Clinical trial NCT04032171
Conditions: Relapsing-remitting Multiple Sclerosis
Keywords: Evobrutinib Avonex® Interferon-beta 1a Relapsing Multiple Sclerosis
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2019-09-10; Completion date: 2020-05-20
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Interferon-beta-1a (Avonex®), once a week intramuscularly in participants with Relapsing Multiple Sclerosis (RMS).

Detailed description:

Arms: arm 1: Participants received active evobrutinib twice daily (BID) along with concomitant intramuscular (IM) injection of placebo matched to Avonex® once a week. Treatment period was planned to be of 96 weeks. arm 2: Participants received IM injection of active Avonex® once a week along with concomitant placebo matched to evobrutinib BID. Treatment period was planned to be of 96 weeks.
Interventions: intervention 1: Evobrutinib intervention 2: Avonex® intervention 3: Avonex® matched Placebo intervention 4: Evobrutinib matched Placebo
Intervention descriptions: intervention 1: Participants received evobrutinib twice daily (BID). intervention 2: Participants received avonex® IM injection once a week. intervention 3: Participants received IM injection of placebo matched to avonex® once a week. intervention 4: Participants received placebo matched to evobrutinib twice a day.

Protocol documents:
Prot_000.pdf: 
Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Phase III, Multicenter, Randomized, Parallel 
Group, Double Blind, Double Dummy, Active 
Controlled Study of Evobrutinib Compared with an 
Interferon Beta 1a (Avonex®), in Participants with 
Relapsing Multiple Sclerosis to Evaluate Efficacy 
and Safety.
Study Number:
MS200527ˍ0074
Amendment Number
1.0
Merck Compound Number:
M2951
Study Phase:
III
Short Title:
Phase III Study of Evobrutinib in RMS
Acronym:
EVOLUTION MS2
Coordinating Investigator:
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Sponsor Name and Legal Registered 
Address:
For all countries, except the US and Canada:
Merck Healthcare KGaA
an affiliate of Merck KGaA, Darmstadt, Germany
Frankfurter Str. 250
Darmstadt, Germany
In the US and Canada:
EMD Serono Research & Development Institute, 
Inc.
an affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA, 01821, USA
Medical Responsible:
Name:
Address:
EMD Serono Research & Development Institute 
Inc. 45A Middlesex Turnpike, Billerica, MA 
01821, USA 
Phone:
Fax: Not Applicable
E-mail:
Regulatory 
Agency 
Identifying 
Numbers:
EudraCT: 2018-004700-19
Protocol Version:
05 Sep 2019 / Version 2.0
Replaces Version:
10 Jul 2019 / Version 1.0
Approval Date:
05 Sep 2019
Medical Monitor Name and Contact 
Information:
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Protocol Amendment Summary of Changes
Type
Example
Notes
Scope
Version Number
Original protocol
Global
1.0
Initial version submitted to the first IRB or 
IEC
Amendment 1
Global
2.0
Based on feedback provided by Voluntary 
Harmonisation Procedure (VHP)
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
10-Jul-2019
2.0
Amendment 1
05-Sep-2019
Protocol Version 2.0 (05-Sep-2019)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
! Restructuring of text on discontinuation of Study Intervention.
! Clarification of role of Sponsor’s Medical Monitor.
! Clarification of statistical approach towards primary and secondary endpoints.
! Adjustment of Exclusion Criteria.
! Clarification of use of concomitant therapy.
The following elements of the protocol have been revised for clarity and specificity (see Table 
below).
Section # and Name
Description of Change
Brief Rationale
Full document
Correction of typos and technical issues
Clarity and consistency
5.2 Exclusion Criteria
Criterion No.7, info added regarding TB skin 
test at Screening
Clarification of TB skin test 
at Screening
5.2 Exclusion Criteria
Criterion No.38, statement added that 
patients should be informed that IMP contains 
lactose
Ensure participant safety
5.2 Exclusion Criteria 
Criterion No.13, text regarding exclusion of 
patients with untreated hypertension and GI 
bleeding has been added
Clarification of participant 
exclusion
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Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Criterion No. 17 modified to include examples 
of specific ECG abnormalities
Clarification of participant 
exclusion
5.2 Exclusion Criteria
No. 29c modified to clarify role of Sponsor’s 
Medical Monitor
Clarification of participant 
exclusion
6.3.3 Emergency Unblinding
Text has been deleted
Clarification of role of 
Sponsor’s Medical Monitor
6.5.1 Rescue Medicine
Text modified to emphasize priority of relapse 
treatment over timing of MRI scan
Ensure participant safety
6.5 Concomitant Therapy,
6.5.3 Prohibited Medicines
Rules for use of antispasticity agents have 
been modified
Clarification of concomitant 
therapy
6.5.4 Other Interventions
Paracetamol has been removed
Clarification of other 
interventions
7.1 Discontinuation of Study 
Intervention
Section revised and reorganized
Clarification of 
discontinuation of study 
intervention
7.2 Participant 
Discontinuation/Withdrawal from 
the Study
Text has been revised
Clarification of participant’s 
withdrawal from the study
8 Assessments and Procedures
Reworded to include examples of specific 
ECG abnormalities
Clarification of ECG 
assessment and procedure
8.2.3 Electrocardiograms
Information has been added regarding 
interpretation of ECG results
Clarification of ECG 
assessment and procedure
8.2.8 Columbia-Suicide Severity 
Rating Scale
Additional monitoring step added
Ensure proper study 
conduct
 
9.4.1.1 Efficacy Analyses related 
to Primary Objective
Description of the Negative Binomial (NB) 
model from which adjusted ARR is estimated
added
Clarification of statistical 
approach
9.4.1 Efficacy Analyses,
9.4.1.1 Efficacy Analyses related 
to Primary Objective,
9.4.1.2 Efficacy Analyses related 
to Secondary Objectives
Information added regarding missing data 
handling in the primary analysis of the 
primary endpoint (including missing data 
handling in the primary analyses of 
secondary endpoints)
Clarification of statistical 
approach 
4.1 Overall Design,
9.4.1.2 Efficacy Analyses related 
to Secondary Objectives,
 
Specific promising zone boundaries added
Clarification of statistical 
approach
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2019 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................5
1
Protocol Summary ..............................................................................10
1.1
Synopsis..............................................................................................10
1.2
Schema................................................................................................13
1.3
Schedule of Activities.........................................................................14
1.3.1
Schedule of Assessments: Screening and Treatment Period (All 
Participants), End of Trial (Participants Not Entering Open Label 
Extension Period)................................................................................14
1.3.2
Schedule of Assessments – Optional Open Label Extension Period..22
2
Introduction.........................................................................................30
2.1
Study Rationale...................................................................................30
2.2
Background.........................................................................................31
2.3
Benefit/Risk Assessment ....................................................................33
3
Objectives and Endpoints ...................................................................35
4
Study Design.......................................................................................42
4.1
Overall Design....................................................................................42
4.2
Scientific Rationale for Study Design ................................................43
4.3
Justification for Dose..........................................................................44
4.4
End of Study Definition......................................................................45
5
Study Population.................................................................................46
5.1
Inclusion Criteria ................................................................................46
5.2
Exclusion Criteria...............................................................................48
5.3
Criteria for Entry into Open Label Extension Period.........................53
5.3.1
Inclusion Criteria for Open Label Extension Period ..........................53
5.3.2
Exclusion Criteria for Open Label Extension Period .........................53
5.4
Lifestyle Considerations .....................................................................54
5.4.1
Meals and Dietary Restrictions...........................................................54
5.4.2
Caffeine, Alcohol, and Tobacco .........................................................54
5.5
Screen Failures....................................................................................54
6
Study Intervention(s) ..........................................................................54
6.1
Study Intervention(s) Administration.................................................54
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6.1.1
Medical Device(s) Use .......................................................................55
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................55
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................57
6.3.1
Study Intervention Assignment ..........................................................57
6.3.2
Blinding ..............................................................................................57
6.3.3
Emergency Unblinding.......................................................................59
6.4
Study Intervention Compliance..........................................................60
6.5
Concomitant Therapy .........................................................................60
6.5.1
Rescue Medicine.................................................................................60
6.5.2
Permitted Medicines...........................................................................61
6.5.3
Prohibited Medicines..........................................................................61
6.5.4
Other Interventions.............................................................................62
6.6
Dose Selection and Modification........................................................62
6.7
Study Intervention after the End of the Study ....................................62
6.8
Special Precautions.............................................................................63
6.9
Management of Adverse Events of Interest........................................63
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................64
7.1
Discontinuation of Study Intervention................................................64
7.1.1
Temporary Discontinuation................................................................69
7.1.2
Rechallenge.........................................................................................69
7.2
Participant Discontinuation/Withdrawal from the Study ...................69
7.3
Lost to Follow-Up...............................................................................70
8
Study Assessments and Procedures....................................................70
8.1
Efficacy Assessments and Procedures................................................73
8.1.1
Neurological Assessment....................................................................73
8.1.1.1
Qualified Relapse................................................................................74
8.1.1.2
Disability progression and Expanded Disability Status Scale............74
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8.1.3
Patient Reported Outcomes ................................................................76
8.1.3.1
Patient Reported Outcomes Measurement Information System.........77
8.2
Safety Assessments and Procedures ...................................................79
8.2.1
Physical Examinations........................................................................79
8.2.2
Vital Signs ..........................................................................................80
8.2.3
Electrocardiograms.............................................................................80
8.2.4
Clinical Safety Laboratory Assessments ............................................81
8.2.5
Pregnancy ...........................................................................................81
8.2.6
Immunoglobulin levels.......................................................................82
8.2.7
Chest X-ray.........................................................................................82
8.2.8
Columbia-Suicide Severity Rating Scale............................................82
8.2.9
Independent Data Monitoring Committee, Endpoint Adjudication 
Committee, and Study Steering Committee .......................................82
8.3
Adverse Events and Serious Adverse Events.....................................83
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................84
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...84
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............84
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....84
8.3.5
Pregnancy ...........................................................................................85
8.3.6
Medical Device Incidents (Including Malfunctions)..........................86
8.3.6.1
Time Period for Detecting Medical Device Incidents........................86
8.3.6.2
Follow-up of Medical Device Incidents .............................................86
8.3.6.3
Prompt Reporting of Medical Device Incidents to Sponsor...............86
8.3.6.4
Regulatory Reporting Requirements for Medical Device Incidents...87
8.4
Treatment of Overdose .......................................................................87
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9
Statistical Considerations....................................................................91
9.1
Statistical Hypotheses.........................................................................91
9.1.1
Statistical Hypotheses related to Primary Objective ..........................91
9.1.2
Statistical Hypotheses related to Secondary Objectives.....................91
9.3
Populations for Analyses ....................................................................93
9.4
Statistical Analyses.............................................................................93
9.4.1
Efficacy Analyses ...............................................................................94
9.4.1.1
Efficacy Analyses related to Primary Objective.................................97
9.4.1.2
Efficacy Analyses related to Secondary Objectives ...........................98
9.4.1.3
Sensitivity Analyses............................................................................99
9.4.2
Safety Analyses ................................................................................101
9.4.2.1
Adverse Events .................................................................................101
9.4.2.2
Clinical Laboratory Test Values.......................................................102
9.4.2.3
Vital Signs ........................................................................................102
9.4.2.4
Electrocardiogram Parameters..........................................................102
9.4.2.5
Concomitant Medication and Procedures.........................................103
9.4.2.6
Columbia-Suicide Severity Rating Scale..........................................103
9.4.3
Other Analyses..................................................................................103
9.4.3.2
Demographics, Baseline Characteristics, Disposition, and 
Compliance.......................................................................................104
9.4.3.3
Patient Reported Outcome Analyses ................................................104
9.4.3.4
Health Resource Utilization..............................................................105
9.4.3.5
Analysis of Open Label Extension Period Endpoints.......................105
9.4.4
Sequence of Analyses.......................................................................105
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9.4.4.2
Primary Analysis ..............................................................................106
9.4.4.3
Final Analysis ...................................................................................107
9.4.4.4
Multiplicity.......................................................................................107
10
References.........................................................................................109
11
Appendices .......................................................................................114
Appendix 1
Abbreviations....................................................................................115
Appendix 2
Study Governance.............................................................................119
Appendix 3
Contraception....................................................................................126
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................128
Appendix 5
Clinical Laboratory Tests .................................................................132
Appendix 6
Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................134
Appendix 8
Guidance for Diagnosis of PML.......................................................137
Appendix 9
Protocol Amendment History...........................................................139
Appendix 10
Sponsor Signature Page....................................................................140
Appendix 11
Coordinating Investigator Signature Page........................................141
Appendix 12
Principal Investigator Signature Page...............................................142
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double 
Dummy, Active Controlled Study of Evobrutinib compared with an Interferon Beta 1a (Avonex®), 
in Participants with Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety.
Short Title: Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
Rationale: The purpose of this study is to characterize the efficacy and safety of evobrutinib 
 
