Clinical Trial Results:
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

Clinical trials

Clinical Trial Results: 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

Clinical Trial Results:
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

Trial information

Subject disposition

Baseline characteristics

End points

Adverse events

More information

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: Annualized relapse rate (ARR) at Week 24

Secondary: Qualified Relapse-Free Status at Week 24

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death

Secondary: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)

Secondary: Number of Subjects With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)

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

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

Secondary: Absolute Numbers of B Cells (Active Treatment Period)

Secondary: Absolute Concentration of B Cells (Blinded Extension Period)

Secondary: Change From Baseline in Absolute B cells (Active Treatment Period)

Secondary: Change From Baseline in Absolute B cells (Blinded Extension Period)

Secondary: Total Number of New gadolinium-positive (Gd+) T1 Lesions

Secondary: Mean Per-scan Number of gadolinium-positive (Gd+) T1 lesions

Secondary: Total Number of New or Enlarging T2 Lesions

Secondary: Change From Baseline in Volume of T2 Lesions at Week 24

Secondary: Change From Baseline in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 24

Secondary: Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Qualified Relapse-free Status

Secondary: Annualized relapse rate (ARR)

Secondary: Total Number of New or Enlarging T2 Lesions at Week 48 relative to Week 24

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

Secondary: Change From Week 24 in Volume of T2 Lesions at Week 48

Secondary: Change From Week 24 in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: OLE Period: Annualized relapse rate (ARR)

Secondary: OLE Period: Percentage of Subjects with Qualified Relapse-Free Status

Secondary: OLE Period: Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336

Secondary: OLE Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)

Secondary: OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels

Secondary: OLE Period: Change from Baseline in Immunoglobulin (Ig) Levels

Primary: Total Number of Gadolinium-Enhancing T1 Lesions

Primary: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: Annualized relapse rate (ARR) at Week 24

Secondary: Annualized relapse rate (ARR) at Week 24

Secondary: Qualified Relapse-Free Status at Week 24

Secondary: Qualified Relapse-Free Status at Week 24

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24

Secondary: Change From Baseline in Expanded Disability Status Scale (EDSS) at Week 24

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death

Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death

Secondary: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)

Secondary: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)

Secondary: Number of Subjects With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values

Secondary: Number of Subjects With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)

Secondary: Absolute Concentrations of Immunoglobulin (Ig) Levels (Blinded Extension Period)

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

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

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

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

Secondary: Absolute Numbers of B Cells (Active Treatment Period)

Secondary: Absolute Numbers of B Cells (Active Treatment Period)

Secondary: Absolute Concentration of B Cells (Blinded Extension Period)

Secondary: Absolute Concentration of B Cells (Blinded Extension Period)

Secondary: Change From Baseline in Absolute B cells (Active Treatment Period)

Secondary: Change From Baseline in Absolute B cells (Active Treatment Period)

Secondary: Change From Baseline in Absolute B cells (Blinded Extension Period)

Secondary: Change From Baseline in Absolute B cells (Blinded Extension Period)

Secondary: Total Number of New gadolinium-positive (Gd+) T1 Lesions

Secondary: Total Number of New gadolinium-positive (Gd+) T1 Lesions

Secondary: Mean Per-scan Number of gadolinium-positive (Gd+) T1 lesions

Secondary: Mean Per-scan Number of gadolinium-positive (Gd+) T1 lesions

Secondary: Total Number of New or Enlarging T2 Lesions

Secondary: Total Number of New or Enlarging T2 Lesions

Secondary: Change From Baseline in Volume of T2 Lesions at Week 24

Secondary: Change From Baseline in Volume of T2 Lesions at Week 24

Secondary: Change From Baseline in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 24

Secondary: Change From Baseline in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 24

Secondary: Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Qualified Relapse-free Status

Secondary: Qualified Relapse-free Status

Secondary: Annualized relapse rate (ARR)

Secondary: Annualized relapse rate (ARR)

Secondary: Total Number of New or Enlarging T2 Lesions at Week 48 relative to Week 24

Secondary: Total Number of New or Enlarging T2 Lesions at Week 48 relative to Week 24

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

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

Secondary: Change From Week 24 in Volume of T2 Lesions at Week 48

Secondary: Change From Week 24 in Volume of T2 Lesions at Week 48

Secondary: Change From Week 24 in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: Change From Week 24 in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 48

Secondary: OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: OLE Period: Annualized relapse rate (ARR)

Secondary: OLE Period: Annualized relapse rate (ARR)

Secondary: OLE Period: Percentage of Subjects with Qualified Relapse-Free Status

Secondary: OLE Period: Percentage of Subjects with Qualified Relapse-Free Status

Secondary: OLE Period: Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336

Secondary: OLE Period: Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336

Secondary: OLE Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

Secondary: OLE Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs

Secondary: OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs

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Summary
EudraCT number	2016-001448-21
Trial protocol	SK ES CZ PL BG
Global end of trial date	02 Apr 2024

Results information
Results version number	v1(current)
This version publication date	17 Apr 2025
First version publication date	17 Apr 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Sponsor protocol code

MS200527-0086

ISRCTN number

US NCT number

NCT02975349

WHO universal trial number (UTN)

Sponsor organisation name

Merck Healthcare KGaA, Darmstadt Germany

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Centre, Merck Healthcare KGaA, Darmstadt Germany, +49 6151725200, service@merckgroup.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Apr 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Apr 2024

Was the trial ended prematurely?

Main objective of the trial

The aim of this study was to find out about the safety and effectiveness of M2951 in subjects with relapsing multiple sclerosis. Subjects were placed into 1 of 3 groups to receive M2951, placebo or tecfidera for 24 weeks. After 24 weeks, the subjects on placebo were given M2951.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 47

Country: Number of subjects enrolled

Czechia: 26

Country: Number of subjects enrolled

Poland: 83

Country: Number of subjects enrolled

Russian Federation: 19

Country: Number of subjects enrolled

Serbia: 17

Country: Number of subjects enrolled

Slovakia: 10

Country: Number of subjects enrolled

Ukraine: 62

Country: Number of subjects enrolled

Spain: 3

Worldwide total number of subjects

267

EEA total number of subjects

169

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

267

From 65 to 84 years

85 years and over

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Recruitment details

Screening details

The study consisted of a 24-week active treatment period, 24-week blinded extension (BE) period and a 336-week open-label extension period. A total of 333 subjects with Relapsing Multiple Sclerosis (RMS) were screened, and 267 subjects were randomized and received treatment in the study.

Period 1 title

Active Treatment Period (24 Weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Placebo (period 1)

Arm description

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

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Evobrutinib 25 mg QD (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Evobrutinib 75 mg QD (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Evobrutinib 75 mg BID (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Tecfidera (Period 1 and 2)

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Tecfidera

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects 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.

Number of subjects in period 1	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Started	54	52	53	54	54
Completed	49	47	48	48	52
Not completed	5	5	5	6	2
Consent withdrawn by subject	-	3	3	-	-
Adverse event, non-fatal	4	2	2	6	2
Lost to follow-up	1	-	-	-	-

Period 2 title

Blinded Extension Period (24 Weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Placebo Then Evobrutinib 25 mg QD (Period 2)

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Placebo +Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Evobrutinib 25 mg QD (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Evobrutinib 75 mg QD (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Evobrutinib 75 mg BID (Period 1 and 2)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Tecfidera (Period 1 and 2)

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

Tecfidera

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects 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.

Number of subjects in period 2	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Started	49	47	48	48	52
Completed	42	43	44	46	52
Not completed	7	4	4	2	0
Consent withdrawn by subject	5	2	1	1	-
Adverse event, non-fatal	1	1	3	1	-
Progressive Disease	1	-	-	-	-
Lack of efficacy	-	1	-	-	-

Period 3 title

Open-label Extension Period (336 Weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo + Evobrutinib 25 mg QD (Period 3)

Arm description

Subjects who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period received Evobrutinib 25 mg orally, QD from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Arm type

Experimental

Investigational medicinal product name

Placebo +Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects who received placebo matched to Evobrutinib tablet orally for 24 weeks in active treatment period 1 received Evobrutinib 25 mg orally, QD from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Evobrutinib 25 mg QD (Period 3)

Arm description

Subjects received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Evobrutinib 75 mg QD (Period 3)

Arm description

Subjects received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Evobrutinib 75 mg BID (Period 3)

Arm description

Subjects Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Arm type

Experimental

Investigational medicinal product name

Evobrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Tecfidera (Period 3)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

Tecfidera

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

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

Number of subjects in period 3 ^[1]	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Started	39	39	42	44	49
Completed	28	25	33	35	39
Not completed	11	14	9	9	10
Adverse event, serious fatal	-	1	-	-	-
Consent withdrawn by subject	4	7	2	4	2
Study reached its predefined end	-	-	1	-	-
Adverse event, non-fatal	3	2	2	1	2
Unspecified	3	3	1	2	3
Lost to follow-up	1	-	-	1	-
COVID-19 Related	-	1	1	1	2
Lack of efficacy	-	-	2	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only 213 subjects started the OLE period.

