, Week 48

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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.

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

  30. 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.

    Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336

  31. 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).

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

  32. 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.

    Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336

  33. 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.

    Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336

  34. 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.

    Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336

  35. 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.

    Time frame: OLE Baseline (BE period Week 48) up to OLE Week 336

  36. OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels

    Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.

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

  37. OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels

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

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

07

Results

Posted Feb 5, 2021
Limitations and caveats
Reported p values are not adjusted for multiple testing.

Participant flow

Active Treatment Period (24 Weeks)
Participant flow — Active Treatment Period (24 Weeks)
MilestonePlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Placebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Started540052535454
Safety analysis set540052535454
Completed490047484852
Not completed5005562
Withdrew: Withdrawal by subject0003300
Withdrew: Lost to follow-up1000000
Withdrew: Adverse event4002262
Blinded Extension Period (24 Weeks)
Participant flow — Blinded Extension Period (24 Weeks)
MilestonePlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Placebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Started049047484852
Completed042043444652
Not completed0704420
Withdrew: Adverse event0101310
Withdrew: Withdrawal by subject0502110
Withdrew: Lack of efficacy0001000
Withdrew: Progressive disease0100000
Open-label Extension Period (336 Weeks)
Participant flow — Open-label Extension Period (336 Weeks)
MilestonePlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Placebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Started003939424449
Completed002825333539
Not completed0011149910
Withdrew: Adverse event0032212
Withdrew: Study reached its predefined end0000100
Withdrew: Lack of efficacy0000201
Withdrew: Death0001000
Withdrew: Covid-19 related0001112
Withdrew: Lost to follow-up0010010
Withdrew: Other0033123
Withdrew: Withdrawal by subject0047242

Outcome measures

PrimaryTotal 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
Reported as:
Mean · Lesions
Total Number of Gadolinium-Enhancing T1 Lesions
LesionsPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Total Number of Gadolinium-Enhancing T1 Lesions3.85 ± 5.4364.06 ± 8.0241.69 ± 4.6931.15 ± 3.7024.78 ± 22.045
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Negative Binomial model · p = 0.2947 · Lesion rate ratio: 1.45 · 95% CI 0.72 to 2.91
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Negative Binomial model · p = 0.0015 · Lesion rate ratio: 0.30 · 95% CI 0.14 to 0.63
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Negative Binomial model · p = 0.0313 · Lesion rate ratio: 0.44 · 95% CI 0.21 to 0.93
SecondaryAnnualized 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
Reported as:
Mean · relapses per year
Annualized Relapse Rate (ARR) at Week 24
relapses per yearPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Annualized Relapse Rate (ARR) at Week 240.37 (0.17 to 0.70)0.57 (0.30 to 0.97)0.13 (0.03 to 0.38)0.08 (0.01 to 0.30)0.20 (0.06 to 0.47)
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Negative Binomial model · p = 0.2692 · Qualified relapse rate ratio: 1.66 · 95% CI 0.67 to 4.09
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Negative Binomial model · p = 0.0896 · Qualified relapse rate ratio: 0.31 · 95% CI 0.08 to 1.20
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Negative Binomial model · p = 0.0633 · Qualified relapse rate ratio: 0.23 · 95% CI 0.05 to 1.09
SecondaryQualified 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
Reported as:
Number · percentage of participants
Qualified Relapse-Free Status at Week 24
percentage of participantsPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Qualified Relapse-Free Status at Week 2477.4 (63.8 to 87.7)74.0 (59.7 to 85.4)88.2 (76.1 to 95.6)86.8 (74.7 to 94.5)88.9 (77.4 to 95.8)
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Logistic model · p = 0.5609 · Odds ratio (or): 0.75 · 95% CI 0.29 to 1.95
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Logistic model · p = 0.0689 · Odds ratio (or): 2.79 · 95% CI 0.92 to 8.41
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Logistic model · p = 0.1767 · Odds ratio (or): 2.08 · 95% CI 0.72 to 5.99
SecondaryChange 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.

