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

Sponsor
EMD Serono Research & Development Institute, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02975349
Collaborator
Merck KGaA, Darmstadt, Germany (Industry)
267
Enrollment
56
Locations
6
Arms
95.3
Anticipated Duration (Months)
4.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
267 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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.
Actual Study Start Date :
Mar 7, 2017
Actual Primary Completion Date :
Jan 24, 2018
Anticipated Study Completion Date :
Feb 15, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Placebo then Evobrutinib 25 mg QD

Participants who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 milligram (mg) orally, once daily (QD) in blinded extension (BE) period from week 25 to week 48.

Drug: Placebo
Placebo were administered for 24 weeks

Drug: Evobrutinib
Following Placebo for 24 weeks, participants received Evobrutinib 25 milligram (mg) orally, once daily (QD) from Week 24 to 48 weeks.
Other Names:
  • M2951

    		•
    Experimental: Evobrutinib 25 mg QD

    Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period.

    Drug: Evobrutinib
    Participants received Evobrutinib 25 mg orally, once daily (QD) up to Week 48
    Other Names:
  • M2951

    		•
    Experimental: Evobrutinib 75 mg QD

    Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period.

    Drug: Evobrutinib
    Participants received Evobrutinib 75 mg orally, QD up to Week 48
    Other Names:
  • M2951

    		•
    Experimental: Evobrutinib 75 mg BID

    Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period.

    Drug: Evobrutinib
    Participants received Evobrutinib 75 milligrams (mg) orally, twice daily (BID) up to Week 48
    Other Names:
  • M2951

    		•
    Active Comparator: 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.

    Drug: Tecfidera
    Tecfidera; 120 mg hard capsule BID for 7 days then 240 mg hard capsule BID for duration of treatment (48 weeks).
    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

    Outcome Measures

    Primary Outcome Measures

    1. Total Number of Gadolinium-Enhancing T1 Lesions [Week 12 to Week 24]

      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.

    Secondary Outcome Measures

    1. Annualized Relapse Rate (ARR) at Week 24 [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.

    2. Qualified Relapse-Free Status at Week 24 [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.

    3. Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24 [Baseline, 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.

    4. Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death [Baseline up to Safety Follow-up (Week 52)]

      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.

    5. Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs) [Baseline up to Safety Follow-up (Week 52)]

      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.

    6. Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values [Baseline up to Safety Follow-up (Week 52)]

      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.

    7. Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period) [Baseline (Day 1), Weeks 4, 16, and 24]

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

    8. Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period) [Weeks 48]

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

    9. Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period) [Baseline (Day 1), Weeks 4, 16, and 24]

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

    10. Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period) [Baseline (Day 1), Week 48]

      Change in the serum levels of IgG, IgA, IgM were to be assessed.

    11. Absolute Numbers of B Cells (Active Treatment Period) [Baseline (Day 1), Weeks 4, and 24]

      Absolute Numbers of B Cells are reported.

    12. Absolute Numbers of B Cells (Blinded Extension Period) [Weeks 48 and 52]

      Absolute Numbers of B Cells to be reported.

    13. Change From Baseline in Absolute B Cells (Active Treatment Period) [Baseline (Day 1), Weeks 4, and 24]

      Change from baseline in absolute B cells are reported.

    14. Change From Baseline in Absolute B Cells (Blinded Extension Period) [Weeks 48 and 52]

      Change from baseline in absolute B cells to be reported.

    15. Total Number of New Gadolinium-positive (Gd+) T1 Lesions [Week 12 to 24]

      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.

    16. Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions [Week 12 to Week 24]

      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.

    17. Total Number of New or Enlarging T2 Lesions [Week 12 to Week 24]

      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.

    18. Change From Baseline in Volume of T2 Lesions at Week 24 [Baseline, 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.

    19. Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24 [Baseline, 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.

    20. Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48 [Week 48]

      Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.

    21. Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48 [Week 48]

      Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.

    22. Annualized Relapse Rate (ARR) [Week 0 to Week 48]

      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.