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Reporting group title

Placebo (period 1)

Reporting group description

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

Reporting group title

Evobrutinib 25 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg BID (Period 1 and 2)

Reporting group description

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

Reporting group title

Tecfidera (Period 1 and 2)

Reporting group description

Subjects 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.

Reporting group values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)	Total
Number of subjects	54	52	53	54	54	267
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	54	52	53	54	54	267
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	-
Sex: Female, Male
Units: subjects
Female	39	32	35	36	39	181
Male	14	18	16	17	15	80
Unknown or Not Reported	1	2	2	1	0	6

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Reporting group title

Placebo (period 1)

Reporting group description

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

Reporting group title

Evobrutinib 25 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg BID (Period 1 and 2)

Reporting group description

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

Reporting group title

Tecfidera (Period 1 and 2)

Reporting group description

Subjects 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.

Reporting group title

Placebo Then Evobrutinib 25 mg QD (Period 2)

Reporting group description

Reporting group title

Evobrutinib 25 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg QD (Period 1 and 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg BID (Period 1 and 2)

Reporting group description

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

Reporting group title

Tecfidera (Period 1 and 2)

Reporting group description

Subjects 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.

Reporting group title

Placebo + Evobrutinib 25 mg QD (Period 3)

Reporting group description

Reporting group title

Evobrutinib 25 mg QD (Period 3)

Reporting group description

Subjects received Evobrutinib 25 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Evobrutinib 75 mg QD (Period 3)

Reporting group description

Subjects received Evobrutinib 75 mg QD orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Evobrutinib 75 mg BID (Period 3)

Reporting group description

Subjects Evobrutinib 75 mg BID orally from Week 48 of BE period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Tecfidera (Period 3)

Reporting group description

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

Subject analysis set title

Placebo

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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

Subject analysis set title

Evobrutinib 25 mg QD

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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

Subject analysis set title

Evobrutinib 75 mg QD

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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

Subject analysis set title

Evobrutinib 75 mg BID

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

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

Subject analysis set title

Tecfidera

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects 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.

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End point title

Total Number of Gadolinium-Enhancing T1 Lesions

End point 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. Modified Intent-To-Treat (mITT) analysis set included subjects who belong to both Intent To Treat (ITT, consisted all subjects who randomly allocated to a treatment, based on the intention to treat "as randomized" principle) and safety analysis sets (consisted all subjects 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.

End point type

Primary

End point timeframe

Week 12 to Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: Lesions
arithmetic mean (standard deviation)	3.85 ( 5.436 )	4.06 ( 8.024 )	1.69 ( 4.693 )	1.15 ( 3.702 )	4.78 ( 22.045 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2947

Method

Negative Binomial model

Parameter type

Lesion rate ratio

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

2.91

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0313

Method

Negative Binomial model

Parameter type

Lesion rate ratio

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

0.93

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0015

Method

Negative Binomial model

Parameter type

Lesion rate ratio

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

0.63

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End point title

Annualized relapse rate (ARR) at Week 24

End point 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. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: relapses per year
arithmetic mean (confidence interval 95%)	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)

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2692

Method

Negative Binomial model

Parameter type

Qualified relapse rate ratio

Point estimate

1.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

4.09

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0633

Method

Negative Binomial model

Parameter type

Qualified relapse rate ratio

Point estimate

0.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

1.09

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0896

Method

Negative Binomial model

Parameter type

Qualified relapse rate ratio

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

1.2

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End point title

Qualified Relapse-Free Status at Week 24

End point 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 subjects with qualified relapse-free status at week 24 were reported. As per planned analysis, Tecfidera treatment group was not included in inferential analysis. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: percentage of subjects
number (confidence interval 95%)	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)

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5609

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

1.95

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1767

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

2.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

5.99

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0689

Method

Logistic model

Parameter type

Odds ratio (OR)

Point estimate

2.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

8.41

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End point title

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

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: Units on a scale
arithmetic mean (standard deviation)	-0.03 ( 0.301 )	0.02 ( 0.622 )	-0.14 ( 0.664 )	0.04 ( 0.216 )	0.02 ( 0.274 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.407

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2732

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5829

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death

End point description

AE: any untoward medical occurrence in a subject which does not necessarily have a causal relationship with 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. SAE: AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs: 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 included both Serious TEAEs and non-serious TEAEs. Safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera.

End point type

Secondary

End point timeframe

Baseline up to Safety Follow-up (Week 52)

No statistical analyses for this end point

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End point title

Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs and Electrocardiograms (ECGs)

End point 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 subjects with clinically significant change from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera.

End point type

Secondary

End point timeframe

Baseline up to Safety Follow-up (Week 52)

End point values	Placebo (period 1)	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	54	49	52	53	54	54
Units: subjects
Vital Sign Abnormalities	0	0	0	0	0	0
ECG Abnormalities	0	0	0	0	0	0

No statistical analyses for this end point

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End point title

Number of Subjects With Grade 3 or Higher Hematology, Biochemistry and Urinalysis Values

End point 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, subjects with a value grade 3 or higher were reported. For the urinalysis parameters, subjects with a value grade 3 or higher, or a value >= 2 upper limit of normal (ULN), or a value classified as ++ Increasing urinalysis values (IUV) were reported. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera.

End point type

Secondary

End point timeframe

Baseline up to Safety Follow-up (Week 52)

No statistical analyses for this end point

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End point title

Absolute Concentrations of Immunoglobulin (Ig) Levels (Active Treatment Period)

End point description

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points.

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 4, 16, and 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	54	52	53	54	54
Units: Gram per Liter
arithmetic mean (standard deviation)
Ig A, Day 1: n = 54, 51, 53, 54, 54	1.99 ( 0.777 )	1.89 ( 0.764 )	1.90 ( 0.722 )	1.87 ( 0.675 )	2.03 ( 0.763 )
Ig A, Week 4: n = 54, 52, 53, 54, 54	1.98 ( 0.777 )	1.92 ( 0.770 )	1.93 ( 0.762 )	1.94 ( 0.748 )	1.90 ( 0.699 )
Ig A, Week 16: n = 53, 50, 49, 53, 52	2.07 ( 0.824 )	2.10 ( 0.813 )	2.13 ( 0.832 )	2.08 ( 0.753 )	2.03 ( 0.752 )
Ig A, Week 24: n = 50, 47, 49, 48, 52	1.99 ( 0.807 )	2.12 ( 0.833 )	2.09 ( 0.838 )	2.09 ( 0.793 )	1.97 ( 0.757 )
Ig G, Day 1: n = 54, 51, 53, 54, 54	9.61 ( 1.897 )	9.43 ( 2.126 )	9.81 ( 1.841 )	9.62 ( 1.960 )	9.47 ( 1.839 )
Ig G, Week 4: n = 54, 52, 53, 54, 54	9.64 ( 2.094 )	9.34 ( 1.972 )	9.79 ( 1.910 )	9.64 ( 1.987 )	9.05 ( 1.922 )
Ig G, Week 16: n = 53, 50, 49, 53, 52	9.68 ( 2.085 )	9.41 ( 2.077 )	9.70 ( 1.991 )	9.56 ( 2.129 )	9.58 ( 1.850 )
Ig G, Week 24: n = 50, 47, 49, 48, 52	9.66 ( 2.081 )	9.46 ( 2.123 )	9.62 ( 2.048 )	9.36 ( 1.988 )	9.27 ( 1.866 )
Ig M, Day 1: n = 54, 51, 53, 54, 54	1.42 ( 0.692 )	1.27 ( 0.542 )	1.44 ( 0.716 )	1.33 ( 0.684 )	1.27 ( 0.589 )
Ig M, Week 4: n = 54, 51, 53, 54, 54	1.40 ( 0.668 )	1.21 ( 0.526 )	1.32 ( 0.654 )	1.28 ( 0.656 )	1.23 ( 0.603 )
Ig M, Week 16: n = 53, 50, 49, 53, 52	1.43 ( 0.703 )	1.13 ( 0.558 )	1.24 ( 0.639 )	1.20 ( 0.689 )	1.28 ( 0.678 )
Ig M, Week 24: n = 49, 47, 49, 48, 52	1.44 ( 0.748 )	1.03 ( 0.499 )	1.20 ( 0.672 )	1.08 ( 0.494 )	1.29 ( 0.667 )

No statistical analyses for this end point

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End point title

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

End point description

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. The safety analysis set included of all subjects who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint. Results reported are for BE period only and no participants took placebo during this period.