Time frame:
Baseline, Week 24
Reported as:
Mean · Units on a scale
Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
Units on a scalePlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24-0.03 ± 0.3010.02 ± 0.622-0.14 ± 0.6640.04 ± 0.2160.02 ± 0.274
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.4070 · Hodges-lehmann estimate: 0.00 · 95% CI 0.00 to 0.00
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.5829 · Hodges-lehmann estimate: 0.00 · 95% CI 0.00 to 0.00
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.2732 · Hodges-lehmann estimate: 0.00 · 95% CI 0.00 to 0.00
SecondaryNumber 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)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
ParticipantsPlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
TEAEs241928353435
Serious TEAEs202242
TEAEs Leading to Death000000
SecondaryNumber 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)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)
ParticipantsPlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Vital Sign Abnormalities000000
ECG Abnormalities000000
SecondaryNumber 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)
Reported as:
Count of participants · Participants
Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values
ParticipantsPlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Grade >= 3 hematology values020101
Grade >= 3 biochemistry values2869169
Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values021226
SecondaryAbsolute 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
Reported as:
Mean · Gram per Liter
Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)
Gram per LiterPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Ig A, Day 11.99 ± 0.7771.89 ± 0.7641.90 ± 0.7221.87 ± 0.6752.03 ± 0.763
Ig A, Week 41.98 ± 0.7771.92 ± 0.7701.93 ± 0.7621.94 ± 0.7481.90 ± 0.699
Ig A, Week 162.07 ± 0.8242.10 ± 0.8132.13 ± 0.8322.08 ± 0.7532.03 ± 0.752
Ig A, Week 241.99 ± 0.8072.12 ± 0.8332.09 ± 0.8382.09 ± 0.7931.97 ± 0.757
Ig G, Day 19.61 ± 1.8979.43 ± 2.1269.81 ± 1.8419.62 ± 1.9609.47 ± 1.839
Ig G, Week 49.64 ± 2.0949.34 ± 1.9729.79 ± 1.9109.64 ± 1.9879.05 ± 1.922
Ig G, Week 169.68 ± 2.0859.41 ± 2.0779.70 ± 1.9919.56 ± 2.1299.58 ± 1.850
Ig G, Week 249.66 ± 2.0819.46 ± 2.1239.62 ± 2.0489.36 ± 1.9889.27 ± 1.866
Ig M, Day 11.42 ± 0.6921.27 ± 0.5421.44 ± 0.7161.33 ± 0.6841.27 ± 0.589
Ig M, Week 41.40 ± 0.6681.21 ± 0.5261.32 ± 0.6541.28 ± 0.6561.23 ± 0.603
Ig M, Week 161.43 ± 0.7031.13 ± 0.5581.24 ± 0.6391.20 ± 0.6891.28 ± 0.678
Ig M, Week 241.44 ± 0.7481.03 ± 0.4991.20 ± 0.6721.08 ± 0.4941.29 ± 0.667
SecondaryAbsolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.

Time frame:
Week 48
Reported as:
Mean · Gram per Liter
Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)
Gram per LiterEvobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
IgA2.13 ± 0.8072.18 ± 0.7902.23 ± 0.8382.06 ± 0.695
IgG9.53 ± 2.0709.74 ± 1.9029.38 ± 2.1899.60 ± 1.968
IgM1.08 ± 0.5571.13 ± 0.6391.10 ± 0.6921.28 ± 0.635
SecondaryChange 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
Reported as:
Mean · Gram per Liter
Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)
Gram per LiterPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Ig A, Week 4-0.02 ± 0.2010.02 ± 0.1650.04 ± 0.1690.07 ± 0.195-0.13 ± 0.238
Ig A, Week 160.10 ± 0.1880.18 ± 0.2450.21 ± 0.3130.22 ± 0.209-0.02 ± 0.274
Ig A, Week 240.06 ± 0.2500.21 ± 0.2830.18 ± 0.4160.22 ± 0.229-0.06 ± 0.207
Ig G, Week 40.02 ± 0.758-0.10 ± 0.697-0.02 ± 0.6880.02 ± 0.581-0.42 ± 0.926
Ig G, Week 160.04 ± 0.747-0.07 ± 0.964-0.10 ± 1.068-0.05 ± 0.7100.07 ± 0.961
Ig G, Week 240.06 ± 0.6820.00 ± 1.228-0.15 ± 1.058-0.28 ± 0.774-0.23 ± 0.882
Ig M, Week 4-0.01 ± 0.210-0.06 ± 0.100-0.12 ± 0.233-0.05 ± 0.133-0.04 ± 0.132
Ig M, Week 160.02 ± 0.177-0.12 ± 0.184-0.18 ± 0.244-0.14 ± 0.189-0.00 ± 0.184
Ig M, Week 240.04 ± 0.163-0.14 ± 0.286-0.20 ± 0.289-0.21 ± 0.167-0.00 ± 0.186
SecondaryChange 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
Reported as:
Mean · Gram per Liter
Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)
Gram per LiterEvobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
IgA0.26 ± 0.2480.28 ± 0.2750.36 ± 0.3200.03 ± 0.316
IgG0.11 ± 1.024-0.08 ± 0.940-0.24 ± 0.8830.10 ± 1.244
IgM-0.18 ± 0.211-0.27 ± 0.287-0.23 ± 0.218-0.01 ± 0.198
SecondaryAbsolute Concentration of B Cells (Active Treatment Period)

Absolute concentration of B Cells are reported.