    23. Qualified Relapse-free Status [Week 25 to Week 48]

      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.

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

    25. Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24 [Week 24 to Week 48]

      Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.

    26. Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48 [Week 24, Week 48]

      Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.

    27. Change From Week 24 in Volume of T2 Lesions at Week 48 [Week 24, Week 48]

      Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    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:

    • 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Blagoevgrad Bulgaria 2700
    2 Research Site Dupnitsa Bulgaria 2600
    3 Research Site 1 Pleven Bulgaria 5800
    4 Research Site 2 Pleven Bulgaria 5800
    5 Research Site Ruse Bulgaria 7002
    6 Research Site Sofia Bulgaria 1142
    7 Research Site Sofia Bulgaria 1309
    8 Research Site Sofia Bulgaria 1336
    9 Research Site Sofia Bulgaria 1407
    10 Research Site Sofia Bulgaria 1431
    11 Research Site Sofia Bulgaria 1606
    12 Research Site Sofia Bulgaria 1797
    13 Research Site Brno Czechia 656 91
    14 Research Site Hradec Kralove Czechia 500 05
    15 Research Site Hradec Kralove Czechia 50003
    16 Research Site Jihlava Czechia 58633
    17 Research Site Prague 5 Czechia 150 06
    18 Research Site Teplice Czechia 41529
    19 Research Site Bydgoszcz Poland 85-654
    20 Research Site Katowice Poland 40-595
    21 Research Site Katowice Poland 40-650
    22 Research Site Lodz Poland 90-324
    23 Research Site Lublin Poland 20-605
    24 Research Site Oswiecim Poland 32-600
    25 Research Site Plewiska Poland 62-064
    26 Research Site Poznan Poland 61-853
    27 Research Site Rzeszow Poland 35-055
    28 Research Site Warszawa Poland 01-697
    29 Research Site Kazan Russian Federation 420021
    30 Research Site Krasnoyarsk Russian Federation 660037
    31 Research Site Krasnoyarsk Russian Federation 660049
    32 Research Site Moscow Russian Federation 129128
    33 Research Site Novosibirsk Russian Federation 630102
    34 Research Site Perm Russian Federation 614000
    35 Research Site Saransk Russian Federation 430032
    36 Research Site Belgrade Serbia 11000
    37 Research Site Kragujevac Serbia 34000
    38 Research Site Nis Serbia 18000
    39 Research Site Uzice Serbia 31000
    40 Research Site Banska Bystrica Slovakia 97404
    41 Research Site Bratislava Slovakia 85101
    42 Research Site Dubnica nad Vahom Slovakia 01841
    43 Research Site A Coruña Spain 15006
    44 Research Site Barcelona Spain 08003
    45 Research Site Barcelona Spain 08035
    46 Research Site Chernivtsi Ukraine 58018
    47 Research Site Ivano-Frankivsk Ukraine 76008
    48 Research Site Kharkiv Ukraine 61058
    49 Research Site Kharkiv Ukraine 61068
    50 Research Site Kharkiv Ukraine 61103
    51 Research Site Kyiv Ukraine 01601
    52 Research Site Kyiv Ukraine 03110
    53 Research Site Lviv Ukraine 79010
    54 Research Site Poltava Ukraine 36011
    55 Research Site Zaporizhzhia Ukraine 69035
    56 Research Site Zaporizhzhia Ukraine 69600

    Sponsors and Collaborators

    • EMD Serono Research & Development Institute, Inc.
    • Merck KGaA, Darmstadt, Germany

    Investigators

    • Study Director: Medical Responsible, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    EMD Serono Research & Development Institute, Inc.
    ClinicalTrials.gov Identifier:
    NCT02975349
    Other Study ID Numbers:
    • MS200527-0086
    • 2016-001448-21
    First Posted:
    Nov 29, 2016
    Last Update Posted:
    May 27, 2021
    Last Verified:
    Apr 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by EMD Serono Research & Development Institute, Inc.
    M2951
    Relapsing Multiple Sclerosis
    Bruton's Tyrosine Kinase inhibitor
    Additional relevant MeSH terms:
    Multiple Sclerosis
    Multiple Sclerosis, Relapsing-Remitting
    Sclerosis
    Dimethyl Fumarate