End point type

Secondary

End point timeframe

Weeks 48

End point values	Tecfidera (Period 1 and 2)	Evobrutinib 25 mg QD	Evobrutinib 75 mg QD	Evobrutinib 75 mg BID
Number of subjects analysed	52	50	51	53
Units: Gram per Liter
arithmetic mean (standard deviation)
IgA	2.06 ( 0.695 )	2.13 ( 0.807 )	2.18 ( 0.790 )	2.23 ( 0.838 )
IgG	9.60 ( 1.968 )	9.53 ( 2.070 )	9.74 ( 1.902 )	9.38 ( 2.189 )
IgM	1.28 ( 0.635 )	1.08 ( 0.557 )	1.13 ( 0.639 )	1.10 ( 0.692 )

No statistical analyses for this end point

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End point title

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

End point description

Change in the serum levels of IgG, IgA, IgM were assessed. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points.

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 4, 16, and 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	54	50	53	54	54
Units: Gram per Liter
arithmetic mean (standard deviation)
Ig A, Week 4: n = 54, 50, 53, 54, 54	-0.02 ( 0.201 )	0.02 ( 0.165 )	0.04 ( 0.169 )	0.07 ( 0.195 )	-0.13 ( 0.238 )
Ig A, Week 16: n = 51, 48, 49, 53, 52	0.10 ( 0.188 )	0.18 ( 0.245 )	0.21 ( 0.313 )	0.22 ( 0.209 )	-0.02 ( 0.274 )
Ig A, Week 24: n = 49, 44, 48, 48, 52	0.06 ( 0.250 )	0.21 ( 0.283 )	0.18 ( 0.416 )	0.22 ( 0.229 )	-0.06 ( 0.207 )
Ig G, Week 4: n = 54, 50, 53, 54, 54	0.02 ( 0.758 )	-0.10 ( 0.697 )	-0.02 ( 0.688 )	0.02 ( 0.581 )	-0.42 ( 0.926 )
Ig G, Week 16: n = 51, 48, 49, 53, 52	0.04 ( 0.747 )	-0.07 ( 0.964 )	-0.10 ( 1.068 )	-0.05 ( 0.710 )	0.07 ( 0.961 )
Ig G, Week 24: n = 50, 45, 49, 48, 52	0.06 ( 0.682 )	0.00 ( 1.228 )	-0.15 ( 1.058 )	-0.28 ( 0.774 )	-0.23 ( 0.882 )
Ig M, Week 4: n = 54, 50, 53, 54, 54	-0.01 ( 0.210 )	-0.06 ( 0.100 )	-0.12 ( 0.233 )	-0.05 ( 0.133 )	-0.04 ( 0.132 )
Ig M, Week 16: n = 53, 48, 49, 53, 52	0.02 ( 0.177 )	-0.12 ( 0.184 )	-0.18 ( 0.244 )	-0.14 ( 0.189 )	-0.00 ( 0.184 )
Ig M, Week 24: n = 50, 45, 49, 48, 52	0.04 ( 0.163 )	-0.14 ( 0.286 )	-0.20 ( 0.289 )	-0.21 ( 0.167 )	-0.00 ( 0.186 )

No statistical analyses for this end point

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End point title

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

End point description

Change from baseline in the serum levels of IgG, IgA, IgM were assessed. The safety analysis set included of all subjects who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of subjects Analyzed" signifies those subjects who were evaluable for this endpoint. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint. Results reported are for BE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

Baseline (Week 25), Week 48

End point values	Tecfidera (Period 1 and 2)	Evobrutinib 25 mg QD	Evobrutinib 75 mg QD	Evobrutinib 75 mg BID
Number of subjects analysed	52	48	51	53
Units: Gram per Liter
arithmetic mean (standard deviation)
IgA	0.03 ( 0.316 )	0.26 ( 0.248 )	0.28 ( 0.275 )	0.36 ( 0.320 )
IgG	0.10 ( 1.244 )	0.11 ( 1.024 )	-0.08 ( 0.940 )	0.320 ( 0.883 )
IgM	-0.01 ( 0.198 )	-0.18 ( 0.211 )	-0.27 ( 0.287 )	-0.23 ( 0.218 )

No statistical analyses for this end point

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End point title

Absolute Numbers of B Cells (Active Treatment Period)

End point description

Absolute Numbers of B Cells are reported. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points.

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 4, and 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	52	52	53	53	52
Units: cells per micro-liter
arithmetic mean (standard deviation)
Day 1: n = 52, 52, 49, 51, 48	242 ( 134.2 )	208 ( 117.5 )	247 ( 131.8 )	219 ( 113.7 )	210 ( 97.4 )
Week 4: n = 52, 50, 53, 53, 52	243 ( 130.8 )	220 ( 92.7 )	277 ( 156.2 )	270 ( 143.2 )	201 ( 114.3 )
Week 24: n = 49, 44, 49, 47, 52	264 ( 154.9 )	230 ( 119.7 )	235 ( 115.3 )	214 ( 105.0 )	180 ( 114.3 )

No statistical analyses for this end point

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End point title

Absolute Concentration of B Cells (Blinded Extension Period)

End point description

Absolute Numbers of B Cells are reported. The safety analysis set included of all subjects who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points. Here, "9999" = Based on pre-specified criteria and statistics perspective, it was not meaningful to calculate Mean and Standard Deviation when "n" is only 2. Results reported are for BE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

Weeks 48 and 52

End point values	Tecfidera (Period 1 and 2)	Evobrutinib 25 mg QD	Evobrutinib 75 mg QD	Evobrutinib 75 mg BID
Number of subjects analysed	47	49	51	53
Units: cells per micro-liter
arithmetic mean (standard deviation)
Week 48: n = 49, 51, 53, 47	181 ( 109.8 )	203 ( 111.9 )	222 ( 148.8 )	187 ( 87.1 )
Week 52: n = 6, 7, 8, 2	9999 ( 9999 )	227 ( 93.7 )	206 ( 140.3 )	154 ( 73.6 )

No statistical analyses for this end point

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End point title

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

End point description

Change from baseline in absolute B cells are reported. The safety analysis set included of all subjects who received at least 1 dose of evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points.

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 4 and 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	52	50	53	53	52
Units: cells per micro-liter
arithmetic mean (standard deviation)
Week 4: n = 52, 50, 53, 53, 52	-5 ( 94.5 )	9 ( 112.2 )	31 ( 114.2 )	50 ( 86.7 )	-3 ( 111.0 )
Week 24: n = 49, 44, 49, 47, 52	7 ( 135.8 )	13 ( 98.2 )	-15 ( 128.5 )	-9 ( 85.1 )	-26 ( 113.9 )

No statistical analyses for this end point

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End point title

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

End point description

Change from baseline in absolute B cells are reported. The safety analysis set included of all subjects who received at least 1 dose evobrutinib or placebo or Tecfidera. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint and "n" signified those subjects who were evaluable for the specified category at given time points. . Here, "9999" = Based on pre-specified criteria and statistics perspective, it was not meaningful to calculate Mean and Standard Deviation when "n" is only 2. Results reported are for BE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

Baseline (Week 25), Weeks 48 and 52

End point values	Tecfidera (Period 1 and 2)	Evobrutinib 25 mg QD	Evobrutinib 75 mg QD	Evobrutinib 75 mg BID
Number of subjects analysed	47	49	51	53
Units: cells per micro-liter
arithmetic mean (standard deviation)
Week 48: n = 49, 51, 53, 47	-15 ( 105.7 )	-5 ( 116.1 )	-30 ( 148.2 )	-32 ( 97.9 )
Week 52: n = 6, 7, 8, 2	9999 ( 9999 )	-28 ( 209.8 )	-25 ( 65.5 )	-81 ( 119.0 )