Time frame:
Baseline (Day 1), Weeks 4, and 24
Reported as:
Mean · cells per micro-liter
Absolute Concentration of B Cells (Active Treatment Period)
cells per micro-literPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Day 1242 ± 134.2208 ± 117.5247 ± 131.8219 ± 113.7210 ± 97.4
Week 4243 ± 130.8220 ± 92.7277 ± 156.2270 ± 143.2201 ± 114.3
Week 24264 ± 154.9230 ± 119.7235 ± 115.3214 ± 105.0180 ± 114.3
SecondaryAbsolute Concentration of B Cells (Blinded Extension Period)

Absolute concentration of B Cells were reported.

Time frame:
Weeks 48 and 52
Reported as:
Mean · cells per micro-liter
Absolute Concentration of B Cells (Blinded Extension Period)
cells per micro-literEvobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Week 48203 ± 111.9222 ± 148.8187 ± 87.1181 ± 109.8
Week 52227 ± 93.7206 ± 140.3154 ± 73.6135 ± 29.0
SecondaryChange 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
Reported as:
Mean · cells per micro-liter
Change From Baseline in Absolute B Cells (Active Treatment Period)
cells per micro-literPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Week 4-5 ± 94.59 ± 112.231 ± 114.250 ± 86.7-3 ± 111.0
Week 247 ± 135.813 ± 98.2-15 ± 128.5-9 ± 85.1-26 ± 113.9
SecondaryChange 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
Reported as:
Mean · cells per micro-liter
Change From Baseline in Absolute B Cells (Blinded Extension Period)
cells per micro-literEvobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Week 48-5 ± 116.1-30 ± 148.2-32 ± 97.9-15 ± 105.7
Week 52-28 ± 209.8-25 ± 65.5-81 ± 119.015 ± 22.6
SecondaryTotal 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
Reported as:
Mean · Lesions
Total Number of New Gadolinium-positive (Gd+) T1 Lesions
LesionsPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Total Number of New Gadolinium-positive (Gd+) T1 Lesions3.08 ± 4.3713.44 ± 6.8461.20 ± 3.4990.98 ± 3.2733.24 ± 15.320
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Negative Binomial · p = 0.3676 · Lesion rate ratio: 1.36 · 95% CI 0.70 to 2.65
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Negative Binomial · p = 0.0005 · Lesion rate ratio: 0.27 · 95% CI 0.13 to 0.57
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Negative Binomial · p = 0.0157 · Lesion rate ratio: 0.41 · 95% CI 0.20 to 0.85
SecondaryMean 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
Reported as:
Mean · Lesions
Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions
LesionsPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions1.02 ± 1.4391.31 ± 3.1300.42 ± 1.1730.34 ± 0.9601.45 ± 7.293
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.9731 · Hodges-lehmann estimate: 0.00 · 95% CI -0.25 to 0.25
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.0017 · Hodges-lehmann estimate: -0.25 · 95% CI -0.50 to 0.00
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = < 0.0001 · Hodges-lehmann estimate: -0.50 · 95% CI -0.75 to -0.25
SecondaryTotal 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
Reported as:
Mean · Lesions
Total Number of New or Enlarging T2 Lesions
LesionsPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Total Number of New or Enlarging T2 Lesions5.96 ± 6.9946.52 ± 11.5693.41 ± 10.7522.19 ± 4.7195.35 ± 16.667
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Negative Binomial · p = 0.4807 · Lesion rate ratio: 1.29 · 95% CI 0.63 to 2.65
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Negative Binomial · p = 0.0620 · Lesion rate ratio: 0.50 · 95% CI 0.24 to 1.04
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Negative Binomial · p = 0.0189 · Lesion rate ratio: 0.42 · 95% CI 0.20 to 0.87
SecondaryChange 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
Reported as:
Mean · cubic centimeter (cc)
Change From Baseline in Volume of T2 Lesions at Week 24
cubic centimeter (cc)Placebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Baseline in Volume of T2 Lesions at Week 240.42 ± 1.0090.93 ± 1.853-0.01 ± 0.5620.09 ± 0.4630.47 ± 2.964
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Mixed Effect Model for Repeat Measures · p = 0.8776 · Difference in least squares means: 0.02 · 95% CI -0.24 to 0.28Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Mixed Effect Model for Repeat Measures · p = 0.0019 · Difference in least squares means: -0.41 · 95% CI -0.66 to -0.15Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Mixed Effect Model for Repeat Measures · p = 0.0063 · Difference in least squares means: -0.36 · 95% CI -0.62 to -0.10Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
SecondaryChange 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
Reported as:
Mean · cc
Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24
ccPlacebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24-0.023 ± 0.22200.057 ± 0.3479-0.111 ± 0.5416-0.051 ± 0.1032-0.050 ± 0.4771
Statistical analysis
  • Placebo (Period 1) vs Evobrutinib 25 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.9315 · Hodges-lehmann estimate: 0.00 · 95% CI -0.004 to 0.009
  • Placebo (Period 1) vs Evobrutinib 75 mg QD (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.0008 · Hodges-lehmann estimate: -0.014 · 95% CI -0.050 to 0.000
  • Placebo (Period 1) vs Evobrutinib 75 mg BID (Period 1, 2 and 3) · Wilcoxon rank-sum test · p = 0.0014 · Hodges-lehmann estimate: -0.018 · 95% CI -0.042 to 0.000
SecondaryNumber 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
Reported as:
Mean · Lesions
Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48
LesionsPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Number of Gadolinium-positive (Gd+) T1 Lesions at Week 481.00 ± 1.6141.91 ± 4.2960.85 ± 2.8670.49 ± 1.2180.42 ± 1.444
SecondaryNumber 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
Reported as:
Mean · Lesions
Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48
LesionsPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 480.95 ± 1.5691.84 ± 4.1540.85 ± 2.8670.49 ± 1.2180.42 ± 1.444
SecondaryAnnualized 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.

