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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02975349
Recruitment Status : Active, not recruiting
First Posted : November 29, 2016
Results First Posted : February 5, 2021
Last Update Posted : May 27, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Relapsing-remitting Multiple Sclerosis
Interventions Drug: Evobrutinib
Drug: Placebo
Drug: Tecfidera
Enrollment 267
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 Details  
Arm/Group Title Placebo Placebo Then Evobrutinib 25 mg QD Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera
Hide 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
Reason Not Completed
Withdrawal by Subject             0             0             3             3             0             0
Lost to Follow-up             1             0             0             0             0             0
Adverse Event             4             0             1             2             6             2
Un-specified             0             0             1             0             0             0
Period Title: Blinded Extension 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
Reason Not Completed
Adverse Event             0             1             1             2             1             0
Withdrawal by Subject             0             5             2             1             1             0
Lack of Efficacy             0             0             1             0             0             0
Progressive Disease             0             1             0             0             0             0
Un-specified             0             0             0             1             0             0
Arm/Group Title Placebo Evobrutinib 25 mg QD Evobrutinib 75 mg QD Evobrutinib 75 mg BID Tecfidera Total
Hide 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 Number of Baseline Participants 53 50 51 53 54 261
Hide Baseline 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.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 53 participants 50 participants 51 participants 53 participants 54 participants 261 participants
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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 50 participants 51 participants 53 participants 54 participants 261 participants
Female
39
  73.6%
32
  64.0%
35
  68.6%
36
  67.9%
39
  72.2%
181
  69.3%
Male
14
  26.4%
18
  36.0%
16
  31.4%
17
  32.1%
15
  27.8%
80
  30.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 50 participants 51 participants 53 participants 54 participants 261 participants
Hispanic or Latino
1
   1.9%
1
   2.0%
0
   0.0%
1
   1.9%
2
   3.7%
5
   1.9%
Not Hispanic or Latino
52
  98.1%
49
  98.0%
51
 100.0%
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%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 50 participants 51 participants 53 participants 54 participants 261 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
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%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
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%
0
   0.0%
0
   0.0%
White
53
 100.0%
50
 100.0%
51
 100.0%
53
 100.0%
54
 100.0%
261
 100.0%
More than one race
0
   0.0%
0
   0.0%
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%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Total Number of Gadolinium-Enhancing T1 Lesions
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: Lesions
3.85  (5.436) 4.06  (8.024) 1.69  (4.693) 1.15  (3.702) 4.78  (22.045)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2947
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 1.45
Confidence Interval (2-Sided) 95%
0.72 to 2.91
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0015
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 0.30
Confidence Interval (2-Sided) 95%
0.14 to 0.63
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0313
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.21 to 0.93
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Annualized Relapse Rate (ARR) at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.37
(0.17 to 0.70)
0.57
(0.30 to 0.97)
0.13
(0.03 to 0.38)
0.08
(0.01 to 0.30)
0.20
(0.06 to 0.47)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2692
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Qualified relapse rate ratio
Estimated Value 1.66
Confidence Interval (2-Sided) 95%
0.67 to 4.09
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0896
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Qualified relapse rate ratio
Estimated Value 0.31
Confidence Interval (2-Sided) 95%
0.08 to 1.20
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0633
Comments [Not Specified]
Method Negative Binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Qualified relapse rate ratio
Estimated Value 0.23
Confidence Interval (2-Sided) 95%
0.05 to 1.09
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Qualified Relapse-Free Status at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
77.4
(63.8 to 87.7)
74.0
(59.7 to 85.4)
88.2
(76.1 to 95.6)
86.8
(74.7 to 94.5)
88.9
(77.4 to 95.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5609
Comments [Not Specified]
Method Logistic model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.75
Confidence Interval (2-Sided) 95%
0.29 to 1.95
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0689
Comments [Not Specified]
Method Logistic model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.79
Confidence Interval (2-Sided) 95%
0.92 to 8.41
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1767
Comments [Not Specified]
Method Logistic model
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.08
Confidence Interval (2-Sided) 95%
0.72 to 5.99
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: Units on a scale
-0.03  (0.301) 0.02  (0.622) -0.14  (0.664) 0.04  (0.216) 0.02  (0.274)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4070
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
0.00 to 0.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5829
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
0.00 to 0.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2732
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
0.00 to 0.00
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 54 49 52 53 54 54
Measure Type: Count of Participants
Unit of Measure: Participants
TEAEs
24
  44.4%
19
  38.8%
28
  53.8%
35
  66.0%
34
  63.0%
35
  64.8%
Serious TEAEs
2
   3.7%
0
   0.0%
2
   3.8%
2
   3.8%
4
   7.4%
2
   3.7%
TEAEs Leading to Death
0
   0.0%
0
   0.0%
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 54 49 52 53 54 54
Measure Type: Count of Participants
Unit of Measure: Participants
Vital Sign Abnormalities
0
   0.0%
0
   0.0%
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%
0
   0.0%
0
   0.0%
7.Secondary Outcome
Title Number of Participants With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 54 49 52 53 54 54
Measure Type: Count of Participants
Unit of Measure: Participants
Grade >= 3 hematology values
0
   0.0%
2
   4.1%
0
   0.0%
1
   1.9%
0
   0.0%
1
   1.9%
Grade >= 3 biochemistry values
2
   3.7%
8
  16.3%
6
  11.5%
9
  17.0%
16
  29.6%
9
  16.7%
Grade >= 3 or value >= 2 ULN or ++ Increasing urinalysis values
0
   0.0%
2
   4.1%
1
   1.9%
2
   3.8%
2
   3.7%
6
  11.1%
8.Secondary Outcome
Title Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)
Hide Description Absolute Concentrations serum levels of IgG, IgA, IgM were assessed.