    Study Results

    Participant Flow

    Recruitment Details The study consisted of a 24-week active treatment period, 24-week blinded extension (BE) period and a 96-week open-label extension period. Primary and secondary outcome measures were planned to be analyzed for active treatment and blinded extension period only. Open-label extension period is ongoing. Primary completion was achieved based on Active treatment period. Complete results will be updated within 1 year of study completion date.
    Pre-assignment Detail
    Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Period Title: Active Treatment Period (24 Weeks)
    STARTED 54 0 52 53 54 54
    COMPLETED 49 0 47 48 48 52
    NOT COMPLETED 5 0 5 5 6 2
    Period Title: Active Treatment Period (24 Weeks)
    STARTED 0 49 47 48 48 52
    COMPLETED 0 42 43 44 46 52
    NOT COMPLETED 0 7 4 4 2 0

    Baseline Characteristics

    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera Total
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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. Total of all reporting groups
    Overall Participants 53 50 51 53 54 261
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    41.6
    (10.77)
    42.4
    (9.37)
    42.9
    (10.07)
    42.2
    (11.50)
    42.8
    (11.70)
    42.4
    (10.67)
    Sex: Female, Male (Count of Participants)
    Female
    39
    73.6%
    32
    64%
    35
    68.6%
    36
    67.9%
    39
    72.2%
    181
    69.3%
    Male
    14
    26.4%
    18
    36%
    16
    31.4%
    17
    32.1%
    15
    27.8%
    80
    30.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    1.9%
    1
    2%
    0
    0%
    1
    1.9%
    2
    3.7%
    5
    1.9%
    Not Hispanic or Latino
    52
    98.1%
    49
    98%
    51
    100%
    52
    98.1%
    52
    96.3%
    256
    98.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    53
    100%
    50
    100%
    51
    100%
    53
    100%
    54
    100%
    261
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Total Number of Gadolinium-Enhancing T1 Lesions
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [Lesions]
    3.85
    (5.436)
    4.06
    (8.024)
    1.69
    (4.693)
    1.15
    (3.702)
    4.78
    (22.045)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2947
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 1.45
    Confidence Interval (2-Sided) 95%
    0.72 to 2.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0015
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 0.30
    Confidence Interval (2-Sided) 95%
    0.14 to 0.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0313
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 0.44
    Confidence Interval (2-Sided) 95%
    0.21 to 0.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Annualized Relapse Rate (ARR) at Week 24
    Description 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