Time frame:
Week 0 to Week 48
Reported as:
Mean · relapses per year
Annualized Relapse Rate (ARR)
relapses per yearPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Annualized Relapse Rate (ARR)0.37 (0.21 to 0.59)0.52 (0.33 to 0.78)0.25 (0.12 to 0.44)0.11 (0.04 to 0.25)0.14 (0.06 to 0.29)
SecondaryQualified 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
Reported as:
Number · percentage of participants
Qualified Relapse-free Status
percentage of participantsPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Qualified Relapse-free Status84.186.478.391.196.0
SecondaryChange 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).

Time frame:
Week 24, Week 48
Reported as:
Mean · Units on a scale
Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48
Units on a scalePlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48-0.05 ± 0.260-0.10 ± 0.351-0.01 ± 0.6190.00 ± 0.238-0.10 ± 0.404
SecondaryTotal 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
Reported as:
Mean · Lesions
Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24
LesionsPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 243.57 ± 4.3465.86 ± 11.3303.84 ± 10.0831.60 ± 3.7991.88 ± 4.796
SecondaryChange 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
Reported as:
Mean · cc
Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48
ccPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 480.092 ± 0.46260.088 ± 0.40060.045 ± 0.22850.024 ± 0.1981-0.203 ± 1.1073
SecondaryChange 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
Reported as:
Mean · cc
Change From Week 24 in Volume of T2 Lesions at Week 48
ccPlacebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Change From Week 24 in Volume of T2 Lesions at Week 480.53 ± 1.3600.67 ± 1.8650.35 ± 1.083-0.03 ± 1.031-0.57 ± 2.699
SecondaryOLE 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
Reported as:
Mean · Lesions
OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions
LesionsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Baseline (BE period Week 48)0.82 ± 2.6681.74 ± 4.3951.46 ± 4.5191.16 ± 3.0502.03 ± 11.829
Week 960.13 ± 0.3410.63 ± 1.8220.49 ± 1.1210.69 ± 1.4110.67 ± 2.255
Week 1440.76 ± 2.2940.41 ± 1.2170.82 ± 3.5120.54 ± 1.1461.29 ± 5.940
Week 1921.00 ± 3.3670.64 ± 1.8900.81 ± 2.2060.84 ± 1.7980.96 ± 3.130
Week 2401.68 ± 5.8000.63 ± 1.9960.37 ± 1.1890.77 ± 2.4170.88 ± 3.204
Week 2880.35 ± 0.6710.35 ± 0.7860.32 ± 1.0901.04 ± 2.9460.35 ± 1.265
Week 3360.83 ± 1.6023.00 ± 5.7451.17 ± 2.8580.29 ± 0.7565.60 ± 18.310
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
Reported as:
Mean · relapses per year
OLE Period: Annualized Relapse Rate (ARR)
relapses per yearPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Baseline (BE period Week 48)0.29 (0.14 to 0.53)0.18 (0.06 to 0.38)0.14 (0.04 to 0.32)0.17 (0.07 to 0.36)0.12 (0.04 to 0.28)
Week 960.16 (0.05 to 0.37)0.13 (0.04 to 0.34)0.09 (0.02 to 0.26)0.08 (0.02 to 0.22)0.03 (0.00 to 0.16)
Week 1440.07 (0.01 to 0.25)0.11 (0.02 to 0.33)0.03 (0.00 to 0.17)0.15 (0.05 to 0.34)0.16 (0.05 to 0.37)
Week 1920.04 (0.00 to 0.20)0.08 (0.01 to 0.29)0.22 (0.09 to 0.45)0.16 (0.05 to 0.38)0.04 (0.00 to 0.20)
Week 2400.16 (0.04 to 0.41)0.04 (0.00 to 0.23)0.10 (0.02 to 0.28)0.13 (0.04 to 0.34)0.00 (NA to 0.15)
Week 2880.13 (0.13 to 0.38)0.05 (0.00 to 0.25)0.07 (0.01 to 0.25)0.00 (NA to 0.13)0.04 (0.00 to 0.24)
Week 3360.00 (NA to 1.75)0.00 (NA to 1.55)0.31 (0.01 to 1.70)0.00 (NA to 1.27)0.00 (NA to 7.97)
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48) up to OLE Week 336
Reported as:
Number · percentage of participants
OLE Period: Percentage of Participants With Qualified Relapse-Free Status
percentage of participantsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Period: Percentage of Participants With Qualified Relapse-Free Status66.768.471.465.983.3
SecondaryOLE 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).

Time frame:
OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240, 288 and 336
Reported as:
Mean · units on a scale
OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336
units on a scalePlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Baseline (BE period Week 48)0.1 ± 0.390.0 ± 0.690.1 ± 0.460.0 ± 0.270.0 ± 0.34
Week 960.1 ± 0.400.1 ± 0.460.2 ± 0.710.0 ± 0.420.0 ± 0.32
Week 1440.1 ± 0.790.1 ± 0.610.2 ± 0.790.0 ± 0.440.0 ± 0.28
Week 1920.2 ± 0.640.1 ± 0.610.2 ± 0.350.2 ± 0.720.0 ± 0.29
Week 2400.3 ± 0.720.3 ± 0.500.2 ± 0.460.2 ± 0.930.1 ± 0.40
Week 2880.4 ± 0.800.1 ± 0.870.4 ± 0.580.4 ± 0.810.2 ± 0.45
Week 3360.0 ± 0.520.5 ± 1.360.7 ± 1.38-0.2 ± 0.570.0 ± 0.52
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48) up to OLE Week 336
Reported as:
Count of participants · Participants
OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
ParticipantsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)3529414037
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48) up to OLE Week 336
Reported as:
Count of participants · Participants
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
ParticipantsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs00000
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48) up to OLE Week 336
Reported as:
Count of participants · Participants
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
ParticipantsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters00000
SecondaryOLE 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.

Time frame:
OLE Baseline (BE period Week 48) up to OLE Week 336
Reported as:
Count of participants · Participants
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)
ParticipantsPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
OLE Period: Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)00000
SecondaryOLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.