Time Frame Baseline (Day 1), Weeks 4, 16, and 24
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 54 52 53 54 54
Mean (Standard Deviation)
Unit of Measure: Gram per Liter
Ig A, Day 1 Number Analyzed 54 participants 51 participants 53 participants 54 participants 54 participants
1.99  (0.777) 1.89  (0.764) 1.90  (0.722) 1.87  (0.675) 2.03  (0.763)
Ig A, Week 4 Number Analyzed 54 participants 52 participants 53 participants 54 participants 54 participants
1.98  (0.777) 1.92  (0.770) 1.93  (0.762) 1.94  (0.748) 1.90  (0.699)
Ig A, Week 16 Number Analyzed 53 participants 50 participants 49 participants 53 participants 52 participants
2.07  (0.824) 2.10  (0.813) 2.13  (0.832) 2.08  (0.753) 2.03  (0.752)
Ig A, Week 24 Number Analyzed 50 participants 47 participants 49 participants 48 participants 52 participants
1.99  (0.807) 2.12  (0.833) 2.09  (0.838) 2.09  (0.793) 1.97  (0.757)
Ig G, Day 1 Number Analyzed 54 participants 51 participants 53 participants 54 participants 54 participants
9.61  (1.897) 9.43  (2.126) 9.81  (1.841) 9.62  (1.960) 9.47  (1.839)
Ig G, Week 4 Number Analyzed 54 participants 52 participants 53 participants 54 participants 54 participants
9.64  (2.094) 9.34  (1.972) 9.79  (1.910) 9.64  (1.987) 9.05  (1.922)
Ig G, Week 16 Number Analyzed 53 participants 50 participants 49 participants 53 participants 52 participants
9.68  (2.085) 9.41  (2.077) 9.70  (1.991) 9.56  (2.129) 9.58  (1.850)
Ig G, Week 24 Number Analyzed 50 participants 47 participants 49 participants 48 participants 52 participants
9.66  (2.081) 9.46  (2.123) 9.62  (2.048) 9.36  (1.988) 9.27  (1.866)
Ig M, Day 1 Number Analyzed 54 participants 51 participants 53 participants 54 participants 54 participants
1.42  (0.692) 1.27  (0.542) 1.44  (0.716) 1.33  (0.684) 1.27  (0.589)
Ig M, Week 4 Number Analyzed 54 participants 51 participants 53 participants 54 participants 54 participants
1.40  (0.668) 1.21  (0.526) 1.32  (0.654) 1.28  (0.656) 1.23  (0.603)
Ig M, Week 16 Number Analyzed 53 participants 50 participants 49 participants 53 participants 52 participants
1.43  (0.703) 1.13  (0.558) 1.24  (0.639) 1.20  (0.689) 1.28  (0.678)
Ig M, Week 24 Number Analyzed 49 participants 47 participants 49 participants 48 participants 52 participants
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)
Hide Description Absolute Concentrations serum levels of IgG, IgA, IgM were to be assessed.
Time Frame Weeks 48
Outcome Measure Data Not Reported
10.Secondary Outcome
Title Change From Baseline in Immunoglobulin (Ig) Levels (Active Treatment Period)
Hide Description Change in the serum levels of IgG, IgA, IgM were assessed.