administered orally twice daily versus Interferon-beta 1a (Avonex) 
 once a week
intramuscularly) in participants with Relapsing Multiple Sclerosis (RMS).
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Primary
To 
demonstrate 
superior 
efficacy 
with 
evobrutinib 
compared to Avonex in terms 
of Annualized Relapse Rate 
(ARR)
ARR based on qualified relapses at Week 96 in participants 
with RMS
Secondary
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex 
on 
disability 
progression
!
Time to first occurrence of 12-week confirmed Expanded 
Disability Status Scale (EDSS) progression over 96 weeks
!
Time to first occurrence of 24-week confirmed EDSS 
progression over 96 weeks
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex on patient reported 
symptoms 
and 
functional 
status
!
Change from Baseline (CFB) in Patient Reported 
Outcomes Measurement Information System (PROMIS) 
physical function (PF) score at 96 weeks
!
CFB in PROMIS Fatigue score at 96 weeks
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex 
on 
magnetic 
resonance 
imaging 
(MRI)
lesion parameters
!
Total number of T1 Gd+ lesions based on assessments at 
Week 24, Week 48, and Week 96
!
Total number of new or enlarging T2 lesions based on 
assessments at Week 24, Week 48, and Week 96
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Objectives
Endpoints (Outcome Measures)
To characterize the safety and 
tolerability of evobrutinib.
Safety as assessed by the nature, severity, and occurrence of 
adverse 
events 
(AEs)
and 
AESIs; 
vital 
signs; 
electrocardiograms (ECGs); absolute concentrations and 
change from Baseline in immunoglobulin (Ig) levels; and 
clinical laboratory safety parameters up to Week 108
OLE Period
To evaluate the long-term 
safety, efficacy, and HRQoL 
of 
evobrutinib
for 
an 
additional up to 144 weeks.
!
Efficacy and HRQoL endpoints at Weeks 48, 96, and 144
o
ARR, based on protocol-defined qualified relapses
o
Change from Baseline in PROMIS PF score
o
Change from Baseline in PROMIS fatigue score
o
Change from Baseline in Medical Outcomes Study 
36 Item Short Form Health Survey (SF-36v2) 
!
Efficacy and HRQoL endpoints over 144 weeks
o
Time to first occurrence of 12-week confirmed 
EDSS progression over 144 weeks
o
Time to first occurrence of 24-week confirmed 
EDSS progression over 144 weeks
o
Time to first occurrence of 12-week confirmed PF 
deterioration compared to Baseline over 144 weeks
!
Efficacy endpoints at Weeks 24, 48, 96, and 144
o
Total number of new or enlarging T2 lesions 
o
Total number of T1 Gd+ lesions
!
Safety as assessed by the nature, severity, and occurrence 
of AEs and AESIs; vital signs; ECGs; absolute 
concentrations and change from Baseline in Ig levels; 
clinical laboratory safety parameters up to Week 144 
Overall Design: This is a Phase III, multicenter, randomized, parallel group, double blind, double 
dummy active controlled study of evobrutinib with an active control Avonex, in participants with 
RMS.
Eligible participants will be randomized 1:1 to treatment with evobrutinib 
 twice daily, or 
Avonex
 once a week (intramuscularly), stratified by region and Baseline EDSS. Blinding 
will be accomplished using a double dummy design.
Number of Participants: The total sample size is planned to be
participants with a 
randomization ratio of 1:1 (approximately 
participants per treatment group)
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Study Intervention Groups and Duration: The 96-week Treatment Period will be preceded by
a 4-week Screening Period (may be extended but cannot exceed 8 weeks) and followed by a 
4-week Safety Follow-up after treatment completion or early discontinuation. 
Participants experiencing initial progression of disability between Week 72 and Week 96 will 
continue participating in the main study for up to 12 additional weeks. The continuation period 
will increase the duration of participation to a maximum of 108 weeks. Upon completion of the 
continuation period, participants will have the option of participating in the OLE, or ending 
treatment (and returning for a 4-week Safety Follow-up).
Participants who complete the 96-week double blind, double dummy Treatment Period will be 
offered participation in the 148-week OLE Period of the study. The double blind Week 96 visit (or 
up to Week 108 visit) will be considered the OLE Day 1 Visit. The Safety Follow-up Visit will be 
deferred until treatment is stopped in the OLE Period, due to either a participant’s premature 
withdrawal/early termination from the OLE, termination of the study by the Sponsor, or 
completion of the OLE treatment period.
For participants experiencing a relapse within 4 weeks of eligibility for OLE, these participants
will be allowed entry into the OLE after approval from Merck/EMD Serono provided that the 
treatment gap does not exceed 60 days from the last dose of study intervention received in the 
double blind, double dummy period (Week 96/up to Week 108 visit), and the start of the study 
intervention treatment in the OLE Period.
Involvement of Special Committee(s): Yes. Independent Data Monitoring Committee, Endpoint 
Adjudication Committee, and Study Steering Committee.
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1.2
Schema
Figure 1
Study Schema
BID = Twice Daily, ED = Early Discontinuation, F/D = Follow-up/Discontinuation, IM = intramuscular, OLE = Open Label Extension, Q1W = Once Weekly.
a 
Participants experiencing initial progression of disability between Week 72 and Week 96 will continue participating in the main study for up to 12 additional 
weeks. The continuation period will increase the duration of participation to a maximum of 108 weeks.
b
For participants who do not enter the OLE period, the F/D visit will be performed 4 weeks after the last study interventions administration. For participants 
entering the OLE, there will be no 4-week follow-up period between the main study and the OLE.
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1.3
Schedule of Activities
1.3.1
Schedule of Assessments: Screening and Treatment Period (All Participants), End of Trial 
(Participants Not Entering Open Label Extension Period)
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Visit
1
1a
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
2
6
Study Day ± 
Visit Window
-28 
to 
-1
-14 
to 
-1
1
1
5
±
3
2
9
±
3
4
3
±
3
5
7
±
3
7
1
±
3
8
5
±
3
9
9
±
3
1
1
3
±
3
1
2
7
±
3
1
4
1
±
3
1
5
5
±
3
1
6
9
±
3
1
9
7
±
3
2
2
5
±
3
2
5
3
±
3
2
8
1
±
3
3
0
9
±
3
3
3
7
±
3
4
2
1
±
3
5
0
5
±
3
5
8
9
±
3
6
7
3
±
3
±
3
±
3
Informed 
Consent
X
Inclusion and 
Exclusion 
Criteria
X
X
Recheck clinical status before 
randomization and/or first dose of study 
intervention.
Demography
X
Full Physical 
Examination 
X
X
X
X
X
X
X
Additional examinations may be 
completed at the discretion of the 
Investigator.
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Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Medical History 
(includes 
substance usage) 
X
Substances: drugs, alcohol, tobacco, and 
caffeine
MS History
X
Serum 
Pregnancy Test 
(WOCBP only)
X
Highly sensitive 
urine pregnancy 
test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly urine pregnancy tests to be 
performed for all WOCBP. In home 
assessment will be accepted, where 
allowed by local regulations.
QuantiFERON®
-TB tuberculosis 
test, ferritin, and 
transferrin 
saturation
X
See Exclusion Criteria 8 and 10.
HIV, HBV and 
HCV testing
X
HIV testing will be conducted and 
analyzed locally. HBV and HCV testing 
will be performed at the central laboratory. 
Participants positive for anti-HCV
antibodies will have reflex testing 
performed for HCV RNA by PCR. See 
Exclusion Criterion 34.
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
16/142
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Efficacy and PRO assessments
Relapse 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Relapse assessment every 4 weeks from 
Week 4 to Week 96
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
The t
version will be completed at 
each assessment.
MRI scan
X
X
X
X
Participants should meet all non-imaging 
inclusion/exclusion criteria before the 
Screening/Baseline MRI is performed 
An MRI may be obtained at the 
Discontinuation Visit if the previous MRI 
was performed more than 4 weeks prior to 
the visit.
PROMIS fatigue 
and physical 
functioning, 
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
Completed on 
'RFXPHQW1R
2EMHFW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
17/142
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Safety assessments
Reflex testing 
for HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
For participants who are anti-hepatitis B 
surface antibody positive and/or 
anti-hepatitis B core antibody positive at 
Screening, reflex testing for hepatitis B 
virus DNA (HBV DNA) by PCR will be 
performed. See Exclusion Criterion 34
Supplemental 
LFT: ALP, 
AST, ALT, 
GGT, and Total 
Bilirubin
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 7.1
Hepatic/
Autoimmune 
Panel
Analysis will only be conducted if elevated LFT(s) are observed.
See Section 7.1 and Appendix 5
Evobrutinib 
concentration 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect all samples as specified, however 
analysis will only be conducted if elevated 
LFT(s) are observed.
Biochemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
See Section 7.1 and Appendix 5.
'RFXPHQW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
18/142
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Coagulation
X
X
X
X
X
Urinalysis/
microscopy and 
urine chemistry
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
Additional ECGs can be done if there are 
concerns about cardiac signs or symptoms
ECG assessments must be conducted 
approximately 0.75 to 1 hour after study 
intervention administration at the site.
Vital Signs, 
Height, and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Height at Screening only.
Chest X-ray
X
See Section 5.2
AE, SAE & 
AESI Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE review to be started after ICF is signed
Concomitant 
Medication and 
Procedures 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
'RFXPHQW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
19/142
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
Immunoglobulin 
levels
X
X
X
X
X
X
X
Study Intervention
Randomization
X
Randomization occurs on Day 1, prior to 
start of study intervention
Dispense Study 
Intervention(s) 
X
X
X
X
X
X
X
X
X
Dispense as needed per IWRS.
Study intervention dispensed at Week 96 
for participants experiencing clinical 
progression and who are assigned to an 
additional 12 weeks of study intervention
Study 
Intervention(s) 
Administration
Administration of study interventions
(Oral study interventions to be administered at the site on Day 1, and Weeks 12, 24, 48, 
72, and 96)
Oral study intervention must be taken in 
the fed state, see Section 6.1.
Study 
Intervention(s) 
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant diary to be completed after 
every study intervention administration. 
See Section 6.4
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
20/142
Assessments 
& Procedures
S
S2
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
tc
F
/
D
b
Notes
D
1
W
2
W
4
W
6
W
8
W
1
0
W
1
2
W
1
4
W
1
6
W
1
8
W
2
0
W
2
2
W
2
4
W
2
8
W
3
2
W
3
6
W
4
0
W
4
4
W
4
8
W
6
0
W
7
2
W
8
4
W
9
6
/
E
D
W
1
0
8
a
a The (up to) W108 visit will apply to a 
subset of participants who have 
disability progressions between 72-
96 weeks
b F/D visit will be performed 28 days 
(±3 days) 
after 
the 
last 
study 
intervention administration
c For unscheduled visits, assessments 
not marked below may be performed 
per Investigator discretion.
'RFXPHQW1R
2EMHFW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
21/142
AE = Adverse Event, ALP = Alkaline phosphatase, ALT = Alanine Aminotransferase, AST = Aspartate Aminotransferase, C-SSRS = Columbia-Suicide Severity 
Rating Scale, DNA = Deoxyribonucleic Acid, ECG = Electrocardiogram, ED = Early Discontinuation, EDSS = Expanded Disability Status Scale, EQ-5D-5L = EuroQoL 
5 Dimension 5 Level, ESR = Erythrocyte Sedimentation Rate, F/D = Follow-up/Discontinuation, GGT = γ-Glutamyl-Transferase, h = hour, HBV = Hepatitis B Virus, 
HFE = High Iron Fe (human hemochromatosis protein), hsCRP = high sensitivity C reactive protein, HIV = Human Immunodeficiency Virus, ICF = Informed Consent 
Form, IWRS = Interactive Web Response System, LFT = Liver Function Test, MRI = Magnetic Resonance Imaging, MS = Multiple Sclerosis,
 