    Outcome Measure Data

    Analysis Population Description
    The modified ITT (mITT) analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (95% Confidence Interval) [relapses per year]
    0.37
    0.57
    0.13
    0.08
    0.20
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2692
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Qualified relapse rate ratio
    Estimated Value 1.66
    Confidence Interval (2-Sided) 95%
    0.67 to 4.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0896
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Qualified relapse rate ratio
    Estimated Value 0.31
    Confidence Interval (2-Sided) 95%
    0.08 to 1.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0633
    Comments
    Method Negative Binomial model
    Comments
    Method of Estimation Estimation Parameter Qualified relapse rate ratio
    Estimated Value 0.23
    Confidence Interval (2-Sided) 95%
    0.05 to 1.09
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Qualified Relapse-Free Status at Week 24
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline MRI assessment.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Number (95% Confidence Interval) [percentage of participants]
    77.4
    146%
    74.0
    148%
    88.2
    172.9%
    86.8
    163.8%
    88.9
    164.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5609
    Comments
    Method Logistic model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.29 to 1.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0689
    Comments
    Method Logistic model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.79
    Confidence Interval (2-Sided) 95%
    0.92 to 8.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1767
    Comments
    Method Logistic model
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 2.08
    Confidence Interval (2-Sided) 95%
    0.72 to 5.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [Units on a scale]
    -0.03
    (0.301)
    0.02
    (0.622)
    -0.14
    (0.664)
    0.04
    (0.216)
    0.02
    (0.274)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4070
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    0.00 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5829
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    0.00 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2732
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    0.00 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
    Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 54 49 52 53 54 54
    TEAEs
    24
    45.3%
    19
    38%
    28
    54.9%
    35
    66%
    34
    63%
    35
    13.4%
    Serious TEAEs
    2
    3.8%
    0
    0%
    2
    3.9%
    2
    3.8%
    4
    7.4%
    2
    0.8%
    TEAEs Leading to Death
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    6. Secondary Outcome
    Title Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
    Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 54 49 52 53 54 54
    Vital Sign Abnormalities
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    ECG Abnormalities
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    7. Secondary Outcome
    Title Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose of evobrutinib or placebo or Tecfidera.
    Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 54 49 52 53 54 54
    Grade >= 3 hematology values
    0
    0%
    2
    4%
    0
    0%
    1
    1.9%
    0
    0%
    1
    0.4%
    Grade >= 3 biochemistry values
    2
    3.8%
    8
    16%
    6
    11.8%
    9
    17%
    16
    29.6%
    9
    3.4%
    Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values
    0
    0%
    2
    4%
    1
    2%
    2
    3.8%
    2
    3.7%
    6
    2.3%
    8. Secondary Outcome
    Title Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)
    Description Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
    Time Frame Baseline (Day 1), Weeks 4, 16, and 24

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time points.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 54 52 53 54 54
    Ig A, Day 1
    1.99
    (0.777)
    1.89
    (0.764)
    1.90
    (0.722)
    1.87
    (0.675)
    2.03
    (0.763)
    Ig A, Week 4
    1.98
    (0.777)
    1.92
    (0.770)
    1.93
    (0.762)
    1.94
    (0.748)
    1.90
    (0.699)
    Ig A, Week 16
    2.07
    (0.824)
    2.10
    (0.813)
    2.13
    (0.832)
    2.08
    (0.753)
    2.03
    (0.752)
    Ig A, Week 24
    1.99
    (0.807)
    2.12
    (0.833)
    2.09
    (0.838)
    2.09
    (0.793)
    1.97
    (0.757)
    Ig G, Day 1
    9.61
    (1.897)
    9.43
    (2.126)
    9.81
    (1.841)
    9.62
    (1.960)
    9.47
    (1.839)
    Ig G, Week 4
    9.64
    (2.094)
    9.34
    (1.972)
    9.79
    (1.910)
    9.64
    (1.987)
    9.05
    (1.922)
    Ig G, Week 16
    9.68
    (2.085)
    9.41
    (2.077)
    9.70
    (1.991)
    9.56
    (2.129)
    9.58
    (1.850)
    Ig G, Week 24
    9.66
    (2.081)
    9.46
    (2.123)
    9.62
    (2.048)
    9.36
    (1.988)
    9.27
    (1.866)
    Ig M, Day 1
    1.42
    (0.692)
    1.27
    (0.542)
    1.44
    (0.716)
    1.33
    (0.684)
    1.27
    (0.589)
    Ig M, Week 4
    1.40
    (0.668)
    1.21
    (0.526)
    1.32
    (0.654)
    1.28
    (0.656)
    1.23
    (0.603)
    Ig M, Week 16
    1.43
    (0.703)
    1.13
    (0.558)
    1.24
    (0.639)
    1.20
    (0.689)
    1.28
    (0.678)
    Ig M, Week 24
    1.44
    (0.748)
    1.03
    (0.499)
    1.20
    (0.672)
    1.08
    (0.494)
    1.29
    (0.667)
    9. Secondary Outcome
    Title Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)
    Description Absolute Concentrations serum levels of IgG, IgA, IgM were to be assessed.
    Time Frame Weeks 48