Time Frame Baseline (Day 1), Weeks 4, 16, and 24
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 54 50 53 54 54
Mean (Standard Deviation)
Unit of Measure: Gram per Liter
Ig A, Week 4 Number Analyzed 54 participants 50 participants 53 participants 54 participants 54 participants
-0.02  (0.201) 0.02  (0.165) 0.04  (0.169) 0.07  (0.195) -0.13  (0.238)
Ig A, Week 16 Number Analyzed 51 participants 48 participants 49 participants 53 participants 52 participants
0.10  (0.188) 0.18  (0.245) 0.21  (0.313) 0.22  (0.209) -0.02  (0.274)
Ig A, Week 24 Number Analyzed 49 participants 44 participants 48 participants 48 participants 52 participants
0.06  (0.250) 0.21  (0.283) 0.18  (0.416) 0.22  (0.229) -0.06  (0.207)
Ig G, Week 4 Number Analyzed 54 participants 50 participants 53 participants 54 participants 54 participants
0.02  (0.758) -0.10  (0.697) -0.02  (0.688) 0.02  (0.581) -0.42  (0.926)
Ig G, Week 16 Number Analyzed 53 participants 48 participants 49 participants 53 participants 52 participants
0.04  (0.747) -0.07  (0.964) -0.10  (1.068) -0.05  (0.710) 0.07  (0.961)
Ig G, Week 24 Number Analyzed 50 participants 45 participants 49 participants 48 participants 52 participants
0.06  (0.682) 0.00  (1.228) -0.15  (1.058) -0.28  (0.774) -0.23  (0.882)
Ig M, Week 4 Number Analyzed 54 participants 50 participants 53 participants 54 participants 54 participants
-0.01  (0.210) -0.06  (0.100) -0.12  (0.233) -0.05  (0.133) -0.04  (0.132)
Ig M, Week 16 Number Analyzed 53 participants 48 participants 49 participants 53 participants 52 participants
0.02  (0.177) -0.12  (0.184) -0.18  (0.244) -0.14  (0.189) -0.00  (0.184)
Ig M, Week 24 Number Analyzed 50 participants 45 participants 49 participants 48 participants 52 participants
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)
Hide Description Change in the serum levels of IgG, IgA, IgM were to be assessed.
Time Frame Baseline (Day 1), Week 48
Outcome Measure Data Not Reported
12.Secondary Outcome
Title Absolute Numbers of B Cells (Active Treatment Period)
Hide Description Absolute Numbers of B Cells are reported.
Time Frame Baseline (Day 1), Weeks 4, and 24
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 52 52 53 53 52
Mean (Standard Deviation)
Unit of Measure: cells per micro-liter
Day 1 Number Analyzed 52 participants 52 participants 49 participants 51 participants 48 participants
242  (134.2) 208  (117.5) 247  (131.8) 219  (113.7) 210  (97.4)
Week 4 Number Analyzed 52 participants 50 participants 53 participants 53 participants 52 participants
243  (130.8) 220  (92.7) 277  (156.2) 270  (143.2) 201  (114.3)
Week 24 Number Analyzed 49 participants 44 participants 49 participants 47 participants 52 participants
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)
Hide Description Absolute Numbers of B Cells to be reported.
Time Frame Weeks 48 and 52
Outcome Measure Data Not Reported
14.Secondary Outcome
Title Change From Baseline in Absolute B Cells (Active Treatment Period)
Hide Description Change from baseline in absolute B cells are reported.
Time Frame Baseline (Day 1), Weeks 4, and 24
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 52 50 53 53 52
Mean (Standard Deviation)
Unit of Measure: cells per micro-liter
Week 4 Number Analyzed 52 participants 50 participants 53 participants 53 participants 52 participants
-5  (94.5) 9  (112.2) 31  (114.2) 50  (86.7) -3  (111.0)
Week 24 Number Analyzed 49 participants 44 participants 49 participants 47 participants 52 participants
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)
Hide Description Change from baseline in absolute B cells to be reported.