Time frame:
OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
Reported as:
Mean · Gram per Liter
OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels
Gram per LiterPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Ig A, OLE Baseline (BE period Week 48)2.31 ± 0.9662.44 ± 0.8972.49 ± 0.9532.52 ± 0.9702.31 ± 0.906
Ig A, Week 722.38 ± 1.0842.53 ± 1.0752.72 ± 1.1372.65 ± 1.0622.43 ± 0.865
Ig A, Week 962.42 ± 1.1732.69 ± 1.0262.91 ± 1.1812.82 ± 1.1132.62 ± 1.072
Ig A, Week 1442.57 ± 1.2742.73 ± 0.9182.82 ± 1.3262.91 ± 1.2332.57 ± 1.025
IgA, Week 1922.60 ± 1.2422.71 ± 0.9872.86 ± 1.2553.15 ± 1.1852.70 ± 1.055
IgA, Week 2402.71 ± 1.2802.85 ± 1.0953.05 ± 1.3143.13 ± 1.2692.65 ± 0.984
IgA, Week 2882.68 ± 1.3053.08 ± 1.2763.12 ± 1.3063.30 ± 1.3472.92 ± 1.108
Ig G, OLE Baseline (BE period Week 48)9.75 ± 2.25310.37 ± 2.51210.73 ± 2.47910.44 ± 2.2919.65 ± 2.165
Ig G, Week 729.63 ± 2.33510.47 ± 2.50910.69 ± 2.51510.42 ± 2.1169.93 ± 2.131
Ig G, Week 969.46 ± 2.49010.10 ± 2.46110.76 ± 2.41310.29 ± 2.1729.93 ± 2.285
Ig G, Week 1449.48 ± 2.29410.43 ± 2.30410.38 ± 2.63810.21 ± 2.5529.32 ± 2.115
IgG, Week 1929.37 ± 2.1569.99 ± 2.19710.36 ± 2.54810.46 ± 2.1359.56 ± 2.094
IgG, Week 2409.28 ± 2.08110.33 ± 2.42210.47 ± 2.56210.47 ± 2.5629.58 ± 2.245
IgG, Week 2889.46 ± 2.06810.48 ± 2.54110.64 ± 2.56610.36 ± 2.2739.72 ± 2.700
Ig M, OLE Baseline (BE period Week 48)1.06 ± 0.5500.89 ± 0.4031.08 ± 0.6800.92 ± 0.4220.99 ± 0.586
Ig M, Week 721.03 ± 0.5510.87 ± 0.3971.05 ± 0.7580.91 ± 0.4250.94 ± 0.561
Ig M, Week 961.01 ± 0.5560.87 ± 0.4131.05 ± 0.7470.92 ± 0.4600.91 ± 0.525
Ig M, Week 1440.88 ± 0.4630.88 ± 0.4680.94 ± 0.6140.89 ± 0.3770.90 ± 0.519
Ig M, Week 1920.89 ± 0.4920.87 ± 0.4610.90 ± 0.4620.84 ± 0.3200.90 ± 0.585
Ig M, Week 2400.85 ± 0.4200.83 ± 0.4190.87 ± 0.4680.88 ± 0.3690.87 ± 0.611
Ig M, Week 2880.85 ± 0.4050.90 ± 0.4900.94 ± 0.5440.87 ± 0.3971.03 ± 0.568
SecondaryOLE Period: Change From Baseline in Immunoglobulin (Ig) Levels