 PCR = polymerase chain reaction, 
, 
, PROMIS = Patient Reported Outcomes Measurement Information 
System, S = Screening, S2 = Screening 2, SAE = Serious Adverse Event, 
 Test, 
 
TB = Tuberculosis,
 W = Week, WOCBP = Women Of Child Bearing Potential.
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
22/142
1.3.2
Schedule of Assessments – Optional Open Label Extension Period
Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Study Day ± 
Visit Window
1±3
1
5
±
3
2
9
±
3
4
3
±
3
5
7
±
3
71
±3
85
±3
99
±3
1 
1 
3 
±3
1
2
7 
±3
1
4
1 
±3
1
5
5
±3
1
6
9
±3
1
9
7
±3
2
2
5
±3
2
5
3
±3
2
8
1
±3
3
0
9
±3
3
3
7
±7
4
2
1
±7
5
0
5
±7
5
8
9
±7
6
7
3
±7
7
5
7
±7
8
4
1
±7
1
0
0
9
±7
1
0
3
7
±7
Informed 
Consent
X
Full Physical 
Examination 
X
X
X
X
X
Additional 
examinations may 
be completed at the 
discretion of the 
Investigator.
Serum 
Pregnancy Test 
(WOCBP only)
X
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
23/142
Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Highly sensitive 
urine pregnancy 
test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Monthly urine 
pregnancy tests to 
be performed for all 
WOCBP. In home 
assessment will be 
accepted.
Efficacy and PRO assessments
Relapse 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Relapse assessment 
every 4 weeks from 
Week 4 to Week 96
C-SSRS
X
X
X
X
X
X
X
X
X
X
The t
version 
will be completed at 
each assessment.
'RFXPHQW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
24/142
Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
MRI scan
X
X
X
X
X
Completed at 
Discontinuation
Participants should 
meet inclusion/
exclusion criteria 
before MRI is 
performed.
PROMIS fatigue 
and physical 
functioning, 
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
Completed on 
'RFXPHQW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
25/142
Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Safety assessments
'RFXPHQW1R
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
26/142
Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Supplemental 
LFT: ALP, 
AST, ALT, 
GGT, and Total 
Bilirubin
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If elevated, LFTs 
will be repeated. 
See Section 7.1.
Evobrutinib 
concentration 
assessment
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect all samples 
as specified, 
however analysis 
will only be 
conducted if 
elevated LFT(s) are 
observed.
Biochemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
See Appendix 5.
Coagulation
X
X
X
X
Urinalysis/
microscopy and 
urine chemistry
X
X
X
X
X
X
X
X
X
X
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
AE, SAE & 
AESI Review
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE review to be 
started after ICF
signed
Concomitant 
Medication and 
Procedures 
Review
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunoglobulin 
levels
X
X
X
X
X
X
X
X
X
Study Intervention
Dispense Study 
Intervention(s) 
X
X
X
X
X
X
X
Dispense as needed 
per IWRS.
Study 
Intervention(s) 
Administration
X
Administration of study intervention
Evobrutinib dosing 
will start the day 
after OLE Day 1.
Evobrutinib must be 
taken in the fed 
state, see Section 
6.1.
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
Study 
Intervention(s) 
Compliance
X
X
X
X
X
X
X
X
X
X
X
Participant diary to 
be completed after 
every study 
intervention 
administration. See 
Section 6.4
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Assessments 
& Procedures
Intervention Period
U
n
s
c
h
e
d
u
l
e
d 
V
i
s
i
t
W
e
e
k
1
4
8
F/
Db
Notes:
a For participants 
entering the OLE 
Period, their last 
visit in the main 
study will be their 
first visit in the 
OLE (see Section 
4.1).
b The OLE F/D 
visit will be 
performed 28 d 
(± 3 d) after last 
study intervention 
administration.
OLE 
D1a
W
2
W
4
W
6
W
8
W
10
W
12
W
14
W
16
W
18
W
20
W
22
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
60
W
72
W
84
W
9
6
W
1
0
8
W
1
2
0
W
1
4
4/
E
D
AE = Adverse Event, AESI = Adverse Event of Special Interest, ALP = Alkaline phosphatase, ALT = Alanine Aminotransferase, AST = Aspartate 
Aminotransferase, BTK = Bruton’s Tyrosine Kinase, C-SSRS = Columbia-Suicide Severity Rating Scale, d = day, DNA = Deoxyribonucleic Acid, ECG = 
Electrocardiogram, ED = Early Discontinuation, EDSS = Expanded Disability Status Scale, EQ-5D-5L = EuroQoL 5 Dimension 5 Level, ESR = Erythrocyte 
Sedimentation Rate, F/D = Follow-up/Discontinuation, GGT = γ-Glutamyl-Transferase, HBV = Hepatitis B Virus, HFE = High Iron Fe (human hemochromatosis 
protein), hsCRP = high sensitivity C reactive protein, ICF = Informed Consent Form, IWRS = Interactive Web Response System, LFT = Liver Function Test, MRI = 
Magnetic Resonance Imaging, MS = Multiple Sclerosis, 
 OLE = Open Label Extension, 
, 
 
PRO = patient reported outcomes, PROMIS = Patient Reported Outcomes Measurement Information System, S = Screening, S2 = Screening 2, SAE = Serious 
Adverse Event, 
 TB = Tuberculosis,
 
 W = Week, WOCBP = Women Of Child Bearing Potential.
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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2
Introduction
Evobrutinib is a potent, orally administered, highly selective, irreversible inhibitor of Bruton’s 
Tyrosine Kinase (BTK) that is being developed for the treatment of relapsing multiple 
sclerosis (RMS).
Complete information on the chemistry, pharmacology, efficacy, and safety of evobrutinib is 
in the current Investigator’s Brochure.
2.1
Study Rationale
The purpose of this study is to characterize the efficacy and safety of evobrutinib 
 
administered orally twice daily versus Interferon-beta 1a (Avonex) (
 once a week 
intramuscularly) in participants with RMS.
Evobrutinib inhibits activation of B cells via the B cell receptor. In addition, evobrutinib 
inhibits activation of myeloid cells by immune complexes via Fc receptors as well as the 
differentiation of proinflammatory macrophages. Thus, evobrutinib may be suitable for the 
treatment of multiple sclerosis (MS).
The main randomized, double blind, placebo-controlled Phase II study of evobrutinib with a 
parallel, open label, active control group (dimethyl fumarate [Tecfidera®]), in patients with 
RMS to evaluate efficacy, safety, tolerability, pharmacokinetics (PK), and biological activity 
(MS200527_0086) is completed; the Open Label Extension (OLE) part of the study is 
ongoing. The study consisted of a first 24-week period, in which 267 participants were 
randomized to evobrutinib 25 mg once daily (n = 52), 75 mg once daily (n = 53), 75 mg twice 
daily (n = 54), dimethyl fumarate 240 mg twice daily (provided open label) (n = 54), or 
placebo (n = 54). Data from the first 24-weeks were analyzed for the primary analysis (PA). 
Following the 24-week period, all remaining participants continued to be treated for an 
additional 24-week period as follows: participants who received previously evobrutinib 25 mg 
once daily, 75 mg once daily, 75 mg twice daily, or dimethyl fumarate, continued to be treated 
with their original treatment, and participants who received placebo for the first 24-weeks 
were switched to evobrutinib 25 mg once daily. Treatment assignment remained blinded with 
the exception of dimethyl fumarate which was open label throughout the study. The first 
48 weeks analysis is referred to as the Blinded Extension Analysis (BEA). For the PA, 
efficacy analysis consisted of the comparison between the placebo and evobrutinib treatment 
groups. No formal comparison between the dimethyl fumarate and the evobrutinib treatment 
groups was performed for either the PA or the BEA.
In the PA, the primary efficacy endpoint of the Phase II study was the total number of 
gadolinium-enhancing T1 lesions at Weeks 12, 16, 20, and 24. The primary efficacy analysis 
was a comparison of each evobrutinib dose arm versus placebo based on lesion rate (lesions 
per scan) ratio, adjusted for Baseline lesion activity. The primary endpoint of the study was 
met, and both evobrutinib 75 mg once daily (lesion rate ratio 0.30, 95% confidence interval 
[CI]: 0.14, 0.63; P = 0.0015 [unadjusted], P = 0.046 [adjusted according to Hochberg]) and 
evobrutinib 75 mg twice daily (lesion rate ratio 0.44, 95% CI: 0.21, 0.93; P = 0.0313
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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[unadjusted], P = 0.0648 [adjusted according to Hochberg]) were associated with a reduction 
in T1 Gd+ lesion rate compared to placebo (Montalban 2019). 
The first key secondary endpoint was annualized relapse rate (ARR) at 24-weeks. A trend 
towards a reduction in ARR (unadjusted [95% CI]) was seen with evobrutinib 75 mg once 
daily (0.13 [0.03, 0.38]; P = 0.09) and evobrutinib 75 mg twice daily (0.08 [0.01, 0.30]; 
P = 0.06) versus placebo (0.37, [0.17, 0.70]), with evidence of a dose response (P = 0.014).
In the BEA, results showed an unadjusted ARR at 48 weeks of 0.11 (95% CI: 0.04, 0.25) for 
evobrutinib 75 mg twice daily and 0.25 (95% CI: 0.12, 0.44) for evobrutinib 75 mg once daily 
indicating that the efficacy trend observed during the first 24-week period was sustained 
during the second 24-week period, with greater clinical sustained efficacy in the 75 mg twice 
daily group.
These results provide evidence of evobrutinib’s efficacy compared to placebo. Clinical 
development efforts in the MS indication will focus specifically on RMS, with potential 
expansion into progressive MS (PPMS and Secondary progressive multiple sclerosis [SPMS]) 
with subclinical central nervous system (CNS) inflammation.
Reversible elevations in transaminases (alanine aminotransferase [ALT] and aspartate 
aminotransferase [AST]) have been observed in participants randomized to evobrutinib in the 
RMS Phase II study (MS200527-0086). This finding, and the overall safety and risk-benefit 
assessment of evobrutinib are discussed further in Section 2.3 and Section 4.3.
Taken together, efficacy and safety data from this study support progression into Phase III.
Refer to the Investigator’s Brochure for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
2.2
Background
Currently there is no cure for MS, but the course of the disease can be altered favorably with 
disease-modifying drugs (DMDs) with varying levels of efficacy, and distinct safety and 
tolerability profiles. Most active RMS patients initiate treatment with an interferon-beta or 
glatiramer acetate therapy. Oral DMDs including dimethyl fumarate and teriflunomide are 
also used as first-line agents. If responding suboptimally, patients can be treated with an 
alternative, second-line oral therapy such as cladribine and fingolimod, or infusion agents 
such as natalizumab and ocrelizumab. Generally, DMDs perceived to be more efficacious 
have also been shown to be associated with more significant adverse effects, ranging from 
serious infections (i.e., progressive multifocal leukoencephalopathy [PML]) to autoimmunity 
and cancer. Switching among these DMDs occurs primarily due to perceived lack of efficacy 
or the occurrence of adverse events (AEs), as well as individual patient preferences.
Despite the recent approvals of newer therapies for the treatment of MS, there remains an 
unmet need for highly effective and well-tolerated therapies for patients with MS at all stages 
of the disease. Early treatment with a highly efficacious, and safer DMD could be 
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
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advantageous for long term quality of life for MS patients and might slow the process of brain 
atrophy, which accompanies axonal damage and loss of gray and white matter.
Evobrutinib is a highly specific, oral inhibitor of BTK that inhibits B cell activation and 
B cell/T cell interaction, decreasing plasma cell formation and autoantibody production 
(Investigator Brochure, Haselmayer 2017). In addition, evobrutinib was shown to inhibit M1 
macrophage survival and proinflammatory cytokine release and promotes M2 polarization of 
reparative human monocytes in vitro (Alankus 2018). In line with the in vitro data, evobrutinib 
demonstrated pharmacological efficacy in both B cell and T cell dependent mouse models of 
MS, by reducing CNS inflammation and amelioration of disease severity (Boschart 2017, 
Torke 2018). Since B cell depletion studies have shown that antibody independent B cell 
functions play an important role in MS pathogenesis (Bar-Or 2010, Fraussen 2016, Jelcic 
2018) and an altered innate immune system contributes to disability progression and repair in 
MS (Vogel 2013, Rawji 2016), evobrutinib may offer advantages over current approved 
DMDs.
Clinical efficacy was recently demonstrated with B cell depleting anti CD20 therapies in 
Phase II and Phase III clinical studies in RMS and progressive MS (Hauser 2008, Hawker 
2009, Montalban 2016, Wolinsky 2016). Ocrelizumab (Ocrevus®) inhibited the formation of 
new inflammatory magnetic resonance imaging (MRI) lesions up to 90% (Hauser 2008) in 
Phase II RMS studies and high efficacy on MRI (-94%), ARR (-46%), and 24-week disease 
progression (-40%) was also reached in OPERA Phase I, II, and III studies against 
interferon-beta. Translational mechanism of action studies in anti CD20 treated RMS patients 
show diminished proliferation and proinflammatory differentiation of T cells (Bar-Or 2010), 
pointing towards abrogation of antigen presenting cell function as the primary mechanism. In 
addition to the role of anti CD20 in B cell antigen presentation, a recent publication of Li et 
al (Li 2015) describes a diminished proinflammatory myeloid cell response in ocrelizumab 
treated MS participants. Evobrutinib shows inhibition of myeloid cell activation by immune 
complexes.
Preclinical proof of concept with evobrutinib has been demonstrated for systemic lupus 
erythematous/lupus nephritis, experimental autoimmune encephalomyelitis, rheumatoid 
arthritis (RA) and passive cutaneous anaphylaxis. Oral evobrutinib does not deplete B cells in 
the studies carried out to date and, upon withdrawal, restoration of immune function can be 
achieved in days. This is less than treatment with anti CD20 therapies, where restoration of 
the immune system can take months, and is important should the need to interrupt or stop 
therapy arise. This suggests a more favorable benefit to risk balance with respect to infections 
for evobrutinib versus anti CD20 therapies may be observed. In addition, BTK inhibitors
might have broader efficacy than agents that cause B cell depletion, due to the importance of 
BTK activation downstream of various receptors expressed in myeloid cells, suggesting an 
additional direct effect of evobrutinib on innate immune cell activation induced by immune 
complexes, cytokines/chemokines, or toll-like receptor (TLR) activation (Block 2012, Lopez-
Herrera 2014, Whang 2014). A direct myeloid inhibition activity also best explains the 
significant reduction of clinical score, relapse rate, and time to first relapse in T cell dependent 
experimental autoimmune encephalomyelitis models, in which anti CD20 antibodies do not 
work.
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
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2.3
Benefit/Risk Assessment
In the PA of the completed MS200527-0086 study, evobrutinib significantly decreased the 
number of Gd+ T1 lesions at Weeks 12, 16, 20, and 24 in RMS subjects. Similar to the 
relationship seen for the MRI endpoints, evobrutinib 75 mg once and twice daily was 
associated with a lower ARR compared to placebo. These results show evobrutinib is 
efficacious in RMS subjects, and consequently warrant further investigation in Phase III
clinical studies.  
A confirmed safety finding of increases in liver transaminases has been observed from Study 
MS200527-0086 in subjects with RMS and the ongoing Study MS200527-0018 in subjects 
with SLE and was considered as important identified risk for evobrutinib. Elevations of liver 
transaminases were frequent, generally mild (Grade 1), asymptomatic and reversible. 
During the first 52 weeks of the MS200527-0086 study, all of the instances of elevated liver 
enzymes occurred during the first 6 months of exposure to evobrutinib and none of the cases 
of elevated transaminases had any clinical signs or symptoms, and the transaminase elevations 
have resolved over time with the withdrawal of evobrutinib. 
 