No statistical analyses for this end point

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End point title

Total Number of New gadolinium-positive (Gd+) T1 Lesions

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

End point type

Secondary

End point timeframe

Week 12 to 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: Lesions
arithmetic mean (standard deviation)	3.08 ( 4.371 )	3.44 ( 6.846 )	1.20 ( 3.499 )	0.98 ( 3.273 )	3.24 ( 15.320 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3676

Method

Negative Binomial

Parameter type

Lesion rate ratio

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.65

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0157

Method

Negative Binomial

Parameter type

Lesion rate ratio

Point estimate

0.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.85

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0005

Method

Negative Binomial

Parameter type

Lesion rate ratio

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.57

Top of page

End point title

Mean Per-scan Number of gadolinium-positive (Gd+) T1 lesions

End point 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. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Week 12 to Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: Lesions
arithmetic mean (standard deviation)	1.02 ( 1.439 )	1.31 ( 3.130 )	0.42 ( 1.173 )	0.34 ( 0.960 )	1.45 ( 7.293 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9731

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

0.25

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.75

upper limit

-0.25

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0017

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

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End point title

Total Number of New or Enlarging T2 Lesions

End point 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. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Week 12 to Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: Lesions
arithmetic mean (standard deviation)	5.96 ( 6.994 )	6.52 ( 11.569 )	3.41 ( 10.752 )	2.19 ( 4.719 )	5.35 ( 16.667 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4807

Method

Negative Binomial

Parameter type

Lesion Rate ratio

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

2.65

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0189

Method

Negative Binomial

Parameter type

Lesion Rate ratio

Point estimate

0.42

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.87

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.062

Method

Negative Binomial

Parameter type

Lesion Rate ratio

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.24

upper limit

1.04

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End point title

Change From Baseline in Volume of T2 Lesions at Week 24

End point description

Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. Tecfidera treatment group was not included in inferential analysis. The modified ITT (mITT) analysis set consists of all subjects 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, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	46	48	46	50
Units: cubic centimeter (cc)
arithmetic mean (standard deviation)	0.42 ( 1.009 )	0.93 ( 1.853 )	-0.01 ( 0.562 )	0.09 ( 0.463 )	0.47 ( 2.964 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8776

Method

Mixed Effect Model for Repeat Measures

Parameter type

Difference in least squares means

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.28

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0063

Method

Mixed Effect Model for Repeat Measures

Parameter type

Difference in least squares means

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

-0.1

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0019

Method

Mixed Effect Model for Repeat Measures

Parameter type

Difference in least squares means

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

-0.15

Top of page

End point title

Change From Baseline in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 24

End point 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. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: cc
arithmetic mean (standard deviation)	-0.023 ( 0.2220 )	0.057 ( 0.3479 )	-0.111 ( 0.5416 )	-0.051 ( 0.1032 )	-0.050 ( 0.4771 )

Placebo vs Evobrutinib 25 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 25 mg QD (Period 1 and 2)

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9315

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.009

Placebo vs Evobrutinib 75 mg BID

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg BID (Period 1 and 2)

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0014

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

Placebo vs Evobrutinib 75 mg QD

Comparison groups

Placebo (period 1) v Evobrutinib 75 mg QD (Period 1 and 2)

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0008

Method

Wilcoxon rank-sum test

Parameter type

Hodges-Lehmann estimate

Point estimate

-0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

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End point title

Number of Gadolinium-positive (Gd+) T1 Lesions at Week 48

End point description

Analysis of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.

End point type

Secondary

End point timeframe

Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: Lesions
arithmetic mean (standard deviation)	1.00 ( 1.614 )	1.91 ( 4.296 )	0.85 ( 2.867 )	0.49 ( 1.218 )	0.42 ( 1.444 )

No statistical analyses for this end point

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End point title

Number of New Gadolinium-positive (Gd+) T1 Lesions at Week 48

End point description

Analysis of new Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.

End point type

Secondary

End point timeframe

Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: Lesions
arithmetic mean (standard deviation)	0.95 ( 1.569 )	1.84 ( 4.154 )	0.85 ( 2.867 )	0.49 ( 1.218 )	0.42 ( 1.444 )

No statistical analyses for this end point

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End point title

Qualified Relapse-free Status

End point 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 subjects with qualified relapse-free status were reported. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.

End point type

Secondary

End point timeframe

Week 25 to Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: percentage of subjects
number (not applicable)	84.1	86.4	78.3	91.1	96.0

No statistical analyses for this end point

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End point title

Annualized relapse rate (ARR)

End point 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. The modified ITT (mITT) analysis set consists of all subjects 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.

End point type

Secondary

End point timeframe

Week 0 to Week 48

End point values	Placebo (period 1)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	53	50	51	53	54
Units: relapses per year
arithmetic mean (confidence interval 95%)	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)

No statistical analyses for this end point

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End point title

Total Number of New or Enlarging T2 Lesions at Week 48 relative to Week 24

End point description

Analysis of New or Enlarging T2 lesions was done using magnetic resonance imaging (MRI) scans. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Week 24 to Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	42	42	43	43	50
Units: Lesions
arithmetic mean (standard deviation)	3.57 ( 4.346 )	5.86 ( 11.330 )	3.84 ( 10.083 )	1.60 ( 3.799 )	1.88 ( 4.796 )

No statistical analyses for this end point

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End point title

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

End point description

End point type

Secondary

End point timeframe

Week 24, Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: Units on a scale
arithmetic mean (standard deviation)	-0.05 ( 0.260 )	-0.10 ( 0.351 )	-0.01 ( 0.619 )	0.00 ( 0.238 )	-0.10 ( 0.404 )

No statistical analyses for this end point

Top of page

End point title

Change From Week 24 in Volume of T2 Lesions at Week 48

End point description

Analysis of volume of T2 lesions was done using magnetic resonance imaging (MRI) scans. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.

End point type

Secondary

End point timeframe

Week 24, Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: cc
arithmetic mean (standard deviation)	0.53 ( 1.360 )	0.67 ( 1.865 )	0.35 ( 1.083 )	-0.03 ( 1.031 )	-0.57 ( 2.699 )

No statistical analyses for this end point

Top of page

End point title

Change From Week 24 in Volume of gadolinium-positive (Gd+) T1 Lesions at Week 48

End point description

Analysis of volume of Gd+ T1 lesions was done using magnetic resonance imaging (MRI) scans. mITT BE analysis set included all subjects who belonged to the mITT analysis set with an MRI assessment during the 24-week blinded extension period.

End point type

Secondary

End point timeframe

Week 24, Week 48

End point values	Placebo Then Evobrutinib 25 mg QD (Period 2)	Evobrutinib 25 mg QD (Period 1 and 2)	Evobrutinib 75 mg QD (Period 1 and 2)	Evobrutinib 75 mg BID (Period 1 and 2)	Tecfidera (Period 1 and 2)
Number of subjects analysed	44	44	46	45	50
Units: cc
arithmetic mean (standard deviation)	0.092 ( 0.4626 )	0.088 ( 0.4006 )	0.045 ( 0.2285 )	0.024 ( 0.1981 )	-0.203 ( 1.1073 )

No statistical analyses for this end point

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End point title

OLE Period: Total Number of Gadolinium-Enhancing T1 Lesions

End point description

Analysis of T1-Gadolinium enhancing lesions was done using magnetic resonance imaging (MRI) scans. modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: subjects randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Here, “Overall Number of Subjects Analyzed” = subjects evaluable for this endpoint and “n” = subjects who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.