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

Time frame:
OLE Baseline (BE period Week 48), OLE Weeks 96, 144, 192, 240 and 288
Reported as:
Mean · Gram per Liter
OLE Period: Change From Baseline in Immunoglobulin (Ig) Levels
Gram per LiterPlacebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)
Ig A, OLE Baseline (BE period Week 48)0.26 ± 0.2370.17 ± 0.3330.19 ± 0.2830.26 ± 0.2910.28 ± 0.355
Ig A, Week 720.40 ± 0.3980.36 ± 0.5150.41 ± 0.4170.38 ± 0.4530.42 ± 0.368
Ig A, Week 960.44 ± 0.4910.45 ± 0.4070.58 ± 0.4850.54 ± 0.4460.59 ± 0.545
Ig A, Week 1440.58 ± 0.5940.41 ± 0.3470.50 ± 0.6700.57 ± 0.5890.54 ± 0.452
IgA, Week 1920.60 ± 0.5970.38 ± 0.4430.55 ± 0.6670.82 ± 0.5300.67 ± 0.492
IgA, Week 2400.67 ± 0.6050.55 ± 0.4710.74 ± 0.6820.78 ± 0.6210.68 ± 0.520
IgA, Week 2880.68 ± 0.9340.75 ± 0.6800.91 ± 0.9151.02 ± 0.6370.93 ± 0.724
Ig G, OLE Baseline (BE period Week 48)0.39 ± 0.9600.54 ± 1.4630.69 ± 1.1471.11 ± 1.1500.23 ± 1.216
Ig G, Week 720.40 ± 1.0190.56 ± 1.3640.79 ± 1.2361.07 ± 0.9940.48 ± 1.288
Ig G, Week 960.17 ± 1.3590.18 ± 1.2280.64 ± 1.1780.84 ± 1.0730.47 ± 1.355
Ig G, Week 1440.35 ± 1.3670.17 ± 1.4510.31 ± 1.3560.68 ± 1.458-0.09 ± 1.176
IgG, Week 1920.14 ± 1.227-0.13 ± 1.1410.18 ± 1.6250.84 ± 1.3840.09 ± 1.324
IgG, Week 240-0.01 ± 1.3360.10 ± 1.5570.37 ± 1.5960.75 ± 1.3620.19 ± 1.314
IgG, Week 2880.18 ± 1.4920.48 ± 1.4650.37 ± 2.2031.01 ± 1.5700.36 ± 1.440
Ig M, OLE Baseline (BE period Week 48)-0.18 ± 0.152-0.10 ± 0.120-0.09 ± 0.122-0.05 ± 0.099-0.28 ± 0.280
IgM, Week 72-0.19 ± 0.170-0.11 ± 0.119-0.10 ± 0.147-0.07 ± 0.104-0.34 ± 0.264
IgM, Week 96-0.23 ± 0.146-0.13 ± 0.141-0.09 ± 0.199-0.08 ± 0.127-0.35 ± 0.301
IgM, Week 144-0.28 ± 0.323-0.14 ± 0.195-0.17 ± 0.174-0.11 ± 0.149-0.40 ± 0.327
IgM, Week 192-0.28 ± 0.254-0.16 ± 0.204-0.19 ± 0.186-0.18 ± 0.197-0.46 ± 0.330
IgM, Week 240-0.29 ± 0.282-0.20 ± 0.187-0.19 ± 0.205-0.16 ± 0.254-0.53 ± 0.348
IgM, Week 288-0.29 ± 0.284-0.11 ± 0.313-0.15 ± 0.315-0.17 ± 0.178-0.39 ± 0.472

Adverse events

Collected over Baseline up to Safety Follow up of blinded extension period (Week 52); OLE Baseline (BE period Week 48) up to OLE Week 336. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo (Period 1)0/54 (0%)2/54 (3.7%)14/54 (25.9%)
Placebo Then Evobrutinib 25 mg QD (Period 2)0/49 (0%)0/49 (0%)9/49 (18.4%)
Evobrutinib 25 mg QD (Period 1 and Period 2)0/52 (0%)2/52 (3.8%)19/52 (36.5%)
Evobrutinib 75 mg QD (Period 1 and Period 2)0/53 (0%)2/53 (3.8%)19/53 (35.8%)
Evobrutinib 75 mg BID (Period 1 and Period 2)0/54 (0%)4/54 (7.4%)20/54 (37%)
Tecfidera (Period 1 and Period 2)0/54 (0%)2/54 (3.7%)30/54 (55.6%)
Placebo + Evobrutinib 25 mg QD (Period 3)0/39 (0%)7/39 (17.9%)30/39 (76.9%)
Evobrutinib 25 mg QD (Period 3)1/39 (2.6%)12/39 (30.8%)26/39 (66.7%)
Evobrutinib 75 mg QD (Period 3)0/42 (0%)8/42 (19%)34/42 (81%)