 
 
 
 
Given these observations, this protocol excludes participants with hemochromatosis, Wilson’s 
disease, alpha-1-antitrypsin deficiency, or any other chronic liver disease including Gilbert’s 
disease and > 2 × ULN values for ALT, AST, amylase, or lipase elevation at Screening. 
During the study, liver transaminase will be monitored every 2 weeks, particularly during the 
first 6 months of exposure to evobrutinib. The protocol has strict stopping criteria for liver 
transaminase elevations leading to treatment
discontinuation and timely medical 
management. Also, data will be reviewed by an Independent Data Monitoring Committee 
(IDMC) with appropriate expertise. Beyond this, risk minimization measures proposed are 
considered standard for this phase of clinical development.
Investigations on embryo-fetal development in toxicological studies showed an increased 
incidence of malformations (mainly cleft palate) and skeletal variations in mice when 
compared to the control group, and abortions and/or vaginal bleeding during the last period 
of gestation in rabbits. In addition, an increase of resorptions, and a lower mean fetal weight 
were also seen.  
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Based on these, embryo-fetal toxicity is considered as an important potential risk in 
participants exposed to evobrutinib. Therefore, female participants of childbearing potential 
must not be pregnant, must have a negative pregnancy test at the time of enrollment and use 
highly effective contraception (as specified in the clinical study protocol) during the study 
period and 120 days after the last dose, not to donate eggs for reproduction, as risk mitigation 
measures.
Although no causal relationship has been established, adverse events of special interests 
(AESI) including infections (serious and opportunistic infections), lipase and amylase 
elevation, and seizure, are under close monitoring. 
Due to the dominant role of CYP3A4/5 in the metabolism of evobrutinib, the compound may 
be a victim of DDI caused by inhibition (competitive/time-dependent) or induction of this 
enzyme by coadministered perpetrator drugs. The results of the completed clinical CYP DDI 
study (MS200527-0054) demonstrated that administration of evobrutinib with the potent CYP 
3A4/5 inhibitor itraconazole resulted in a 3.35-fold increase in Cmax and a 2.99-fold increase 
of AUC. Based on these observations, the administration of medications that are moderate or 
strong inhibitors or inducers of CYP3A4/5 is not permitted during ongoing clinical trials. 
Following the review of the totality of the safety data from the clinical studies with 
evobrutinib, overall, evobrutinib was well tolerated in MS patients up to 75 mg BID. The 
safety profile of evobrutinib has been consistent across doses and indications. No dose-related 
relationship has been observed for the most frequently reported TEAEs. 
Overall, considering the unmet medical need in MS patients, reduction of MS activities 
(decreased in the number of Gd+ T1 lesions and lower ARR compare with placebo), 
convenience of an oral therapy and the measures put in place to mitigate the important 
identified and important potential risks, the benefit-risk of evobrutinib 
 BID fed 
supports continued clinical development of evobrutinib in this population.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of evobrutinib may be found in Section 4.2 and the Investigator’s 
Brochure. More detailed information about the known risks and benefits of Avonex are 
provided in the locally approved product information (e.g. relevant SmPC or the US 
Prescribing Information).
Based on the available nonclinical and clinical data to date, the conduct of the study, as 
specified in this protocol, is considered justifiable.
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
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3
Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
Primary
To demonstrate superior efficacy with 
evobrutinib compared to Avonex in 
terms of ARR
ARR based on qualified relapses at Week 96 in 
participants with RMS
Secondary
To 
demonstrate 
the 
efficacy 
of 
evobrutinib relative to that of Avonex on 
disability progression
!
Time to first occurrence of 12-week 
confirmed Expanded Disability Status Scale 
(EDSS) progression over 96 weeks
! Time to first occurrence of 24-week 
confirmed EDSS progression over 96 weeks
To 
demonstrate 
the 
efficacy 
of 
evobrutinib relative to that of Avonex on 
patient 
reported 
symptoms 
and 
functional status
!
Change from Baseline (CFB) in Patient 
Reported 
Outcomes 
Measurement 
Information System [PROMIS] PF score at 
96 weeks
! CFB in PROMIS Fatigue score at 96 weeks
To 
demonstrate 
the 
efficacy 
of 
evobrutinib relative to that of Avonex on 
MRI lesion parameters
!
Total number of T1 Gd+ lesions based on 
assessments at Week 24, Week 48, and 
Week 96.
! Total number of new or enlarging T2 lesions 
based on assessments at Week 24, Week 48, 
and Week 96
To 
characterize 
the 
safety 
and 
tolerability of evobrutinib.
Safety as assessed by the nature, severity, and 
occurrence of adverse events (AEs) and adverse 
events of special interest (AESIs); vital signs; 
electrocardiograms 
(ECGs); 
absolute 
concentrations and change from Baseline in 
immunoglobulin (Ig) levels; and clinical 
laboratory safety parameters up to Week 108
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
37/142
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
38/142
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
39/142
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
40/142
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Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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Objectives
Endpoints (Outcome Measures)
OLE Period
To evaluate the long-term safety, 
efficacy, and HRQoL of evobrutinib for 
an additional up to 144 weeks.
!
Efficacy and HRQoL endpoints at Weeks
48, 96, and 144
o
ARR, based on protocol-defined 
qualified relapses
o
Change from Baseline in PROMIS 
PF score
o
Change from Baseline in PROMIS 
fatigue score
o
Change from Baseline in Medical 
Outcomes Study 36 Item Short 
Form Health Survey (SF-36v2)
!
Efficacy and HRQoL endpoints over 144 
weeks
o
Time to first occurrence of 12-week 
confirmed EDSS progression over 
144 weeks
o
Time to first occurrence of 24-week 
confirmed EDSS progression over 
144 weeks
o
Time to first occurrence of 12-week 
confirmed PF deterioration 
compared to Baseline over 144 
weeks
!
Efficacy endpoints at Weeks 24, 48, 96, and 
144
o
Total number of new or enlarging 
T2 lesions 
o
Total number of T1 Gd+ lesions
! Safety as assessed by the nature, severity, and 
occurrence of AEs and AESIs; vital signs; 
ECGs; absolute concentrations and change 
from Baseline in Ig levels; clinical 
laboratory safety parameters up to Week 144
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Evobrutinib
Phase III Study of Evobrutinib in RMS (EVOLUTION MS2)
MS200527_0074
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4
Study Design
4.1
Overall Design
This is a Phase III, multicenter, randomized, parallel-group, double blind, double dummy, 
active controlled study of evobrutinib with an active control group Avonex, in participants 
with RMS.
Eligible participants will be randomized 1:1 to treatment with evobrutinib 
 twice daily, 
or Avonex
 once-weekly (intramuscular injection), stratified by region and Baseline 
EDSS. Blinding will be accomplished using a double dummy design.
The 96-week Treatment Period will be preceded by a 4-week Screening Period (may be 
extended but cannot exceed 8 weeks) and followed by a 4-week Safety Follow-up after 
treatment completion or early discontinuation. 
Participants experiencing initial progression of disability between Week 72 and Week 96 will 
continue participating in the main study for up to 12 additional weeks. The continuation period 
will increase the duration of participation to a maximum of 108 weeks. Upon completion of 
the continuation period, participants will have the option of participating in the OLE or ending 
treatment (and returning for a 4-week Safety Follow-up).
Participants who complete the 96-week double blind, double dummy Treatment Period will 
be offered participation in the 148-week OLE Period of the study. The purpose of the OLE 
Period is to allow all the participants the opportunity to receive active treatment with 
evobrutinib and to collect long term safety and efficacy data. The Investigator should review 
the optional OLE Period with the participant prior to the double blind, double dummy
Week 96 visit. Signed consent will be obtained prior to participation in the OLE Period. The 
double blind Week 96 visit (or up to Week 108 visit) will be considered the OLE Day 1 Visit. 
The Safety Follow-up Visit will be deferred until treatment is stopped in the OLE Period, due 
to either a participant’s premature withdrawal/early termination from the OLE, termination of 
the study by the Sponsor, or completion of the OLE treatment period.
In some cases, due to relapse, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approval, regulatory-specific, or other administrative delays, a participant 
may experience a treatment gap between the study intervention last dose received in the 
double blind, double dummy period (Week 96/up to Week 108 visit) and the start of the OLE 
study intervention treatment. Upon Principal Investigator request, these participants may still 
be able to enroll in the OLE with approval from Merck/EMD Serono, on a case-by-case basis, 
provided that the treatment gap does not exceed 60 days from the last dose of study 
intervention received in the double blind, double dummy period (Week 96/up to Week 108
visit), and the start of the study intervention treatment in the OLE Period. If the day of rollover 
to the OLE occurs after the double blind, double dummy Safety Follow-up visit, all 
assessments noted at the OLE Day 1 visit will need to be completed. For participants that 
rollover after the Week 96/up to Week 108 visit but prior to their scheduled Safety Follow-up 
visit, concomitant medications and AEs will need to be reviewed and updated, and the 
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Principal Investigator will need to ensure that the participant remains eligible for the study 
(see Section 5.3). No other additional assessments other than dispensing of study intervention 
will need to be completed.
4.2
Scientific Rationale for Study Design
This study was designed to determine the efficacy and safety of evobrutinib in participants 
with RMS. The primary objective will focus on reduction of relapses relative to Avonex over 
96 weeks in adult participants with RMS based on the ARR at Week 96. The OLE will allow 
for assessment of long term safety and efficacy of evobrutinib.
The findings in Section 2 support the pathogenic contribution of B cells to MS damage. In 
contrast, a failed clinical study with another B cell targeting agent, atacicept, supports the 
notion that certain B cell subtypes may mediate beneficial anti-inflammatory effects 
(Kappos 2014). Novel nondepleting B cell therapies may deliver a more favorable benefit risk 
profile than current B cell directed therapeutic approaches.
There is consensus in the MS community, that the use of placebo in Phase III studies with 
RMS participants is no longer ethical, due to the availability of established and effective 
therapies (Polman 2008). Interferon-beta 1a is an acknowledged therapy that has been used in 
past pivotal studies as a comparator and is well-suited for the objective of this study. It is 
currently used as part of the standard of care platform therapies in the treatment of MS and 
has a well-established efficacy and safety profile. 
As the active treatment is oral and the active comparator is an injectable, the study will have 
a double dummy design. This design minimizes the potential for bias and maintains the 
integrity of the clinical data generated from this study. It also reduces the risk of concluding 
that superiority to the active comparator was driven by participant and assessor bias. 
This study plans to enroll RMS participants according to the McDonald MS 2017 criteria 
(Thompson 2018) with an EDSS score of 0 to 5.5 at Screening who had at least 2 documented 
clinical attacks within the previous 2 years, who had at least 1 or more documented relapses 
within the 2 years before Screening with either: 1 relapse which occurred within the last year 
prior to randomization, OR the presence of at least 1 Gd+ T1 lesion within 6 months prior to 
randomization. These criteria have been implemented to further characterize the benefits of 
treatment with evobrutinib in a wide range of RMS participants with varying degrees of 
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disease activity and severity. The age range will be limited to ≤ 55 years with the aim to avoid 
confounding by neurological conditions prevalent in older participants.
The proposed study endpoints are widely accepted as clinically relevant, and have been used 
in numerous pivotal clinical studies in RMS. The primary endpoint for the study will be ARR 
over 96 weeks, based on qualified relapses. Secondary efficacy endpoints will include total 
number of new or enlarging T2 lesions at Week 96 (based on post-baseline assessments at 
Weeks 24, 48, and 96), total number of T1 Gd+ lesions at Week 96 (based on post-baseline 
assessments at Weeks 24, 48, and 96), and time to 12 or 24-week CDP. Prevention of relapses, 
prevention/delay of accumulation of sustained neurological disability, as well as effect on 
MRI are meaningful goals in the treatment of participants with RMS.
Patient Reported Outcomes (PROs) including those assessing fatigue and PF, are included as
a secondary endpoint (PF) and
 in the current study. Fatigue has 
been reported as the most bothersome symptom for MS patients among other concerns, such 
as bladder and bowel problems, cognitive impairment, visual disorders, musculoskeletal 
issues e.g. stiffness, spasm, walking difficulty and balance problems (Martin 2017, Patti 2011, 
Branas 2000). In turn, these are associated with impairments in various functional areas, 
including instrumental activities of daily living (IADLs), limitations with physical activities 
such as participating in sports, limitations related to ability to work or study, and social 
interactions (Patti 2014, Larocca 2011). The current data from randomized controlled trial
studies support positive treatment effects of currently available DMDs (including, 
teriflunomide, dimethyl fumarate, natalizumab, and ocrelizumab) on Health-related Quality
of Life (HRQoL), i.e., improving or preventing the worsening of HRQoL (Jongen 2017).
Refer to the Investigator’s Brochure for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
4.3
Justification for Dose
Selection of the Phase III dose was based on pharmacodynamic, efficacy, and safety data from 
the ongoing Phase IIb study MS200527-0086, and supported by clinical pharmacology studies 
where dosing of the tablet was included (Studies MS200527-0017 and MS200527-0019). The 
models describing 
 