End point type

Secondary

End point timeframe

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

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	34	35	37	44	37
Units: Lesions
arithmetic mean (standard deviation)
Baseline(BE period Week 48): n =34, 35, 37, 44, 37	0.82 ( 2.668 )	1.74 ( 4.395 )	1.46 ( 4.519 )	1.16 ( 3.050 )	2.03 ( 11.829 )
Week 96: n = 31, 27, 35, 36, 36	0.13 ( 0.341 )	0.63 ( 1.822 )	0.49 ( 1.121 )	0.69 ( 1.411 )	0.67 ( 2.255 )
Week 144: n = 29, 27, 34, 35, 31	0.76 ( 2.294 )	0.41 ( 1.217 )	0.82 ( 3.512 )	0.54 ( 1.146 )	1.29 ( 5.940 )
Week 192: n = 28, 25, 32, 32, 26	1.00 ( 3.367 )	0.64 ( 1.890 )	0.81 ( 2.206 )	0.84 ( 1.798 )	0.96 ( 3.130 )
Week 240: n = 25, 24, 30, 30, 26	1.68 ( 5.800 )	0.63 ( 1.996 )	0.37 ( 1.189 )	0.77 ( 2.417 )	0.88 ( 3.204 )
Week 288: n = 20, 17, 28, 26, 23	0.35 ( 0.671 )	0.35 ( 0.786 )	0.32 ( 1.090 )	1.04 ( 2.946 )	0.35 ( 1.265 )
Week 336: n = 6, 7, 6, 7, 15	0.83 ( 1.602 )	3.00 ( 5.745 )	1.17 ( 2.858 )	0.29 ( 0.756 )	5.60 ( 18.310 )

No statistical analyses for this end point

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End point title

OLE Period: Annualized relapse rate (ARR)

End point 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. modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: subjects randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Here, “n” = subjects who were evaluable for the specified category. Results reported are for OLE period only and no participants took placebo during this period.

End point type

Secondary

End point timeframe

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

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	38	42	44	48
Units: relapses per year
arithmetic mean (confidence interval 95%)
Baseline(BE period Week 48): n =39, 38, 42, 44, 48	0.29 (0.14 to 0.53)	0.18 (0.06 to 0.38)	0.14 (0.04 to 0.32)	0.17 (0.07 to 0.36)	0.12 (0.04 to 0.28)
Week 96: n = 37, 36, 37, 44, 40	0.16 (0.05 to 0.37)	0.13 (0.04 to 0.34)	0.09 (0.02 to 0.26)	0.08 (0.02 to 0.22)	0.03 (0.00 to 0.16)
Week 144: n = 33, 30, 37, 40, 36	0.07 (0.01 to 0.25)	0.11 (0.02 to 0.33)	0.03 (0.00 to 0.17)	0.15 (0.05 to 0.34)	0.16 (0.05 to 0.37)
Week 192: n = 31, 27, 35, 35, 33	0.04 (0.00 to 0.20)	0.08 (0.01 to 0.29)	0.22 (0.09 to 0.45)	0.16 (0.05 to 0.38)	0.04 (0.00 to 0.20)
Week 240: n = 30, 27, 34, 33, 30	0.16 (0.04 to 0.41)	0.04 (0.00 to 0.23)	0.10 (0.02 to 0.28)	0.13 (0.04 to 0.34)	0.00 (0.00 to 0.15)
Week 288: n = 25, 24, 32, 32, 26	0.13 (0.13 to 0.38)	0.05 (0.00 to 0.25)	0.07 (0.01 to 0.25)	0.00 (0.00 to 0.13)	0.04 (0.00 to 0.24)
Week 336: n = 24, 22, 26, 29, 7	0.00 (0.00 to 1.75)	0.00 (0.00 to 1.55)	0.31 (0.01 to 1.70)	0.00 (0.00 to 1.27)	0.00 (0.00 to 7.97)

No statistical analyses for this end point

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End point title

OLE Period: Percentage of Subjects with Qualified Relapse-Free Status

End point 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 subjects with qualified relapse-free status from OLE Baseline (BE period Week 48) up to Week 336 were reported. The modified ITT (mITT) analysis set consists of all subjects 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. esults reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

OLE Baseline (BE period Week 48) up to OLE Week 336

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	38	42	44	48
Units: percentage of subjects
number (not applicable)	66.7	68.4	71.4	65.9	83.3

No statistical analyses for this end point

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End point title

OLE Period: Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 96, 144, 192, 240, 288 and 336

End point 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). modified ITT OLE Analysis Set (mITT-OLE) Analysis Set: subjects randomly allocated to a treatment who belong to Safety OLE Analysis Set, and who have at least 1 Magnetic Resonance Imaging (MRI) assessment on or after OLE Week 0. Here, “Overall Number of Subjects Analyzed” = subjects evaluable for this endpoint and “n” = subjects who were evaluable for the specified category. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

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

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	37	35	28	44	40
Units: units on a scale
arithmetic mean (standard deviation)
Baseline(BE period Week 48): n =37, 35, 28, 44, 40	0.1 ( 0.39 )	0.0 ( 0.69 )	0.1 ( 0.46 )	0.0 ( 0.27 )	0.0 ( 0.34 )
Week 96: n = 34, 30, 35, 38, 36	0.1 ( 0.40 )	0.1 ( 0.46 )	0.2 ( 0.71 )	0.0 ( 0.42 )	0.0 ( 0.32 )
Week 144: n = 31, 27, 36, 35, 32	0.1 ( 0.79 )	0.1 ( 0.61 )	0.2 ( 0.79 )	0.0 ( 0.44 )	0.0 ( 0.28 )
Week 192: n = 28, 26, 34, 33, 28	0.2 ( 0.64 )	0.1 ( 0.61 )	0.2 ( 0.35 )	0.2 ( 0.72 )	0.0 ( 0.29 )
Week 240: n = 25, 25, 32, 32, 26	0.3 ( 0.72 )	0.3 ( 0.50 )	0.2 ( 0.46 )	0.2 ( 0.93 )	0.1 ( 0.40 )
Week 288: n = 25, 23, 29, 29, 25	0.4 ( 0.80 )	0.1 ( 0.87 )	0.4 ( 0.58 )	0.4 ( 0.81 )	0.2 ( 0.45 )
Week 336: n = 11, 10, 10, 7, 15	0.0 ( 0.52 )	0.5 ( 1.36 )	0.7 ( 1.38 )	-0.2 ( 0.57 )	0.0 ( 0.52 )

No statistical analyses for this end point

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End point title

OLE Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

End point description

AE: any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the study drug. SAE: 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. TEAEs: 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 included both Serious TEAEs and non-serious TEAEs. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

OLE Baseline (BE period Week 48) up to OLE Week 336

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	39	42	44	49
Units: subjects	35	29	41	40	37

No statistical analyses for this end point

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End point title

OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Laboratory Parameters

End point description

Laboratory parameters included hematology, biochemistry, and urinalysis. Number of subjects with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

OLE Baseline (BE period Week 48) up to OLE Week 336

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	39	42	44	49
Units: subjects	0	0	0	0	0

No statistical analyses for this end point

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End point title

OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Vital Signs

End point description

Vital signs, including semi supine blood pressure, pulse rate, respiratory rate, weight, and oral temperature were assessed. Number of subjects with clinically significant change from baseline in vital signs were reported. Clinical Significance was decided by the investigator. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

OLE Baseline (BE period Week 48) up to OLE Week 336

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	39	42	44	49
Units: subjects	0	0	0	0	0

No statistical analyses for this end point

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End point title

OLE Period: Number of Subjects With Clinically Significant Changes From Baseline in Electrocardiograms (ECGs)

End point description

ECG parameters included rhythm, ventricular rate, PR interval, QRS duration, and QT interval. Number of subjects with clinically significant change from baseline in ECG were reported. Clinical Significance was decided by the investigator. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

OLE Baseline (BE period Week 48) up to OLE Week 336

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	39	39	42	44	49
Units: subjects	0	0	0	0	0

No statistical analyses for this end point

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End point title

OLE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels

End point description

Absolute Concentrations serum levels of IgG, IgA, IgM were assessed. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Here, “Overall Number of Subjects Analyzed” = subjects evaluable for this endpoint and “n” = subjects who were evaluable for the specified category. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