Evobrutinib 75 mg BID (Period 3)1/44 (2.3%)5/44 (11.4%)31/44 (70.5%)
Tecfidera (Period 3)1/49 (2%)10/49 (20.4%)26/49 (53.1%)
Most frequent serious events
Showing 10 of 69
Most frequent serious events
EventPlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1 and Period 2)Evobrutinib 75 mg QD (Period 1 and Period 2)Evobrutinib 75 mg BID (Period 1 and Period 2)Tecfidera (Period 1 and Period 2)Placebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 3)Evobrutinib 75 mg QD (Period 3)Evobrutinib 75 mg BID (Period 3)Tecfidera (Period 3)
PneumoniaInfections and infestations1/540/490/520/530/540/540/392/390/420/440/49
OsteonecrosisMusculoskeletal and connective tissue disorders0/540/490/520/530/540/540/390/392/420/440/49
COVID-19 pneumoniaInfections and infestations0/540/490/520/530/540/540/391/390/420/442/49
Restless legs syndromeNervous system disorders0/540/490/520/531/540/541/390/390/420/440/49
Abortion spontaneousPregnancy, puerperium and perinatal conditions0/540/490/521/530/540/540/391/390/420/440/49
Microcytic anaemiaBlood and lymphatic system disorders0/540/490/520/530/540/540/391/390/420/440/49
Myocardial ischaemiaCardiac disorders0/540/490/520/530/540/541/390/390/420/440/49
Sinus tachycardiaCardiac disorders0/540/490/520/530/540/540/391/390/420/440/49
Supraventricular tachycardiaCardiac disorders0/540/490/520/530/540/540/391/390/420/440/49
CholelithiasisHepatobiliary disorders0/540/490/520/530/540/540/391/391/420/441/49
Most frequent other events
Showing 10 of 46
Most frequent other events
EventPlacebo (Period 1)Placebo Then Evobrutinib 25 mg QD (Period 2)Evobrutinib 25 mg QD (Period 1 and Period 2)Evobrutinib 75 mg QD (Period 1 and Period 2)Evobrutinib 75 mg BID (Period 1 and Period 2)Tecfidera (Period 1 and Period 2)Placebo + Evobrutinib 25 mg QD (Period 3)Evobrutinib 25 mg QD (Period 3)Evobrutinib 75 mg QD (Period 3)Evobrutinib 75 mg BID (Period 3)Tecfidera (Period 3)
FlushingVascular disorders0/540/490/520/530/5412/540/390/390/420/440/49
Back painMusculoskeletal and connective tissue disorders0/540/490/520/530/540/541/395/399/423/440/49
COVID-19Infections and infestations0/540/490/520/530/540/546/398/393/426/447/49
NasopharyngitisInfections and infestations5/541/499/523/537/542/547/397/398/429/444/49
Lipase increasedInvestigations2/543/492/525/535/543/545/396/396/428/445/49
Urinary tract infectionInfections and infestations3/540/492/521/530/540/547/395/397/425/443/49
Upper respiratory tract infectionInfections and infestations0/540/491/521/531/543/545/392/396/424/443/49
HeadacheNervous system disorders2/540/493/522/531/541/543/392/395/426/444/49
ErythemaSkin and subcutaneous tissue disorders0/540/490/520/530/547/540/390/390/420/440/49
ArthralgiaMusculoskeletal and connective tissue disorders1/540/492/523/530/544/545/393/391/422/442/49