 
 
 
 
 
 
 
 
 
 
 
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Thus, the criteria for selection of an efficacious dose to be used in Phase III is based on 
targeting exposure of ≥ 468 ng•h/mL
 
Elevated ALT values were observed based on laboratory blood tests at all dose levels in 
16 participants with RMS in Study MS200527-0086, with 7.4% of the participants receiving 
placebo, 5.8% of the participants at 25 mg once daily, 3.8% of the participants at 75 mg once 
daily, and 13% of the participants at 75 mg twice daily experiencing elevated ALT levels. The 
mechanism for the elevated ALTs has not been identified, and there is inconclusive evidence 
of dose-response or exposure-response relationship.
Avonex will be administered intramuscularly at the highest approved dose of 
 once a 
week. Refer to the locally approved product information (e.g. relevant SmPC or US 
Prescribing Information) for further details.
Additional information about the justification for dose for evobrutinib may be found in the 
Investigator’s Brochure.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts, including the 
Treatment Period and the last visit (Safety Follow-up Visit).
The end of the study is defined as the date of the last visit of the last participant.
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5
Study Population
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are 
appropriate for the study; thereby, ensuring the study fulfills its objectives. All relevant 
medical and nonmedical conditions should be taken into consideration when deciding whether 
a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will confirm that the participant or the participant’s legal representative 
has provided written informed consent, as indicated in Appendix 2 Study Governance.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are 18 to 55 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or secondary 
progressive multiple sclerosis [SPMS] with relapses) in accordance with 2017 Revised 
McDonald criteria (Thompson 2018).
3. One or more documented relapses within the 2 years before Screening with either:
a.
one relapse which occurred within the last year prior to randomization, OR
b. the presence of at least 1 Gd+ T1 lesion within 6 months prior to randomization.
4. Have an EDSS score of 0 to 5.5 at Baseline
a.
Participants with an EDSS score ≤2 at Screening are only eligible for 
participation if their disease duration (time since onset of symptoms) is no more 
than 10 years.
5. Are neurologically stable for ≥30 days prior to both Screening and Baseline.
Sex
6. Are female or male
a.
Female participants 
!
Are not pregnant or breastfeeding, and at least one of the following conditions 
applies:
o
Not a Woman of Child Bearing Potential 
OR
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o
If a Woman of Child Bearing Potential, use a highly effective contraceptive 
method (i.e., with a failure rate of < 1% per year), preferably with low user 
dependency, as described in Appendix 3 for the following time periods:

Before the first dose of the study intervention(s), if using 
hormonal contraception:
o
Has completed at least one 4-week cycle of an oral 
contraception pill and either had or has begun her 
menses
OR
o
Has used a depot contraceptive or extended-cycle oral 
contraceptive for at least 28 days and has a documented 
negative pregnancy test using a highly sensitive assay.
AND
o
A barrier method, as described in Appendix 3.

During the Intervention Period
After the study Intervention Period (i.e., after the last dose of 
study intervention is administered) for at least 90 days, plus 
30 days (a menstrual cycle) after the last dose of study 
intervention and agree not to donate eggs (ova, oocytes) for 
reproduction during this period.
The Investigator evaluates the effectiveness of the 
contraceptive method in relationship to the first dose of study 
intervention.