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

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	37	37	37	44	40
Units: Gram per Liter
arithmetic mean (standard deviation)
Ig A,Baseline (Week 48):n = 37, 37, 37, 44, 40	2.31 ( 0.966 )	2.44 ( 0.897 )	2.49 ( 0.953 )	2.52 ( 0.970 )	2.31 ( 0.906 )
Ig A, Week 96: n = 32, 30, 36, 39, 38	2.42 ( 1.173 )	2.69 ( 1.026 )	2.91 ( 1.181 )	2.82 ( 1.113 )	2.62 ( 1.072 )
Ig A, Week 144: n = 30, 27, 36, 35, 33	2.57 ( 1.274 )	2.73 ( 0.918 )	2.82 ( 1.326 )	2.91 ( 1.233 )	2.57 ( 1.025 )
IgA, Week 192: n = 29, 26, 33, 32, 26	2.60 ( 1.242 )	2.71 ( 0.987 )	2.86 ( 1.255 )	3.15 ( 1.185 )	2.70 ( 1.055 )
IgA, Week 240: n = 24,22, 33, 28, 23	2.71 ( 1.280 )	2.85 ( 1.095 )	3.05 ( 1.314 )	3.13 ( 1.269 )	2.65 ( 0.984 )
IgA, Week 288: n = 37, 20, 26, 27, 17	2.68 ( 1.305 )	3.08 ( 1.276 )	3.12 ( 1.306 )	3.30 ( 1.347 )	2.92 ( 1.108 )
Ig G, Baseline(Week 48): n = 37, 37, 37, 44, 40	9.75 ( 2.253 )	10.37 ( 2.512 )	10.73 ( 2.479 )	10.44 ( 2.291 )	9.65 ( 2.165 )
Ig G, Week 96: n = 32, 30, 36, 39, 38	9.46 ( 2.490 )	10.10 ( 2.461 )	10.76 ( 2.413 )	10.29 ( 2.172 )	9.93 ( 2.285 )
Ig G, Week 144: n = 30, 27, 36, 35, 33	9.48 ( 2.294 )	10.43 ( 2.304 )	10.38 ( 2.638 )	10.21 ( 2.552 )	9.32 ( 2.115 )
IgG, Week 192: n = 29, 26, 33, 32, 26	9.37 ( 2.156 )	9.99 ( 2.197 )	10.36 ( 2.548 )	10.46 ( 2.135 )	9.56 ( 2.094 )
IgG, Week 240: n = 24,22, 33, 28, 23	9.28 ( 2.081 )	10.33 ( 2.422 )	2.422 ( 2.562 )	10.47 ( 2.562 )	9.58 ( 2.245 )
IgG, Week 288: n = 25, 20, 26, 27, 17	9.46 ( 2.068 )	10.48 ( 2.541 )	10.64 ( 2.566 )	10.36 ( 2.273 )	9.72 ( 2.700 )
Ig M, Baseline (Week 48): n = 37, 37, 37, 44, 40	1.06 ( 0.550 )	0.89 ( 0.403 )	1.08 ( 0.680 )	0.92 ( 0.422 )	0.99 ( 0.586 )
Ig M, Week 96: n = 32, 30, 36, 39, 38	1.01 ( 0.556 )	0.87 ( 0.413 )	1.05 ( 0.747 )	0.92 ( 0.460 )	0.91 ( 0.525 )
Ig M, Week 144: n = 30, 27, 36, 35, 33	0.88 ( 0.463 )	0.88 ( 0.468 )	0.94 ( 0.614 )	0.89 ( 0.377 )	0.90 ( 0.519 )
Ig M, Week 192: n = 28, 26, 33, 32, 26	0.89 ( 0.492 )	0.87 ( 0.461 )	0.90 ( 0.462 )	0.84 ( 0.320 )	0.90 ( 0.585 )
Ig M, Week 240: n = 24,22, 33, 28, 23	0.85 ( 0.420 )	0.83 ( 0.419 )	0.87 ( 0.468 )	0.88 ( 0.369 )	0.87 ( 0.611 )
Ig M, Week 288: n = 25, 22, 27, 28, 18	0.85 ( 0.405 )	0.90 ( 0.490 )	0.94 ( 0.544 )	0.87 ( 0.397 )	1.03 ( 0.568 )

No statistical analyses for this end point

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End point title

OLE Period: Change from Baseline in Immunoglobulin (Ig) Levels

End point description

Change from baseline in the serum levels of IgG, IgA, IgM were assessed. The Safety OLE Analysis Set included all subjects who receive at least 1 dose of Evobrutinib during the OLE. Here, “Overall Number of Subjects Analyzed” = subjects evaluable for this endpoint and “n” = subjects who were evaluable for the specified category. Results reported are for OLE period only and no subjects took placebo during this period.

End point type

Secondary

End point timeframe

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

End point values	Placebo + Evobrutinib 25 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (Period 3)
Number of subjects analysed	37	37	37	44	40
Units: Gram per Liter
arithmetic mean (standard deviation)
Ig A, Baseline (Week 48): n = 37, 37, 37, 44, 40	0.26 ( 0.237 )	0.17 ( 0.333 )	0.19 ( 0.283 )	0.26 ( 0.291 )	0.28 ( 0.355 )
Ig A, Week 96: n = 32, 30, 36, 39, 38	0.44 ( 0.491 )	0.45 ( 0.407 )	0.58 ( 0.485 )	0.54 ( 0.446 )	0.59 ( 0.545 )
Ig A, Week 144: n = 30, 27, 36, 35, 33	0.58 ( 0.594 )	0.41 ( 0.347 )	0.50 ( 0.670 )	0.57 ( 0.589 )	0.54 ( 0.452 )
IgA, Week 192: n = 29, 26, 33, 32, 36	0.60 ( 0.597 )	0.38 ( 0.443 )	0.55 ( 0.667 )	0.82 ( 0.530 )	0.67 ( 0.492 )
IgA, Week 240: n = 24, 22, 33, 28, 23	0.67 ( 0.605 )	0.55 ( 0.471 )	0.74 ( 0.682 )	0.78 ( 0.621 )	0.68 ( 0.520 )
IgA, Week 288: n = 25, 20, 26, 27, 17	0.68 ( 0.934 )	0.75 ( 0.680 )	0.91 ( 0.915 )	1.02 ( 0.637 )	0.93 ( 0.724 )
Ig G, Baseline (Week 48): n = 37, 37, 37, 44, 40	0.39 ( 0.960 )	0.54 ( 1.463 )	0.69 ( 1.147 )	1.11 ( 1.150 )	0.23 ( 1.216 )
Ig G, Week 96: n = 32, 30, 36, 39, 38	0.17 ( 1.359 )	0.18 ( 1.228 )	0.64 ( 1.178 )	0.84 ( 1.073 )	0.47 ( 1.355 )
Ig G, Week 144: n = 30, 27, 36, 35, 33	0.35 ( 1.367 )	0.17 ( 1.451 )	0.31 ( 1.356 )	0.68 ( 1.458 )	-0.09 ( 1.176 )
IgG, Week 192: n = 29, 26, 33, 32, 26	0.14 ( 1.227 )	-0.13 ( 1.141 )	0.18 ( 1.625 )	0.84 ( 1.384 )	0.09 ( 1.324 )
IgG, Week 240: n = 24, 22, 33, 28, 23	-0.01 ( 1.336 )	0.10 ( 1.557 )	0.37 ( 1.596 )	0.75 ( 1.362 )	0.19 ( 1.314 )
IgG, Week 288: n = 25, 20, 26, 27, 17	0.18 ( 1.492 )	0.48 ( 1.465 )	0.37 ( 2.203 )	1.01 ( 1.570 )	0.36 ( 1.440 )
Ig M, Baseline (Week 48): n = 37, 37, 37, 44, 40	-0.18 ( 0.152 )	-0.10 ( 0.120 )	-0.09 ( 0.122 )	-0.05 ( 0.099 )	-0.28 ( 0.280 )
IgM, Week 96: n = 32, 30, 36, 39, 38	-0.23 ( 0.146 )	-0.13 ( 0.141 )	-0.09 ( 0.199 )	-0.08 ( 0.127 )	-0.35 ( 0.301 )
IgM, Week 144: n = 30, 27, 36, 35, 33	-0.28 ( 0.323 )	-0.14 ( 0.195 )	-0.17 ( 0.174 )	-0.11 ( 0.149 )	-0.40 ( 0.327 )
IgM, Week 192: n = 28, 26, 33, 32, 26	-0.28 ( 0.254 )	-0.16 ( 0.204 )	-0.19 ( 0.186 )	-0.18 ( 0.197 )	-0.46 ( 0.330 )
IgM, Week 240: n = 24, 22, 33, 28, 23	-0.29 ( 0.282 )	-0.20 ( 0.187 )	-0.19 ( 0.205 )	-0.16 ( 0.254 )	-0.53 ( 0.348 )
IgM, Week 288: n = 25, 22, 27, 28, 18	-0.29 ( 0.284 )	-0.11 ( 0.313 )	-0.15 ( 0.315 )	-0.17 ( 0.178 )	-0.39 ( 0.472 )