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)
    Description Change in the serum levels of IgG, IgA, IgM were assessed.
    Time Frame Baseline (Day 1), Weeks 4, 16, and 24

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time points.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 54 50 53 54 54
    Ig A, Week 4
    -0.02
    (0.201)
    0.02
    (0.165)
    0.04
    (0.169)
    0.07
    (0.195)
    -0.13
    (0.238)
    Ig A, Week 16
    0.10
    (0.188)
    0.18
    (0.245)
    0.21
    (0.313)
    0.22
    (0.209)
    -0.02
    (0.274)
    Ig A, Week 24
    0.06
    (0.250)
    0.21
    (0.283)
    0.18
    (0.416)
    0.22
    (0.229)
    -0.06
    (0.207)
    Ig G, Week 4
    0.02
    (0.758)
    -0.10
    (0.697)
    -0.02
    (0.688)
    0.02
    (0.581)
    -0.42
    (0.926)
    Ig G, Week 16
    0.04
    (0.747)
    -0.07
    (0.964)
    -0.10
    (1.068)
    -0.05
    (0.710)
    0.07
    (0.961)
    Ig G, Week 24
    0.06
    (0.682)
    0.00
    (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 16
    0.02
    (0.177)
    -0.12
    (0.184)
    -0.18
    (0.244)
    -0.14
    (0.189)
    -0.00
    (0.184)
    Ig M, Week 24
    0.04
    (0.163)
    -0.14
    (0.286)
    -0.20
    (0.289)
    -0.21
    (0.167)
    -0.00
    (0.186)
    11. Secondary Outcome
    Title Change From Baseline in Immunoglobulin (Ig) Levels (Blinded Extension Period)
    Description Change in the serum levels of IgG, IgA, IgM were to be assessed.
    Time Frame Baseline (Day 1), Week 48

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    Title Absolute Numbers of B Cells (Active Treatment Period)
    Description Absolute Numbers of B Cells are reported.
    Time Frame Baseline (Day 1), Weeks 4, and 24

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time points.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 52 52 53 53 52
    Day 1
    242
    (134.2)
    208
    (117.5)
    247
    (131.8)
    219
    (113.7)
    210
    (97.4)
    Week 4
    243
    (130.8)
    220
    (92.7)
    277
    (156.2)
    270
    (143.2)
    201
    (114.3)
    Week 24
    264
    (154.9)
    230
    (119.7)
    235
    (115.3)
    214
    (105.0)
    180
    (114.3)
    13. Secondary Outcome
    Title Absolute Numbers of B Cells (Blinded Extension Period)
    Description Absolute Numbers of B Cells to be reported.
    Time Frame Weeks 48 and 52

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    Title Change From Baseline in Absolute B Cells (Active Treatment Period)
    Description Change from baseline in absolute B cells are reported.
    Time Frame Baseline (Day 1), Weeks 4, and 24

    Outcome Measure Data

    Analysis Population Description
    The safety analysis set included of all participants who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number Analyzed" signified those participants who were evaluable for the specified category at given time points.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 52 50 53 53 52
    Week 4
    -5
    (94.5)
    9
    (112.2)
    31
    (114.2)
    50
    (86.7)
    -3
    (111.0)
    Week 24
    7
    (135.8)
    13
    (98.2)
    -15
    (128.5)
    -9
    (85.1)
    -26
    (113.9)
    15. Secondary Outcome
    Title Change From Baseline in Absolute B Cells (Blinded Extension Period)
    Description Change from baseline in absolute B cells to be reported.
    Time Frame Weeks 48 and 52