Have a negative serum or highly sensitive urine pregnancy test,
as required by local regulations, within 4 to 8 weeks and a 
highly sensitive urine pregnancy test at Baseline before the first 
dose of study intervention. If a urine test cannot be confirmed 
as negative (e.g., an ambiguous result), a serum pregnancy test 
is required.
!
Additional requirements for pregnancy testing during and after study intervention 
are in Section 8.2.4.
!
The Investigator reviews the medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a female with an early 
undetected pregnancy
Informed Consent
7. Capable of giving signed informed consent, as indicated in Appendix 2, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and this protocol.
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8. Participants must be contactable by email or telephone throughout the study.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Participants diagnosed with Progressive MS, in accordance with the 2017 Revised 
McDonald criteria, as follows:
a. Participants with Primary Progressive MS.
b. Participants with Secondary Progressive MS without evidence of relapse.
2.
Disease duration > 10 years in participants with an EDSS ≤2.0 at Screening.
3.
Immunologic disorder other than MS or any other condition requiring oral, 
intravenous (IV), intramuscular, or intra-articular corticosteroid therapy, with the 
exception of well-controlled Type 2 diabetes mellitus or well controlled thyroid 
disease.
4.
History or current diagnosis of other neurological disorders that may mimic MS, 
including but not limited to: neuromyelitis optica, transverse myelitis, bilateral optic 
neuritis of simultaneous onset, Lyme disease, HTLV-1-associated myelopathy, 
untreated vitamin B12 deficiency, neurosarcoidosis, and cerebrovascular disorders.
5.
History or current diagnosis of PML. If a brain MRI has findings suggestive of PML, 
cerebrospinal fluid JC virus polymerase chain reaction (CSF JCV PCR) should be 
tested to rule out PML (see Appendix 8).
6.
Active, clinically significant viral, bacterial, or fungal infection, or any major episode 
of infection requiring hospitalization or treatment with parenteral anti-infectives 
within 4 weeks of Screening, or completion of oral anti-infectives within 2 weeks 
before or during Screening, or a history of recurrent infections (i.e., 3 or more of the 
same type of infection in a 12-month rolling period). Vaginal candidiasis, 
onychomycosis, and genital or oral herpes simplex virus considered by the 
Investigator to be sufficiently controlled would not be exclusionary.
7.
The participant:
o
Has a history of or current diagnosis of active tuberculosis (TB)
OR
o
Is currently undergoing treatment for latent TB infection (LTBI)
OR
o
Has an untreated LTBI as determined by documented results within 3 months 
of the Screening Visit of a positive TB skin test with purified protein derivative 
(PPD) with induration ≥5 mm
OR
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o
Has current household contacts with active TB, unless prophylaxis treatment 
has been completed and documented evidence that household contacts have 
completed treatment
OR
o
Has a positive QuantiFERON-TB test at Screening, unless the participant has
completed chemoprophylaxis for LTBI (as per applicable local guidelines) 
prior to the Screening Visit. 
Participants with documented completed appropriate LTBI treatment would not be 
excluded and are not required to be tested.
Note: TB skin test with PPD will not be performed at Screening. Reference to TB 
skin test results above is in reference to a potential participant’s past results. 
8.
Indeterminate QuantiFERON-TB test results may be repeated once and will be 
considered positive if retest results are positive. However, if results continue to be 
indeterminate, then the individuals will be evaluated with T-SPOT.TB at the request 
of the Investigator. In this case, if the T-SPOT.TB is negative, the individual may be 
enrolled after approval by the Medical Monitor (see Section 8 for exceptions to tests 
analyzed by a central laboratory). If T-SPOT.TB is not available, then for the next 
steps the Medical Monitor should be contacted.
9.
Individuals with a diagnosis of hemochromatosis, Wilson’s disease, alpha-1-
antitrypsin deficiency, or any other chronic liver disease including Gilbert’s disease 
will be excluded from the study.
10.
Individuals with elevated transferrin saturation (> 50% transferrin saturation in males; 
and > 40% transferrin saturation in females) and/or with elevated ferritin levels 
> 500 μg/L will be excluded.
11.
Individuals with sickle cell anemia, thalassemia and/or any chronic blood disorder 
requiring blood transfusions will be excluded from the study. 
12.
History of splenectomy at any time, or any major surgery within 2 months prior 
to Screening.
13.
History of myocardial infarction or cerebrovascular event within 6 months prior to 
Screening, or current active angina pectoris, history of or current congestive heart 
failure New York Heart Association (NYHA) Class III or Class IV, uncontrolled 
seizures (remote infantile febrile seizures are not exclusionary), prolonged untreated 
hypertension (Systolic ≥160 mm Hg and/or diastolic ≥100 mm Hg), active GI 
bleeding, or any other significant active medical condition in the Investigator’s 
opinion or Sponsor’s/designee’s opinion.
14.
A history of attempted suicide within 6 months prior to Screening or a positive 
response to items 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Screening.
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15.
An episode of major depression within the last 6 months prior to Screening (clinically 
stable minor depression is not exclusionary).
16.
History of cancer with the following exceptions:
! A confirmed history of non-melanoma skin cancer Stage 0 (in situ) or Stage 1, 
considered cured > 5 years is not exclusionary.
! A history of in situ cervical cancer, considered cured > 5 years, is not exclusionary.
! A history of Stage I prostate cancer with normal Prostate-Specific Antigen (PSA), 
considered cured for > 5 years, is not exclusionary.
Any history of cancer not meeting these exceptions is exclusionary.
17.
On Screening ECG, any abnormality (e.g., uncontrolled second or third degree AV 
conduction block, ventricular tachyarrhythmias) that in the Investigator’s opinion 
may impact participation in the study.
18.
An active infective process or any other clinically significant abnormality on 
Screening Chest X-ray (CXR) taken within 4 weeks of the first dose, per Investigator 
opinion. If a CXR has been taken within the previous 3 months and results are 
available and normal, the CXR does not need to be repeated.
Prior/Concomitant Therapy
19.
Contraindication to Avonex or incompatibility with Avonex use, including;
a.
Hypersensitivity to natural or recombinant interferon-beta, or to any excipients.
b. Cessation of interferon therapy due to poor tolerability or safety concerns, or 
suboptimal response.
20.
IV or oral glucocorticoids within 4 weeks prior to randomization (inhaled 
corticosteroids are allowed) (see Section 8).
21.
Treatment with monthly IV methylprednisolone (see Section 6.5.1).
22.
Treatment with beta-interferons or glatiramer acetate within 4 weeks prior to 
randomization.
23.
Treatment with dimethyl fumarate within 4 weeks prior to randomization provided 
lymphocyte count is > 1000 cells/μL prior to randomization.
24.
Treatment with teriflunomide within 12 weeks or after the accelerated elimination 
procedure 12 days prior to randomization.
25.
Use of lymphocyte trafficking blockers (natalizumab or fingolimod) within 48 weeks 
prior to randomization.
26.
Use of IV Ig or plasmapheresis within 12 weeks prior to randomization.
27.
Treatment with rituximab and/or ocrelizumab. Participants who have received 1 dose 
of rituximab or ocrelizumab, and reason for treatment discontinuation was not 
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treatment failure, will be eligible to enter the study if the last dose of rituximab or 
ocrelizumab was at least 48 weeks prior to randomization. 
28.
Treatment with any other B cell depleting therapy, BTK inhibitors (including 
evobrutinib), mitoxantrone, or lymphocyte-depleting therapies (e.g., alemtuzumab, 
anti-CD4, cladribine, cyclophosphamide, total body irradiation, bone marrow 
transplantation).
29.
Concomitant treatment with medications commonly used for symptom management 
of MS patients will be exclusionary as follows:
a.
Participants taking dantrolene are to be excluded. Participants on other 
antispasticity agents can be included if they have been on a stable dose over the 
3 months prior to randomization.
b. Participants on dalfampridine (Ampyra) or fampridine can be included only if they 
have been on a stable dose 3 months prior to randomization. 
c.
Medications known to lower the seizure threshold are not permitted unless 
reviewed and the eligibility of the participant is confirmed by the Medical Monitor. 
30.
Treatment with medical marijuana for MS symptoms, unless it is consistent with local 
MS treatment guidelines and local regulations.
31.
On anticoagulation, or antiplatelet therapy other than daily aspirin for 
cardioprotection. Use of fish oil supplements within 4 weeks prior to randomization.
32.
Participants currently receiving (or unable to stop using prior to receiving the first 
dose of study intervention) potent (strong to moderate) inducers of cytochrome P450 
3A (CYP3A) (must stop at least 3 weeks prior), medications or herbal supplements 
known to be potent (strong to moderate) inhibitors of CYP3A (must stop at least 
1 week prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic 
index (must be stopped at least 1 day prior) (See Section 6.5).
Prior/Concurrent Clinical Study Experience
33.
Participation in any investigational drug study within 6 months or 5 half-lives of the 
investigational drug, whichever is longest, prior to Screening.
Diagnostic Assessments
34.
Any of the following: 
a.
History of or positive for human immunodeficiency virus (HIV) at Screening.
b. History of or positive for hepatitis C virus (HCV) antibody and/or HCV RNA 
by polymerase chain reaction (PCR) at Screening. However, if a participant
has a history of HCV infection and has completed, documented and 
appropriate treatment at least 1 year prior to Screening AND is negative for 
HCV RNA by PCR at Screening, participants will not be excluded from the 
study.
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Note: All participants found to be positive for anti-HCV antibody at Screening 
will have reflex testing performed for HCV RNA by PCR to assess study 
eligibility.
c.
Positive for hepatitis B surface antigen (HBsAg) at Screening.
d. For participants who are negative for HBsAg at Screening but are anti-hepatitis
B surface antibody positive without history of vaccination for Hepatitis B 
and/or anti-hepatitis B core antibody positive with or without history of 
vaccination for Hepatitis B at Screening, reflex testing for hepatitis B virus 
DNA (HBV DNA) by PCR will be performed:
i. Hepatitis B antibody positive participants who have detectable HBV DNA 
are excluded.
ii. Hepatitis B antibody positive participants who are HBV DNA negative are 
not excluded from the study. However, these participants will have HBV 
DNA monitoring by PCR at visits noted in the Schedule of Activities (SoA)
(Section 1.3).
35.
Estimated glomerular filtration rate (eGFR) by the 4-variable Modification of Diet in 
Renal Disease equation of < 60 mL/min/1.73 m2 or any renal condition that would 
preclude the administration of gadolinium (e.g., acute kidney injury).
36.
ALT, AST, amylase, or lipase > 2 × upper limit of normal (ULN) of laboratory 
reference range, total bilirubin > 1.5 × ULN, or any other clinically significant 
laboratory abnormality.
37.
Significant cytopenia, including neutrophil count < 1,500/mm3, platelet count 
< 75,000/mm3, absolute lymphocyte count < 1,000/mm3, or a white blood cell count 
< 3500/mm3.
Other Exclusions
38.
Any allergy, contraindication, or inability to tolerate Avonex or evobrutinib or any of 
their excipients, including lactose, which is an excipient in the oral Study Intervention 
(e.g., evobrutinib 
, placebo
).
Note: Individuals with acquired lactose intolerance are not excluded, but should be 
aware that the oral Study Intervention contains lactose and should be monitored for 
gastrointestinal symptoms related to the increased consumption of lactose in the IMP, 
and made aware of the risks.
39.
Inability to comply with MRI scanning, including contraindications to MRI such as 
known allergy or other contraindications to gadolinium contrast media, 
claustrophobia, presence of a pacemaker, cochlear implants, ferromagnetic devices 
or clips, intracranial vascular clips, insulin pumps, nerve stimulators.
40.
Vaccination with live or live-attenuated virus vaccine within 1 month prior to 
Screening.
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41.
Regular alcohol consumption within 6 months prior to the study defined as: an 
average weekly intake of > 14 units for males or > 7 units for females. One unit is 
equivalent to 8 g of alcohol: a half pint (~240 mL) of beer, 1 glass (125 mL) of wine 
or 1 (25 mL) measure of spirits.
5.3
Criteria for Entry into Open Label Extension Period
5.3.1
Inclusion Criteria for Open Label Extension Period
Participants who meet the following entry criteria may participate in the OLE Period:
1.
Complete the 96-week, double blind, double dummy Treatment Period, and who, in 
the opinion of the Investigator, may benefit from treatment with evobrutinib.
2.
Are able and willing to provide written informed consent for the OLE Phase (e.g., 
before the first administration on OLE Day 1) and to comply with the study protocol.
3.
Are willing to continue to use the contraceptive methods as described in Section 5.1
(Inclusion Criterion 6) and Appendix 3.
5.3.2
Exclusion Criteria for Open Label Extension Period
Participants will be excluded from the OLE if they meet any of the following exclusion criteria
at the OLE screening (OLE Day 1): 
1.
Participants who did not complete study treatment in main study/Week 96 Visit or 
Week 108 Visit.
2.
Treatment with high-dose oral or IV steroids within 30 days before OLE Day 1. 
3.
Contraindications to MRI, for example, presence of pacemakers or other implanted 
metal devices (excluding dental braces), an allergy to gadolinium based MRI contrast, 
renal impairment, or claustrophobia that cannot be medically managed. 
4.
History of suicidal ideation or an episode of clinically severe depression (as 
determined by the Investigator) within 12 weeks prior to OLE Day 1. 
5.
History of abnormal laboratory results that, in the opinion of the Investigator, are 
indicative of a significant cardiac, endocrine, hematologic, immunologic, metabolic 
urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic 
(other than MS), and/or other major diseases. 
6.
Any of the following abnormal blood tests during the Treatment Period requiring 
discontinuation of study intervention, and/or at End of Study visit or at OLE Day 1: 
alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), 
gamma glutamyl-transferase, amylase, or lipase ≥2 × ULN, creatinine clearance 
< 60 mL/min (estimated by Cockcroft-Gault equation) 
7.
Female participants who have a positive pregnancy test result, are pregnant, or are 
currently breast feeding. 
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8.
Inability to comply with study requirements.
5.4
Lifestyle Considerations
5.4.1
Meals and Dietary Restrictions
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, grapefruit hybrids, exotic citrus fruits, cranberries, or their juices from 7 days before 
the start of study intervention until after the final dose.
5.4.2
Caffeine, Alcohol, and Tobacco
During each dosing session, participants will abstain from alcohol for 24 hours before the start 
of dosing until after collection of the final PK and/or pharmacodynamic sample. See 
Exclusion Criterion 41 for alcohol consumption while participating in the study.
There are no restrictions on caffeine or tobacco intake.
5.5
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once with approval by the Medical Monitor. The second Screening Period is a new 
28-day Screening Period. Rescreened participants will be assigned a new identification 
number. See Section 8 for required testing to be redone at rescreening.
6
Study Intervention(s)
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol.
6.1
Study Intervention(s) Administration
Study 
Intervention 
Name:
Evobrutinib 
Avonex (Interferon-beta 1a)
Route of 
Administration:
Oral
Intramuscular
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Dosing 
Instructions:
At the Day 1, Week 12, Week 24, Week 48, Week 72, and Week 96 
study visits in the main study, oral study interventions should be 
administered during the study visit to allow pre-dose assessments (see 
SoA [Section 1.3.1]).
Supplier/
Manufacturer:
Evobrutinib and placebo will be 