No statistical analyses for this end point

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Timeframe for reporting adverse events

Baseline up to Safety Follow up of blinded extension period (Week 52); OLE Baseline (BE period Week 48) up to OLE Week 336

Adverse event reporting additional description

Active treatment period and BE period: MedDRA version 21.0; OLE Period: MedDRA version 26.1

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.026.1

Reporting group title

Evobrutinib 25 mg QD (Period 1 and Period 2)

Reporting group description

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

Reporting group title

Placebo

Reporting group description

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

Reporting group title

Evobrutinib 75 mg BID (Period 1 and Period 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg QD (Period 1 and Period 2)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg BID (Period 3)

Reporting group description

Subjects received Evobrutinib 75 mg BID orally from Week 48 of main period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Tecfidera (period 3)

Reporting group description

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

Reporting group title

Evobrutinib 75 mg QD (Period 3)

Reporting group description

Subjects received Evobrutinib 75 mg QD orally from Week 48 of main period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Evobrutinib 25 mg QD (Period 3)

Reporting group description

Subjects received Evobrutinib 25 mg QD orally from Week 48 of main period (OLE period Day 1) to Week 336 in OLE period.

Reporting group title

Placebo Then Evobrutinib 25 mg QD

Reporting 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.

Reporting group title

Tecfidera (Period 1 and Period 2)

Reporting group description

Subjects 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.

Reporting group title

Placebo + Evobrutinib 25 mg QD (Period 3)

Reporting group description

Subjects who received placebo matched to Evobrutinib tablet orally for 24 weeks in main treatment period were switched to receive Evobrutinib 25 mg orally, QD up to 301 weeks in OLE period.

Serious adverse events	Evobrutinib 25 mg QD (Period 1 and Period 2)	Placebo	Evobrutinib 75 mg BID (Period 1 and Period 2)	Evobrutinib 75 mg QD (Period 1 and Period 2)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Placebo Then Evobrutinib 25 mg QD	Tecfidera (Period 1 and Period 2)	Placebo + Evobrutinib 25 mg QD (Period 3)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 52 (3.85%)	2 / 54 (3.70%)	4 / 54 (7.41%)	2 / 53 (3.77%)	5 / 44 (11.36%)	10 / 49 (20.41%)	8 / 42 (19.05%)	12 / 39 (30.77%)	0 / 49 (0.00%)	2 / 54 (3.70%)	7 / 39 (17.95%)
number of deaths (all causes)	0	0	0	0	1	1	0	1	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 52 (0.00%)	1 / 54 (1.85%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian germ cell teratoma benign
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papilloma
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral embolism
subjects affected / exposed	0 / 52 (0.00%)	1 / 54 (1.85%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood pressure fluctuation
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Heavy menstrual bleeding
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine cervix stenosis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Nasal polyps
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mood disorder due to a general medical condition
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Transaminases increased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	1 / 52 (1.92%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial ischaemia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Restless legs syndrome
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar ischaemia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral venous sinus thrombosis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple sclerosis pseudo relapse
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar artery dissection
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo CNS origin
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Microcytic anaemia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Keratoconus
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis toxic
subjects affected / exposed	1 / 52 (1.92%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	1 / 42 (2.38%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Bladder hypertrophy
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	2 / 42 (4.76%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture pain
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lyme disease
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	1 / 54 (1.85%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 52 (0.00%)	1 / 54 (1.85%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	2 / 49 (4.08%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervicitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometritis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Serratia infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Haemochromatosis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Evobrutinib 25 mg QD (Period 1 and Period 2)	Placebo	Evobrutinib 75 mg BID (Period 1 and Period 2)	Evobrutinib 75 mg QD (Period 1 and Period 2)	Evobrutinib 75 mg BID (Period 3)	Tecfidera (period 3)	Evobrutinib 75 mg QD (Period 3)	Evobrutinib 25 mg QD (Period 3)	Placebo Then Evobrutinib 25 mg QD	Tecfidera (Period 1 and Period 2)	Placebo + Evobrutinib 25 mg QD (Period 3)
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 52 (36.54%)	14 / 54 (25.93%)	20 / 54 (37.04%)	19 / 53 (35.85%)	31 / 44 (70.45%)	26 / 49 (53.06%)	34 / 42 (80.95%)	26 / 39 (66.67%)	9 / 49 (18.37%)	30 / 54 (55.56%)	30 / 39 (76.92%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	1	0	2	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	12 / 54 (22.22%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	12	0
Hypertension
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 44 (4.55%)	2 / 49 (4.08%)	2 / 42 (4.76%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	2	2	2	0	0	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	3 / 42 (7.14%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	1	0	3	2	0	0	1
Vaccination site pain
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	2 / 42 (4.76%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	1	2	0	0	0	2
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 44 (4.55%)	1 / 49 (2.04%)	3 / 42 (7.14%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	2	1	3	1	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	2 / 49 (4.08%)	2 / 42 (4.76%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	2	2	0	0	0	2
Depressed mood
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	3 / 42 (7.14%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	1	0	3	0	0	0	1
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 52 (1.92%)	1 / 54 (1.85%)	4 / 54 (7.41%)	2 / 53 (3.77%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	2 / 54 (3.70%)	0 / 39 (0.00%)
occurrences all number	1	1	4	2	0	0	0	0	0	2	0
Blood creatinine increased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	3 / 54 (5.56%)	3 / 53 (5.66%)	3 / 44 (6.82%)	1 / 49 (2.04%)	2 / 42 (4.76%)	1 / 39 (2.56%)	0 / 49 (0.00%)	1 / 54 (1.85%)	2 / 39 (5.13%)
occurrences all number	0	0	3	3	3	1	2	1	0	1	2
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 52 (1.92%)	0 / 54 (0.00%)	3 / 54 (5.56%)	1 / 53 (1.89%)	0 / 44 (0.00%)	3 / 49 (6.12%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	1 / 54 (1.85%)	2 / 39 (5.13%)
occurrences all number	1	0	3	1	0	3	1	0	0	1	2
Lipase increased
subjects affected / exposed	2 / 52 (3.85%)	2 / 54 (3.70%)	5 / 54 (9.26%)	5 / 53 (9.43%)	8 / 44 (18.18%)	5 / 49 (10.20%)	6 / 42 (14.29%)	6 / 39 (15.38%)	3 / 49 (6.12%)	3 / 54 (5.56%)	5 / 39 (12.82%)
occurrences all number	2	2	5	5	8	5	6	6	3	3	5
Alanine aminotransferase increased
subjects affected / exposed	3 / 52 (5.77%)	3 / 54 (5.56%)	5 / 54 (9.26%)	6 / 53 (11.32%)	0 / 44 (0.00%)	5 / 49 (10.20%)	0 / 42 (0.00%)	1 / 39 (2.56%)	1 / 49 (2.04%)	3 / 54 (5.56%)	1 / 39 (2.56%)
occurrences all number	3	3	5	6	0	5	0	1	1	3	1
Lymphocyte count decreased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	1 / 44 (2.27%)	2 / 49 (4.08%)	0 / 42 (0.00%)	2 / 39 (5.13%)	0 / 49 (0.00%)	5 / 54 (9.26%)	1 / 39 (2.56%)
occurrences all number	0	0	1	0	1	2	0	2	0	5	1
White blood cell count decreased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	3 / 54 (5.56%)	0 / 39 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	3	0
Amylase increased
subjects affected / exposed	0 / 52 (0.00%)	3 / 54 (5.56%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	1 / 49 (2.04%)	1 / 42 (2.38%)	2 / 39 (5.13%)	3 / 49 (6.12%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	3	0	0	1	1	1	2	3	0	1
Weight increased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	2
Blood bilirubin increased
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	4 / 49 (8.16%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	4	0	0	0	0	0
Injury, poisoning and procedural complications
Immunisation reaction
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	3 / 49 (6.12%)	1 / 42 (2.38%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	1	3	1	2	0	0	2
Fall
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	4 / 44 (9.09%)	0 / 49 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	4	0	0	1	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	3 / 52 (5.77%)	2 / 54 (3.70%)	1 / 54 (1.85%)	2 / 53 (3.77%)	6 / 44 (13.64%)	4 / 49 (8.16%)	5 / 42 (11.90%)	2 / 39 (5.13%)	0 / 49 (0.00%)	1 / 54 (1.85%)	3 / 39 (7.69%)
occurrences all number	3	2	1	2	6	4	5	2	0	1	3
Hypoaesthesia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 44 (4.55%)	1 / 49 (2.04%)	1 / 42 (2.38%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	2	1	1	1	0	0	2
Sciatica
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	0 / 42 (0.00%)	3 / 39 (7.69%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	1	0	3	0	0	2
Balance disorder
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	0 / 49 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	1	0	0	2	0	0	1
Muscle spasticity
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	3 / 42 (7.14%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0	0
Blood and lymphatic system disorders
Microcytic anaemia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	4 / 39 (10.26%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	1	4	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	1 / 49 (2.04%)	1 / 42 (2.38%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	1	1	1	0	0	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 52 (3.85%)	0 / 54 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 44 (0.00%)	3 / 49 (6.12%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	3 / 54 (5.56%)	3 / 39 (7.69%)
occurrences all number	2	0	1	0	0	3	0	0	0	3	3
Diarrhoea
subjects affected / exposed	1 / 52 (1.92%)	1 / 54 (1.85%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	3 / 49 (6.12%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	4 / 54 (7.41%)	1 / 39 (2.56%)
occurrences all number	1	1	0	0	0	3	1	0	0	4	1
Vomiting
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	3 / 49 (6.12%)	1 / 42 (2.38%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	0	3	1	0	0	0	1
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	7 / 54 (12.96%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	7	0
Rash
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	3 / 42 (7.14%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	3	2	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 52 (3.85%)	1 / 54 (1.85%)	0 / 54 (0.00%)	3 / 53 (5.66%)	2 / 44 (4.55%)	2 / 49 (4.08%)	1 / 42 (2.38%)	3 / 39 (7.69%)	0 / 49 (0.00%)	4 / 54 (7.41%)	5 / 39 (12.82%)
occurrences all number	2	1	0	3	2	2	1	3	0	4	5
Pain in extremity
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	3 / 49 (6.12%)	3 / 42 (7.14%)	4 / 39 (10.26%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	1	3	3	4	0	0	2
Back pain
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	3 / 44 (6.82%)	0 / 49 (0.00%)	9 / 42 (21.43%)	5 / 39 (12.82%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	3	0	9	5	0	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	9 / 52 (17.31%)	5 / 54 (9.26%)	7 / 54 (12.96%)	3 / 53 (5.66%)	9 / 44 (20.45%)	4 / 49 (8.16%)	8 / 42 (19.05%)	7 / 39 (17.95%)	1 / 49 (2.04%)	2 / 54 (3.70%)	7 / 39 (17.95%)
occurrences all number	9	5	7	3	9	4	8	7	1	2	7
Upper respiratory tract infection
subjects affected / exposed	1 / 52 (1.92%)	0 / 54 (0.00%)	1 / 54 (1.85%)	1 / 53 (1.89%)	4 / 44 (9.09%)	3 / 49 (6.12%)	6 / 42 (14.29%)	2 / 39 (5.13%)	0 / 49 (0.00%)	3 / 54 (5.56%)	5 / 39 (12.82%)
occurrences all number	1	0	1	1	4	3	6	2	0	3	5
Urinary tract infection
subjects affected / exposed	2 / 52 (3.85%)	3 / 54 (5.56%)	0 / 54 (0.00%)	1 / 53 (1.89%)	5 / 44 (11.36%)	3 / 49 (6.12%)	7 / 42 (16.67%)	5 / 39 (12.82%)	0 / 49 (0.00%)	0 / 54 (0.00%)	7 / 39 (17.95%)
occurrences all number	2	3	0	1	5	3	7	5	0	0	7
Cystitis
subjects affected / exposed	1 / 52 (1.92%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	3 / 49 (6.12%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	3	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Laryngitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)	0 / 49 (0.00%)	0 / 54 (0.00%)	0 / 39 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 44 (2.27%)	1 / 49 (2.04%)	4 / 42 (9.52%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	1	1	4	1	0	0	1
Pharyngitis
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	2 / 44 (4.55%)	2 / 49 (4.08%)	3 / 42 (7.14%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	1 / 39 (2.56%)
occurrences all number	0	0	0	0	2	2	3	1	0	0	1
COVID-19
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	6 / 44 (13.64%)	7 / 49 (14.29%)	3 / 42 (7.14%)	8 / 39 (20.51%)	0 / 49 (0.00%)	0 / 54 (0.00%)	6 / 39 (15.38%)
occurrences all number	0	0	0	0	6	7	3	8	0	0	6
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	0 / 52 (0.00%)	0 / 54 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 44 (0.00%)	0 / 49 (0.00%)	1 / 42 (2.38%)	1 / 39 (2.56%)	0 / 49 (0.00%)	0 / 54 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	2