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Secondary Outcome
    Title Total Number of New Gadolinium-positive (Gd+) T1 Lesions
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [Lesions]
    3.08
    (4.371)
    3.44
    (6.846)
    1.20
    (3.499)
    0.98
    (3.273)
    3.24
    (15.320)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3676
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 1.36
    Confidence Interval (2-Sided) 95%
    0.70 to 2.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 0.27
    Confidence Interval (2-Sided) 95%
    0.13 to 0.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0157
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion rate ratio
    Estimated Value 0.41
    Confidence Interval (2-Sided) 95%
    0.20 to 0.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [Lesions]
    1.02
    (1.439)
    1.31
    (3.130)
    0.42
    (1.173)
    0.34
    (0.960)
    1.45
    (7.293)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9731
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.25 to 0.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value -0.25
    Confidence Interval (2-Sided) 95%
    -0.50 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value -0.50
    Confidence Interval (2-Sided) 95%
    -0.75 to -0.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Total Number of New or Enlarging T2 Lesions
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [Lesions]
    5.96
    (6.994)
    6.52
    (11.569)
    3.41
    (10.752)
    2.19
    (4.719)
    5.35
    (16.667)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4807
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion Rate ratio
    Estimated Value 1.29
    Confidence Interval (2-Sided) 95%
    0.63 to 2.65
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0620
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion Rate ratio
    Estimated Value 0.50
    Confidence Interval (2-Sided) 95%
    0.24 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0189
    Comments
    Method Negative Binomial
    Comments
    Method of Estimation Estimation Parameter Lesion Rate ratio
    Estimated Value 0.42
    Confidence Interval (2-Sided) 95%
    0.20 to 0.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Change From Baseline in Volume of T2 Lesions at Week 24
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 46 48 46 50
    Mean (Standard Deviation) [cubic centimeter (cc)]
    0.42
    (1.009)
    0.93
    (1.853)
    -0.01
    (0.562)
    0.09
    (0.463)
    0.47
    (2.964)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8776
    Comments
    Method Mixed Effect Model for Repeat Measures
    Comments
    Method of Estimation Estimation Parameter Difference in least squares means
    Estimated Value 0.02
    Confidence Interval (2-Sided) 95%
    -0.24 to 0.28
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0019
    Comments
    Method Mixed Effect Model for Repeat Measures
    Comments
    Method of Estimation Estimation Parameter Difference in least squares means
    Estimated Value -0.41
    Confidence Interval (2-Sided) 95%
    -0.66 to -0.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0063
    Comments
    Method Mixed Effect Model for Repeat Measures
    Comments
    Method of Estimation Estimation Parameter Difference in least squares means
    Estimated Value -0.36
    Confidence Interval (2-Sided) 95%
    -0.62 to -0.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
    20. Secondary Outcome
    Title Change From Baseline in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 24
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
    Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (Standard Deviation) [cc]
    -0.023
    (0.2220)
    0.057
    (0.3479)
    -0.111
    (0.5416)
    -0.051
    (0.1032)
    -0.050
    (0.4771)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9315
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.004 to 0.009
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0008
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value -0.014
    Confidence Interval (2-Sided) 95%
    -0.050 to 0.000
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0014
    Comments
    Method Wilcoxon rank-sum test
    Comments
    Method of Estimation Estimation Parameter Hodges-Lehmann estimate
    Estimated Value -0.018
    Confidence Interval (2-Sided) 95%
    -0.042 to 0.000
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Secondary Outcome
    Title Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48
    Description Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Mean (Standard Deviation) [Lesions]
    1.00
    (1.614)
    1.91
    (4.296)
    0.85
    (2.867)
    0.49
    (1.218)
    0.42
    (1.444)
    22. Secondary Outcome
    Title Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48
    Description Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Mean (Standard Deviation) [Lesions]
    0.95
    (1.569)
    1.84
    (4.154)
    0.85
    (2.867)
    0.49
    (1.218)
    0.42
    (1.444)
    23. Secondary Outcome
    Title Annualized Relapse Rate (ARR)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT analysis set consists of all participants who belong to both the ITT and safety analysis sets, and who have at least one baseline and one post-baseline magnetic resonance imaging (MRI) assessment.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 53 50 51 53 54
    Mean (95% Confidence Interval) [relapses per year]
    0.37
    0.52
    0.25
    0.11
    0.14
    24. Secondary Outcome
    Title Qualified Relapse-free Status
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Number [percentage of participants]
    84.1
    158.7%
    86.4
    172.8%
    78.3
    153.5%
    91.1
    171.9%
    96.0
    177.8%
    25. Secondary Outcome
    Title Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48
    Description 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