supplied by the Sponsor.
Avonex and
placebo will be 
supplied by the Sponsor.
Packaging and 
Labeling
Evobrutinib and placebo will be packed in blister wallets/kits. Avonex 
and matching placebo syringes will be packed in trays/kits.
Each kit will be packaged and labeled per all applicable regulatory 
requirements and Good Manufacturing Practice Guidelines.
6.1.1
Medical Device(s) Use
1. The Sponsor-manufactured medical devices or devices manufactured for the Sponsor 
by a third party that are provided for use in this study are the Avonex, single-use 
syringes and the Avonex placebo single-use syringes, including needle.
2. Instructions for medical device use are provided in the Instructions for Use.
3. The participant will be trained at the investigational site on the appropriate use of the 
single-use syringe, to minimize potential injection site reactions due to poor injection 
technique. The participants will also be trained on the correct storage according to the 
Instructions for Use. The initial training will occur on the day of randomization after 
which the study intervention will be dispensed. The first injection will be performed 
under supervision. Any refresher training or additional training will be provided as 
needed. The participant will be instructed to contact the site if questions or problems 
arise.
4. The Investigator must detect, document, and report medical device incidents, including 
those resulting from device malfunctions, throughout the study, as specified in 
Section 8.3.6.3.
6.2
Study Intervention(s) Preparation, Handling, Storage, 
and Accountability
Storage
All study intervention supplied to each site must be stored in their original containers 
carefully, safely, and separately from other drugs. The storage facility at the study site must 
be locked and temperature controlled. Evobrutinib and placebo must be stored below 30°C 
(86°F). Avonex and Avonex placebo must be stored at 2°C to 8°C. The study intervention 
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temperature will be monitored and documented per the standard process for refrigerated 
medication.
In case there has been a temperature deviation at the clinical site, the site must contact the 
clinical research associate without delay for further evaluation and assessment by the 
designated quality assurance personnel at Merck Healthcare KGaA or delegated personnel at 
the packaging and distribution provider. The medication with the temperature excursion 
should still be stored at the required temperature, but quarantined during the investigations 
and must be appropriately labeled as “quarantine storage”.
Detailed recommendations for the use of Avonex is described in the summary of product 
characteristics or prescribing information, as appropriate.
The preparation, handling and storage of the study interventions will be documented in a 
separate Pharmacy Manual.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
! Upon receipt of the study intervention(s), the Investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit and any 
discrepancies are reported and resolved before use. Also, the responsible person will 
check for accurate delivery. Further guidance and information for study intervention 
accountability are provided in the Study Reference Manual.
! Only participants enrolled in the study may receive study intervention(s) and only 
authorized site staff may supply it. All study intervention(s) must be stored in a secure, 
environmentally-controlled, and monitored (manual or automated) area, in accordance 
with the labeled storage conditions, and with access limited to the Investigator and 
authorized site staff.
! Dispensing will be recorded on the appropriate accountability forms so that accurate 
records will be available for verification at each monitoring visit.
! Study intervention(s) accountability records at the study site will include the following:
! Confirmation of receipt, in good condition and in the defined temperature range.
! The inventory provided for the clinical study and prepared at the site.
! The dose(s) each participant used during the study.
! The disposition (including return, if applicable) of any unused study intervention(s).
! Dates, quantities, batch numbers, container numbers, expiry dates, and the 
participant numbers.
! The Investigator site will maintain records, which adequately documents that 
participants were provided the doses specified in this protocol, and all study 
intervention(s) provided were fully reconciled.
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! Unused study intervention(s) must not be discarded or used for any purpose other than 
the present study. No study intervention that is dispensed to a participant may be re-
dispensed to a different participant.
! A Study Monitor will periodically collect the study intervention(s) accountability forms.
! Further guidance and information for the final disposition of unused study 
intervention(s) are provided in the Study Reference Manual.
6.3
Measures 
to 
Minimize 
Bias: 
Study 
Intervention 
Assignment and Blinding
6.3.1
Study Intervention Assignment
Participants will be randomized in a blinded fashion to either evobrutinib or Avonex treatment 
in a 1:1 ratio. The randomization will be stratified by 2 factors: region (4 levels: North 
America, Western Europe, Eastern Europe, Rest of World) and Baseline EDSS (2 levels: 
< 4.0, ≥4.0). A unique participant identification number, assigned according to the Study 
Reference Manual, will be used throughout the trial.
Study using IWRS
After confirmation of participant’s eligibility and at the last 
practical moment prior to study intervention administration, 
participants will be centrally allocated to either evobrutinib or 
Avonex in a 1:1 ratio using an Interactive Web Response System 
(IWRS) and per a computer-generated randomization list.
The IWRS will be used to assign unique participant numbers, 
allocate participants to study intervention group at the 
randomization visit, and study intervention to participants at each 
study intervention visit.
Before the study is initiated, the log in information and directions 
for the IWRS will be provided to each site. The site will contact 
the IWRS prior to starting study intervention administration for 
each participant.
6.3.2
Blinding
Blinding Method
! Study intervention assignment will be randomized and blinded. Blinding will be 
accomplished using a double-dummy design given the differences in administration 
between the study intervention and the active control.
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Assignment Method Retention
! The IWRS will give the Investigator the ability to break the blind with respect to 
study intervention for any participant, removing the need for physical retention of 
the intervention assignment at the site. 
Unblinding Clinical Studies for Sample Analysis of Special Data
! The bioanalytical monitors and analytical laboratory for measurement of evobrutinib
concentrations will be unblinded since obtaining the result reveals the study 
intervention arm for the participant. Evobrutinib concentration information that 
would unblind the study will not be reported to investigative sites or blinded 
personnel until the study has been unblinded for the PA.
6.3.3
Emergency Unblinding
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
participant’s study intervention assignment is warranted. Participant safety must always be 
the first consideration in this decision. The Sponsor must be notified within 24 hours after 
unblinding. The Investigator must provide the Sponsor the reason for unblinding without 
revealing the study intervention, except to the designated drug safety representative via the 
Emergency Unblinding Notification Form. The date of and reason for unblinding must be 
recorded in the source documents and CRF. Contact information for unblinding in an 
emergency is given on the participant emergency card provided to each participant, as noted 
in Appendix 2 (Study Governance).
The Sponsor’s drug safety department will submit any Suspected Unexpected Serious 
Adverse Reactions (SUSAR) reports to regulatory authorities and ethics committees with 
unblinded information, per applicable regulations. Only blinded information will be provided 
to the study team.
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6.4
Study Intervention Compliance
The study intervention will be administered at the site on trial visit days as defined in the SoA 
(Section 1.3). All other administrations of study intervention will be done by the participant 
or participant’s caregiver at home throughout the rest of the trial. Participants or participant’s 
caregiver will be asked to record the date and time of dosing and food intake around dosing 
in a participant diary.
Participants will be instructed to bring all study intervention, including the used 
packaging/empty boxes and all blisters, to each trial visit indicated in the SoA (Section 1.3), 
and to allow for the assessment of compliance with study intervention. Prior to discharge from 
each scheduled visit, participants will be given sufficient study intervention for at-home 
administration until the next scheduled visit during the Treatment Period. On study visit days 
indicated in the SoA (Section 1.3), the previous week’s study intervention adherence will be 
documented using pill counts.
Insufficient compliance with the protocol-specified dosing regimen is defined as receiving 
< 80% of the required number of scheduled doses of trial medication. Noncompliance is 
further addressed in Sections 7.1 and 8.4.
6.5
Concomitant Therapy
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study, 
including any changes. For prescription and over-the-counter medicines, vaccines, vitamins, 
and herbal supplements, record the name, reason for use, dates administered, and dosing 
information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
Treatment for Symptoms of Multiple Sclerosis
The Treating Investigator should attempt to maintain therapies or treatments for symptoms 
related to MS (e.g., walking ability, spasticity, incontinence, pain, fatigue) reasonably 
constant throughout the study. However, if such therapies need to be added or modified during 
the study due to changes in the participant’s clinical presentation, then this could be done at 
the Investigator’s discretion, with the exception of those treatments listed in Section 6.5.3
(Prohibited Medications). Nonetheless, any medications that are considered necessary for the 
participant’s well-being may be given at the discretion of the Investigator.
During the OLE, initiation of therapy with dalfampridine (Ampyra) is allowed, if indicated 
by the treating Investigator.
6.5.1
Rescue Medicine
Participants who experience a MS relapse during study intervention may receive rescue 
medication pursuant to the following restrictions: 
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1. Up to 1 g daily of methylprednisolone administered intravenous for up to 5 consecutive 
days. Where possible, the use of corticosteroids should be avoided in the 3 weeks prior 
to a scheduled MRI scan. If participants receive corticosteroids for a relapse, every 
effort will be made to obtain the scan prior to the first steroid dose if the pre-steroid 
scan is within 1 week of the scheduled visit. In all instances, the treatment of the relapse 
per the investigator’s clinical judgement takes priority over the timing of the MRI scan.
2. Oral tapering of corticosteroid rescue medication is permitted, with a maximum of 
15 days of tapering allowed.
3. In the treatment of acute exacerbations of MS, daily intramuscular or subcutaneous 
doses of Acthar gel, 80-120 units and not exceeding 3 weeks may be administered. An 
additional taper of up to 2 weeks with less frequent dosing frequency will be permitted 
as indicated. 
6.5.2
Permitted Medicines
The only permitted medications are the following:
! Medications required per the medical history that:
o
Are not specifically prohibited by the protocol during the study, 
o
Are considered necessary for the participants’ welfare, and 
o
Will not interfere with the study intervention 
Medications under the conditions described above may be given at the Investigator’s 
discretion.
Treatment with medical marijuana for MS symptoms is permitted, if it is consistent with local 
MS treatment guidelines and local regulations.
Any medicines that are considered necessary to protect the participant’s welfare in 
emergencies may be given at the Investigator’s discretion, regardless if it results in a protocol 
deviation.
6.5.3
Prohibited Medicines
Medications prohibited before the study are listed in the exclusion criteria (Section 5.2).
The following medications and therapies are not permitted during the study and would require 
discontinuation of the study intervention:
! Rituximab, ocrelizumab, and any other B cell depleting therapy, BTK inhibitors 
(including evobrutinib), mitoxantrone, or lymphocyte-depleting therapies (e.g., 
alemtuzumab, anti CD4, cladribine, cyclophosphamide, total body irradiation, bone 
marrow transplantation) 
! Lymphocyte trafficking blockers (e.g., natalizumab, fingolimod) 
! Intravenous Ig therapy and/or plasmapheresis and immunosuppressive treatments 
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! Beta-interferons (independent of study intervention) or glatiramer acetate 
! Dimethyl fumarate or Teriflunomide
! Dantrolene. Other antispasticity agents are permitted at study entry if the participant 
has been on a stable dose over the 3 months prior to randomization. During the study, 
antispasticity agents can be added and/or the regimen modified based on the 
Investigator’s clinical judgement in order to manage the participant’s symptoms (see 
Section 6.5).
! Medications known to lower the seizure threshold should be avoided but may be used 
at the Investigator’s discretion. Should such a medication be required, the Medical 
Monitor will evaluate ongoing participation in the study based on discussion with the 
Investigator. Dalfampridine (Ampyra) or fampridine are permitted only if the 
participant has been on a stable dose for 3 months prior to randomization due to the 
possibility of confounding effects on key study measures.
! Anticoagulation, fish oil supplements, or antiplatelet therapy other than daily aspirin 
for cardioprotection
! Medications known to be potent (strong to moderate) inhibitors of CYP3A, potent 
inducers of CYP3A, or drugs mainly metabolized by CYP3A with a narrow 
therapeutic index
! Biologic therapies with systemic side effects.
6.5.4
Other Interventions
Participants will be advised to use nonsteroidal anti-inflammatory drugs as needed, to 
counteract the side effects commonly associated with Avonex administration, or as otherwise 
indicated, up to the maximum recommended dose per local labeling during the trial. Caution 
should be exercised while using medications known to cause liver injury.
Herbal or nutritional supplements (including, but not limited to, St. John’s wort, grapefruit, 
Seville oranges, cranberries, or juices of these fruits) known to be potent inhibitors of CYP3A 
must be stopped at least 1 week prior to randomization.
6.6
Dose Selection and Modification
Not applicable.
6.7
Study Intervention after the End of the Study
The Sponsor will not provide any additional care to participants after they leave the study 
because such care would not differ from what is normally expected for participants with 
relapsing forms of MS.
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6.8
Special Precautions
See Section 7.1 for precautions related to abnormal liver function.
If any of the MRIs of the brain have findings suggestive of PML, cerebrospinal fluid JC virus 
polymerase chain reaction (CSF JCV PCR) should be tested to rule out PML, see Appendix 8
for further details.
6.9
Management of Adverse Events of Interest
Adverse events of special interests (AESI) are liver AEs (possible drug-induced, 
non-infectious, non-alcoholic and immune-mediated), infections (serious and opportunistic 
infections), lipase and amylase elevation, and seizure. All serious and nonserious AESIs must 
be additionally documented and reported using the appropriate Report Form as specified in 
Appendix 4.
Liver adverse events
The elevations of transaminases observed in subjects treated with evobrutinib were frequent, 
asymptomatic, and reversible on discontinuation of evobrutinib. The mechanism is unknown. 
Evobrutinib liver AESI will include transaminases and bilirubin elevations, biological Hy’s 
Law cases based on laboratory data; any type of acute or chronic hepatitis (any grade), 
suspected drug-induced liver injury, acute or chronic hepatic failure, fibrosis, cirrhosis and 
other liver damage-related conditions. 
Infections  
As per its mechanism of action, evobrutinib may impair B cell function which might lead to 
a decreased humoral immunity and consequently an increased risk of infection. Overall in 
completed studies in participants the MedDRA system organ class (SOC)
 