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2017

• Addition of 2-week safety visits for chemistry monitoring (including ALT, AST, alkaline phosphatase, GGT, and bilirubin) until the IDMC determines the optimum monitoring interval for participant randomized to the M2951/placebo arm; • Addition of a comprehensive hepatic panel for participants randomized to the M2951/placebo arm for whom withdrawal criteria are met or who permanently discontinue dosing because of elevated transaminases; • Addition of blood tests (ESR, hsCRP, and fibrinogen) for all participants at any 1 point during the trial; • Addition of Open-label extension period, with modifications to planned trial period, addition of objective and endpoints, addition of statistical analyses and analysis set, addition of informed consent prior to participation, and clarification that there will be a second clinical trial report; • Addition of pharmacokinetic endpoints and statistical analyses • Clarification of pharmacodynamics endpoints • Clarification that separate informed consent will be collected for the MRI dummy run; • Clarification that soluble factors may be measured from pharmacokinetic blood samples if there is sufficient volume; • Clarification that blood pressure will be collected in a semisupine position;

29 May 2018

• Update exploratory endpoints; • Remove Futility analyses (also referred to as interim analyses) • Remove 2-week additional safety visits after Week 16 and update to a monthly (4-week) schedule; • Clarify that phone calls for confirmation of home pregnancy testing is required only if urine pregnancy tests are completed at home; • Include monthly urine pregnancy tests for all sites in all countries during the main study and OLE period; • Clarify the schedule of collection of additional PK samples;

08 Aug 2018

To include recommendations from the Czech Republic Regulatory Authority on reinitiating IMP following increase in AST, ALT, or bilirubin to Grade 2.

21 Nov 2018

• Based on the efficacy and safety data from the primary analysis at 24 weeks and the blinded extension analysis at 48 weeks, the optimal tested dose is 75 mg twice daily. • Increased liver monitoring was added following an urgent safety measure. • Provide direction to sites to consult with Medical Monitor regarding potential withdrawal, continued participation in study, additional monitoring, and retesting. • Updated liver enzyme stopping criteria to ensure the safety of the patients within the study.

08 Nov 2019

To extend the optional open-label extension period of the study by 5 years (60 months), to allow patients continued access to study treatment and long-term characterization of the study drug in patients with relapsing multiple sclerosis. The Sponsor evaluated the duration of the extension on an annual basis.

02 Dec 2022

To include an opportunity for participants who completed their treatment under the current protocol to transition into the long-term follow-up study under a new protocol allowing continued access to study treatment. Additionally, the prohibited medicines section was revised to include an additional concomitant therapeutic option, as well as other prohibited medications.

06 Jul 2023

• To reflect the recent update to the risk profile of evobrutinib (i.e., important identified risk of drug-induced liver injury) by adapting monitoring and discontinuation criteria, as well as language on tolerability and safety of evobrutinib across the protocol. • To extend the OLE period by up to one additional year to allow an opportunity for participants to transition into the long-term follow-up study under a new protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Reported p values are not adjusted for multiple testing.

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End point values

Placebo (period 1)

Placebo Then Evobrutinib 25 mg QD (Period 2)

Evobrutinib 25 mg QD (Period 1 and 2)

Evobrutinib 75 mg QD (Period 1 and 2)

Evobrutinib 75 mg BID (Period 1 and 2)

Tecfidera (Period 1 and 2)

Number of subjects analysed

Units: subjects

Serious TEAEs

TEAEs Leading to Death