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Mean (Standard Deviation) [Units on a scale]
    -0.05
    (0.260)
    -0.10
    (0.351)
    -0.01
    (0.619)
    0.00
    (0.238)
    -0.10
    (0.404)
    26. Secondary Outcome
    Title Total Number of New or Enlarging T2 Lesions at Week 48 Relative to Week 24
    Description Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.
    Time Frame Week 24 to Week 48

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period. Here, "Number of Participants Analyzed" signified those participants who were evaluable for this outcome measure.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 42 42 43 43 50
    Mean (Standard Deviation) [Lesions]
    3.57
    (4.346)
    5.86
    (11.330)
    3.84
    (10.083)
    1.60
    (3.799)
    1.88
    (4.796)
    27. Secondary Outcome
    Title Change From Week 24 in Volume of Gadolinium-positive (Gd+) T1 Lesions at Week 48
    Description Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
    Time Frame Week 24, Week 48

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Mean (Standard Deviation) [cc]
    0.092
    (0.4626)
    0.088
    (0.4006)
    0.045
    (0.2285)
    0.024
    (0.1981)
    -0.203
    (1.1073)
    28. Secondary Outcome
    Title Change From Week 24 in Volume of T2 Lesions at Week 48
    Description Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.
    Time Frame Week 24, Week 48

    Outcome Measure Data

    Analysis Population Description
    mITT BE analysis set included all participants who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.
    Arm/Group Title Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
    Arm/Group Description 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    Measure Participants 44 44 46 45 50
    Mean (Standard Deviation) [cc]
    0.53
    (1.360)
    0.67
    (1.865)
    0.35
    (1.083)
    -0.03
    (1.031)
    -0.57
    (2.699)