Baseline characteristics

Modified Intent-To-Treat (mITT) analysis set included participants who belong to both Intent To Treat (ITT, consisted all participants who randomly allocated to a treatment, based on the intention to treat "as randomized" principle) and safety analysis sets (consisted all participants who receive at least 1 dose of trial treatment), and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.

Age, Continuous
Age, Continuous(Years)Placebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)Total
Mean41.6 ± 10.7742.4 ± 9.3742.9 ± 10.0742.2 ± 11.5042.8 ± 11.7042.4 ± 10.67
Sex: Female, Male
Sex: Female, Male(Participants)Placebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)Total
Female3932353639181
Male141816171580
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Placebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)Total
Hispanic or Latino110125
Not Hispanic or Latino5249515252256
Unknown or Not Reported000000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Placebo (Period 1)Evobrutinib 25 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg QD (Period 1, 2 and 3)Evobrutinib 75 mg BID (Period 1, 2 and 3)Tecfidera (Period 1, 2 and 3)Total
American Indian or Alaska Native000000
Asian000000
Native Hawaiian or Other Pacific Islander000000
Black or African American000000
White5350515354261
More than one race000000
Unknown or Not Reported000000
08

Study locations

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

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. PubMed 31075187 ↗
  • 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. PubMed 38335474 ↗
  • 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. PubMed 36126241 ↗
  • 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. PubMed 36418156 ↗
  • 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. PubMed 37626477 ↗

Study documents

  • Study protocol · Jul 6, 2023
  • Statistical analysis plan · Jun 3, 2024

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol, Sap, Csr, Analytic code

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 14, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT02975349
Lead sponsor
EMD Serono Research & Development Institute, Inc.
Collaborators
Merck KGaA, Darmstadt, Germany
Responsible party
Sponsor
First posted
Nov 29, 2016
Start date
Mar 7, 2017
Primary completion
Jan 24, 2018
Completion
Apr 2, 2024
Results posted
Feb 5, 2021
Last update
May 14, 2025

Study contacts

Medical Responsible
study director · EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in May 2025. You cannot join it, but the record below documents what was studied.

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