Time Frame Weeks 48 and 52
Outcome Measure Data Not Reported
16.Secondary Outcome
Title Total Number of New Gadolinium-positive (Gd+) T1 Lesions
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: Lesions
3.08  (4.371) 3.44  (6.846) 1.20  (3.499) 0.98  (3.273) 3.24  (15.320)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3676
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 1.36
Confidence Interval (2-Sided) 95%
0.70 to 2.65
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 0.27
Confidence Interval (2-Sided) 95%
0.13 to 0.57
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0157
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion rate ratio
Estimated Value 0.41
Confidence Interval (2-Sided) 95%
0.20 to 0.85
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Mean Per-scan Number of Gadolinium-positive (Gd+) T1 Lesions
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: Lesions
1.02  (1.439) 1.31  (3.130) 0.42  (1.173) 0.34  (0.960) 1.45  (7.293)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9731
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.25 to 0.25
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0017
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value -0.25
Confidence Interval (2-Sided) 95%
-0.50 to 0.00
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value -0.50
Confidence Interval (2-Sided) 95%
-0.75 to -0.25
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Total Number of New or Enlarging T2 Lesions
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: Lesions
5.96  (6.994) 6.52  (11.569) 3.41  (10.752) 2.19  (4.719) 5.35  (16.667)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4807
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion Rate ratio
Estimated Value 1.29
Confidence Interval (2-Sided) 95%
0.63 to 2.65
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0620
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion Rate ratio
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.24 to 1.04
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0189
Comments [Not Specified]
Method Negative Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Lesion Rate ratio
Estimated Value 0.42
Confidence Interval (2-Sided) 95%
0.20 to 0.87
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Change From Baseline in Volume of T2 Lesions at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 46 48 46 50
Mean (Standard Deviation)
Unit of Measure: cubic centimeter (cc)
0.42  (1.009) 0.93  (1.853) -0.01  (0.562) 0.09  (0.463) 0.47  (2.964)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8776
Comments [Not Specified]
Method Mixed Effect Model for Repeat Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least squares means
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.24 to 0.28
Estimation Comments Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0019
Comments [Not Specified]
Method Mixed Effect Model for Repeat Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least squares means
Estimated Value -0.41
Confidence Interval (2-Sided) 95%
-0.66 to -0.15
Estimation Comments Difference in least squares means of change from baseline in cube root of volume measured in centimeter.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0063
Comments [Not Specified]
Method Mixed Effect Model for Repeat Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least squares means
Estimated Value -0.36
Confidence Interval (2-Sided) 95%
-0.62 to -0.10
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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (Standard Deviation)
Unit of Measure: cc
-0.023  (0.2220) 0.057  (0.3479) -0.111  (0.5416) -0.051  (0.1032) -0.050  (0.4771)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 25 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9315
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.004 to 0.009
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg QD
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value -0.014
Confidence Interval (2-Sided) 95%
-0.050 to 0.000
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Evobrutinib 75 mg BID
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann estimate
Estimated Value -0.018
Confidence Interval (2-Sided) 95%
-0.042 to 0.000
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48
Hide Description Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame Week 48
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame Week 48
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Mean (Standard Deviation)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 53 50 51 53 54
Mean (95% Confidence Interval)
Unit of Measure: relapses per year
0.37
(0.21 to 0.59)
0.52
(0.33 to 0.78)
0.25
(0.12 to 0.44)
0.11
(0.04 to 0.25)
0.14
(0.06 to 0.29)
24.Secondary Outcome
Title Qualified Relapse-free Status
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Measure Type: Number
Unit of Measure: percentage of participants
84.1 86.4 78.3 91.1 96.0
25.Secondary Outcome
Title Change From Week 24 in Expanded Disability Status Scale (EDSS) at Week 48
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame Week 24 to Week 48
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 42 42 43 43 50
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame Week 24, Week 48
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans.
Time Frame Week 24, Week 48