    Adverse Events

    Time Frame Baseline up to Safety Follow up of blinded extension period (Week 52)
    Adverse Event Reporting Description
    Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD 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)
    Arm/Group Description Participants received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1. 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. Participants received Evobrutinib 25 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, QD up to Week 48 in active treatment period 1 and BE period. Participants received Evobrutinib 75 mg orally, twice daily (BID) up to Week 48 in active treatment period 1 and BE period. 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.
    All Cause Mortality
    Placebo Placebo Then Evobrutinib 25 mg QD 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Serious Adverse Events
    Placebo Placebo Then Evobrutinib 25 mg QD 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/54 (3.7%) 0/49 (0%) 2/52 (3.8%) 2/53 (3.8%) 4/54 (7.4%) 2/54 (3.7%)
    Hepatobiliary disorders
    Hepatitis toxic 0/54 (0%) 0/49 (0%) 1/52 (1.9%) 0/53 (0%) 1/54 (1.9%) 0/54 (0%)
    Infections and infestations
    Lyme disease 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 1/54 (1.9%)
    Pneumonia 1/54 (1.9%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Injury, poisoning and procedural complications
    Overdose 0/54 (0%) 0/49 (0%) 1/52 (1.9%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Road traffic accident 0/54 (0%) 0/49 (0%) 0/52 (0%) 1/53 (1.9%) 0/54 (0%) 0/54 (0%)
    Investigations
    Transaminases increased 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 1/54 (1.9%) 0/54 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 1/54 (1.9%)
    Lung neoplasm 1/54 (1.9%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Nervous system disorders
    Epilepsy 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 1/54 (1.9%) 0/54 (0%)
    Restless legs syndrome 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 1/54 (1.9%) 0/54 (0%)
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous 0/54 (0%) 0/49 (0%) 0/52 (0%) 1/53 (1.9%) 0/54 (0%) 0/54 (0%)
    Vascular disorders
    Peripheral embolism 1/54 (1.9%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Other (Not Including Serious) Adverse Events
    Placebo Placebo Then Evobrutinib 25 mg QD 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 14/54 (25.9%) 9/49 (18.4%) 19/52 (36.5%) 19/53 (35.8%) 20/54 (37%) 30/54 (55.6%)
    Gastrointestinal disorders
    Nausea 0/54 (0%) 0/49 (0%) 2/52 (3.8%) 0/53 (0%) 1/54 (1.9%) 3/54 (5.6%)
    Diarrhoea 1/54 (1.9%) 0/49 (0%) 1/52 (1.9%) 0/53 (0%) 0/54 (0%) 4/54 (7.4%)
    Infections and infestations
    Nasopharyngitis 5/54 (9.3%) 1/49 (2%) 9/52 (17.3%) 3/53 (5.7%) 7/54 (13%) 2/54 (3.7%)
    Upper respiratory tract infection 0/54 (0%) 0/49 (0%) 1/52 (1.9%) 1/53 (1.9%) 1/54 (1.9%) 3/54 (5.6%)
    Urinary tract infection 3/54 (5.6%) 0/49 (0%) 2/52 (3.8%) 1/53 (1.9%) 0/54 (0%) 0/54 (0%)
    Cystitis 0/54 (0%) 3/49 (6.1%) 1/52 (1.9%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Investigations
    Alanine aminotransferase increased 3/54 (5.6%) 1/49 (2%) 3/52 (5.8%) 6/53 (11.3%) 5/54 (9.3%) 3/54 (5.6%)
    Lipase increased 2/54 (3.7%) 3/49 (6.1%) 2/52 (3.8%) 5/53 (9.4%) 5/54 (9.3%) 3/54 (5.6%)
    Aspartate aminotransferase increased 1/54 (1.9%) 0/49 (0%) 1/52 (1.9%) 2/53 (3.8%) 4/54 (7.4%) 2/54 (3.7%)
    Blood creatinine increased 0/54 (0%) 0/49 (0%) 0/52 (0%) 3/53 (5.7%) 3/54 (5.6%) 1/54 (1.9%)
    Gamma-glutamyltransferase increased 0/54 (0%) 0/49 (0%) 1/52 (1.9%) 1/53 (1.9%) 3/54 (5.6%) 1/54 (1.9%)
    Lymphocyte count decreased 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 1/54 (1.9%) 5/54 (9.3%)
    White blood cell count decreased 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 1/54 (1.9%) 3/54 (5.6%)
    Amylase increased 3/54 (5.6%) 3/49 (6.1%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 0/54 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/54 (1.9%) 0/49 (0%) 2/52 (3.8%) 3/53 (5.7%) 0/54 (0%) 4/54 (7.4%)
    Nervous system disorders
    Headache 2/54 (3.7%) 0/49 (0%) 3/52 (5.8%) 2/53 (3.8%) 1/54 (1.9%) 1/54 (1.9%)
    Skin and subcutaneous tissue disorders
    Erythema 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 7/54 (13%)
    Vascular disorders
    Flushing 0/54 (0%) 0/49 (0%) 0/52 (0%) 0/53 (0%) 0/54 (0%) 12/54 (22.2%)

    Limitations/Caveats

    Reported p values are not adjusted for multiple testing.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Communication Center
    Organization Merck KGaA, Darmstadt, Germany
    Phone +49-6151-72-5200
    Email service@emdgroup.com
    Responsible Party:
    EMD Serono Research & Development Institute, Inc.
    ClinicalTrials.gov Identifier:
    NCT02975349
    Other Study ID Numbers:
    • MS200527-0086
    • 2016-001448-21
    First Posted:
    Nov 29, 2016
    Last Update Posted:
    May 27, 2021
    Last Verified:
    Apr 1, 2021