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 44 44 46 45 50
Mean (Standard Deviation)
Unit of Measure: cc
0.53  (1.360) 0.67  (1.865) 0.35  (1.083) -0.03  (1.031) -0.57  (2.699)
Time Frame Baseline up to Safety Follow up of blinded extension period (Week 52)
Adverse Event Reporting Description [Not Specified]
 
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)
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/54 (0.00%)   0/49 (0.00%)   0/52 (0.00%)   0/53 (0.00%)   0/54 (0.00%)   0/54 (0.00%) 
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/54 (3.70%)   0/49 (0.00%)   2/52 (3.85%)   2/53 (3.77%)   4/54 (7.41%)   2/54 (3.70%) 
Hepatobiliary disorders             
Hepatitis toxic * 1  0/54 (0.00%)  0/49 (0.00%)  1/52 (1.92%)  0/53 (0.00%)  1/54 (1.85%)  0/54 (0.00%) 
Infections and infestations             
Lyme disease * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  1/54 (1.85%) 
Pneumonia * 1  1/54 (1.85%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
Injury, poisoning and procedural complications             
Overdose * 1  0/54 (0.00%)  0/49 (0.00%)  1/52 (1.92%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
Road traffic accident * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  1/53 (1.89%)  0/54 (0.00%)  0/54 (0.00%) 
Investigations             
Transaminases increased * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  1/54 (1.85%)  0/54 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Gastric cancer * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  1/54 (1.85%) 
Lung neoplasm * 1  1/54 (1.85%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
Nervous system disorders             
Epilepsy * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  1/54 (1.85%)  0/54 (0.00%) 
Restless legs syndrome * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  1/54 (1.85%)  0/54 (0.00%) 
Pregnancy, puerperium and perinatal conditions             
Abortion spontaneous * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  1/53 (1.89%)  0/54 (0.00%)  0/54 (0.00%) 
Vascular disorders             
Peripheral embolism * 1  1/54 (1.85%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
1
Term from vocabulary, MedDRA version 21.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   14/54 (25.93%)   9/49 (18.37%)   19/52 (36.54%)   19/53 (35.85%)   20/54 (37.04%)   30/54 (55.56%) 
Gastrointestinal disorders             
Nausea * 1  0/54 (0.00%)  0/49 (0.00%)  2/52 (3.85%)  0/53 (0.00%)  1/54 (1.85%)  3/54 (5.56%) 
Diarrhoea * 1  1/54 (1.85%)  0/49 (0.00%)  1/52 (1.92%)  0/53 (0.00%)  0/54 (0.00%)  4/54 (7.41%) 
Infections and infestations             
Nasopharyngitis * 1  5/54 (9.26%)  1/49 (2.04%)  9/52 (17.31%)  3/53 (5.66%)  7/54 (12.96%)  2/54 (3.70%) 
Upper respiratory tract infection * 1  0/54 (0.00%)  0/49 (0.00%)  1/52 (1.92%)  1/53 (1.89%)  1/54 (1.85%)  3/54 (5.56%) 
Urinary tract infection * 1  3/54 (5.56%)  0/49 (0.00%)  2/52 (3.85%)  1/53 (1.89%)  0/54 (0.00%)  0/54 (0.00%) 
Cystitis * 1  0/54 (0.00%)  3/49 (6.12%)  1/52 (1.92%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
Investigations             
Alanine aminotransferase increased * 1  3/54 (5.56%)  1/49 (2.04%)  3/52 (5.77%)  6/53 (11.32%)  5/54 (9.26%)  3/54 (5.56%) 
Lipase increased * 1  2/54 (3.70%)  3/49 (6.12%)  2/52 (3.85%)  5/53 (9.43%)  5/54 (9.26%)  3/54 (5.56%) 
Aspartate aminotransferase increased * 1  1/54 (1.85%)  0/49 (0.00%)  1/52 (1.92%)  2/53 (3.77%)  4/54 (7.41%)  2/54 (3.70%) 
Blood creatinine increased * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  3/53 (5.66%)  3/54 (5.56%)  1/54 (1.85%) 
Gamma-glutamyltransferase increased * 1  0/54 (0.00%)  0/49 (0.00%)  1/52 (1.92%)  1/53 (1.89%)  3/54 (5.56%)  1/54 (1.85%) 
Lymphocyte count decreased * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  1/54 (1.85%)  5/54 (9.26%) 
White blood cell count decreased * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  1/54 (1.85%)  3/54 (5.56%) 
Amylase increased * 1  3/54 (5.56%)  3/49 (6.12%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  0/54 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia * 1  1/54 (1.85%)  0/49 (0.00%)  2/52 (3.85%)  3/53 (5.66%)  0/54 (0.00%)  4/54 (7.41%) 
Nervous system disorders             
Headache * 1  2/54 (3.70%)  0/49 (0.00%)  3/52 (5.77%)  2/53 (3.77%)  1/54 (1.85%)  1/54 (1.85%) 
Skin and subcutaneous tissue disorders             
Erythema * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  7/54 (12.96%) 
Vascular disorders             
Flushing * 1  0/54 (0.00%)  0/49 (0.00%)  0/52 (0.00%)  0/53 (0.00%)  0/54 (0.00%)  12/54 (22.22%) 
1
Term from vocabulary, MedDRA version 21.0
*
Indicates events were collected by non-systematic assessment
Reported p values are not adjusted for multiple testing.
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
Layout table for Results Point of Contact information
Name/Title: Communication Center
Organization: Merck KGaA, Darmstadt, Germany
Phone: +49-6151-72-5200
EMail: service@emdgroup.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
ClinicalTrials.gov Identifier: NCT02975349    
Other Study ID Numbers: MS200527-0086
2016-001448-21 ( EudraCT Number )
First Submitted: November 23, 2016
First Posted: November 29, 2016
Results First Submitted: January 13, 2021
Results First Posted: February 5, 2021
Last Update Posted: May 27, 2021