 
 
 
 Treatment of 
infections must be prompt and done in accordance with local standard of care depending on 
considerations such as the nature and severity of the infection and participant’s overall health 
status. Any CTCAE Grade ≥3 or SAEs of infection and opportunistic infection are considered 
as an AESI.
Amylase and lipase elevations
Asymptomatic elevations in amylase or lipase or both in participants treated with evobrutinib 
have been observed at a variety of time points and reported as TEAEs or noted as laboratory 
abnormalities
 
 
 
 
 
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7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
The Investigator should discontinue study intervention when a participant meets one of the 
conditions outlined below or if the Investigator believes that it is in the best interest of the 
participant. 
If a participant’s Baseline value (D1 or OLE D1, as applicable) is abnormal and/or falls within 
any of the conditions outlined below, consult with the Medical Monitor regarding potential 
discontinuation of study intervention, continued participation in study, and additional 
monitoring if needed. Further treatment will be at the discretion of the Investigator. 
For any study treatment discontinuation related to laboratory or assessment results, the 
participant should be followed with additional testing as needed until a return to within normal 
limits or acceptable value as agreed upon by the Investigator and Medical Monitor. In cases 
for which permanent discontinuation of study intervention is required, no rechallenge will be 
allowed.
Criteria for Permanent Discontinuation of Study Intervention:
The Investigator should permanently discontinue study intervention and inform the 
Medical Monitor for the criteria outlined below.
For laboratory or assessment related criteria:
• a neutrophil count < 500 / mm3 (Grade 4)
• a neutrophil count 500–999 / mm3 (Grade 3) with fever
• platelet count < 25,000 / mm3 (Grade 4)
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• platelet count 25,000–49,999 / mm3 (Grade 3) with bleeding
• an increase in lipase to > 5 × ULN (Grade 4)
• an increase in amylase to > 5 × ULN (Grade 4)
• an increase in serum creatinine to > 3 × ULN (Grade 3 or higher)
• any other laboratory abnormality of Grade 4 severity, with the exception of lymphopenia 
(see below)
• QTcF > 500 ms OR an increase in QTcF > 60 ms relative to the participant’s Baseline ECG 
(D1) is observed and confirmed (with a second ECG).
• Detectable HBV DNA. Should this occur, consultations with specialists, such as a 
hepatologist, can be performed at the discretion of the Investigator and the Medical 
Monitor should be informed. In addition, a comprehensive hepatic/autoimmune panel is 
required (see below).
Note: HBV DNA is assessed only in Hepatitis B antibody-positive participants during the 
study (see SoA and Exclusion Criterion 34).
For other reasons:
• Pregnancy.
• Any events that endanger the safety of the participant.
• Sponsor decision to end clinical study.
• Adverse events, if discontinuation of study intervention is desired or considered necessary 
by the Investigator and/or participant.
• Use of prohibited medications, as defined in Section 6.5.3. Any medications that are 
considered necessary for the participant’s well-being may be given at the discretion of the 
Investigator. Use of a prohibited medication may be cause for a participant to permanently 
discontinue study intervention; however, continuing study intervention and participation 
in the trial should be discussed on a case-by-case basis with the Medical Monitor.
• Lack of efficacy and/or progression of MS as defined by Investigator judgement or when 
a medication other than permitted medications (as defined in Section 6.5.2) is needed for 
treatment (see above regarding prohibited medications).
Criteria for Temporary Discontinuation of Study Intervention:
The Investigator should temporarily discontinue study intervention for the discontinuation 
criteria outlined below, inform the Medical Monitor, and perform confirmatory testing as 
instructed. Depending on the result of the confirmatory test, the Investigator should follow 
instructions as outlined below, including permanently discontinuing study intervention
when indicated.
For any study treatment discontinuation related to laboratory or assessment results, the 
participant should be followed with additional testing as needed until a return to within normal 
limits or acceptable value as agreed upon by the Investigator and Medical Monitor. In cases 
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for which permanent discontinuation of study intervention is required, no rechallenge will be 
allowed.
Liver Function Testing criteria:
• For an increase in AST or ALT to > 3 × ULN (Grade 2 or higher), temporarily discontinue 
the study intervention and recheck the value within 72 hours (and no later than 1 week).
!
If the value is still Grade 2 or higher upon retest, the study intervention 
should be permanently discontinued and the Medical Monitor informed.
!
If the value has decreased to Grade 1 or lower, the Investigator may re-initiate 
study intervention (see Section 7.1.1).
• For an increase in bilirubin of > 1.5 × ULN (Grade 2 or higher), temporarily discontinue 
the study intervention and recheck the value within 72 hours (and no later than 1 week).
!
If the value is still Grade 2 or higher upon retest, the study intervention 
should be permanently discontinued and the Medical Monitor informed.
!
If the value has decreased to Grade 1 or lower, the Investigator may re-initiate 
study intervention (see Section 7.1.1).
Other Laboratory Criteria:
• For a Grade 3 decrease in neutrophil count (500–999 / mm3) without fever, temporarily 
discontinue study intervention and recheck the value within 1 week. 
!
If the value is still <1000 / mm3 (Grade 3 or higher) upon retest, permanently 
discontinue study intervention and inform the Medical Monitor. 
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!
For an improvement to Grade 2 (1000–1499 / mm3) upon retest, continue to hold 
the study intervention and recheck the value within 1 week. 

If a further downward trend is observed, permanently discontinue study 
intervention and inform the Medical Monitor. 

If no further downward trend is observed, the Investigator may re-initiate 
study intervention (see Section 7.1.1)
!
If the neutrophil count returns to ≥1500 / mm3 upon retest (i.e. returns to Grade 1 
or within normal limits), the Investigator may re-initiate study intervention (see 
Section 7.1.1).
• For a Grade 2 decrease in neutrophil count (1000–1499 / mm3), temporarily discontinue 
study intervention and recheck the value within 1 week. 
!
If a downward trend is observed upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 
!
If no downward trend is observed, the Investigator may re-initiate study 
intervention (see Section 7.1.1).
• For a Grade 3 decrease in platelet count (25,000–49,999 / mm3) without bleeding, 
temporarily discontinue study intervention and recheck the value within 1 week. 
!
If the value is still <50,000 / mm3 (Grade 3 or higher) upon retest, 
permanently discontinue study intervention and inform the Medical Monitor. 
!
For an improvement to Grade 2 (50,000–74,999 / mm3) upon retest, continue to 
hold the study intervention and recheck the value within 1 week. 

If a further downward trend is observed upon retest, permanently 
discontinue study intervention and inform the Medical Monitor. 

If no further downward trend is observed, the Investigator may re-initiate 
study intervention (see Section 7.1.1).
!
If the platelet count returns to ≥75,000 / mm3 upon retest (i.e. returns to Grade 1 
or within normal limits), the Investigator may re-initiate study intervention (see 
Section 7.1.1).
• For a Grade 2 decrease in platelet count (50,000–74,999 / mm3), temporarily discontinue 
study intervention and recheck the value within 1 week. 
!
If a downward trend is observed upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 
!
If no downward trend is observed upon retest, the Investigator may re-initiate 
study intervention (see Section 7.1.1).
• For an increase in amylase to > 2 to 5 × ULN (Grade 3), temporarily discontinue study 
intervention and recheck the value within 72 hours of receipt (and no later than 1 week). 
!
If the value is still Grade 3 or higher upon retest, permanently discontinue 
study intervention and inform the Medical Monitor.
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!
For an improvement to Grade 2 (> 1.5 to 2 × ULN) upon retest, continue to hold 
the study intervention and recheck the value within 1 week. 

If the value does not decrease upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 

If a downward trend is observed, the Investigator may re-initiate study 
intervention (see Section 7.1.1).
!
If the amylase returns to ≤1.5 × ULN upon retest (i.e. returns to Grade 1 or within 
normal limits), the Investigator may re-initiate study intervention (see 
Section 7.1.1).
• For an increase in amylase to > 1.5 to 2 × ULN (Grade 2), temporarily discontinue study 
intervention and recheck the value within 72 hours of receipt (and no later than 1 week). 
!
If the value does not decrease upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 
!
If a downward trend is observed, the Investigator may re-initiate study intervention 
(see Section 7.1.1).
• For an increase in lipase to > 2 to 5 × ULN (Grade 3), temporarily discontinue study 
intervention and recheck the value within 72 hours of receipt (and no later than 1 week). 
!
If the value is still Grade 3 or higher, permanently discontinue study 
intervention and inform the Medical Monitor.
!
For an improvement to Grade 2 (> 1.5 to 2 × ULN) upon retest, continue to hold 
the study intervention and recheck the value within 1 week. 

If the value does not decrease upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 

If a downward trend is observed, the Investigator may re-initiate study 
intervention (see Section 7.1.1).
!
If the lipase returns to ≤1.5 × ULN upon retest (i.e. returns to Grade 1 or within 
normal limits), the Investigator may re-initiate study intervention (see 
Section 7.1.1).
• For an increase in lipase to > 1.5 to 2 × ULN (Grade 2), temporarily discontinue study 
intervention and recheck the value within 72 hours of receipt (and no later than 1 week). 
!
If the value does not decrease upon retest, permanently discontinue study 
intervention and inform the Medical Monitor. 
!
If a downward trend is observed, the Investigator may re-initiate study intervention 
(see Section 7.1.1).
• For any increase in serum creatinine > 1.5 × ULN but < 3 × ULN (Grade 2), temporarily 
discontinue study intervention and recheck the value within 72 hours of receipt (and no 
later than 1 week). 
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!
If the value does not decrease upon retest, permanently discontinue study 
intervention and inform the Medical Monitor.
!
If a downward trend is observed, the Investigator may re-initiate study intervention 
(see Section 7.1.1).
• For an absolute lymphocyte count < 200 / mm3 (Grade 4), study intervention should be 
temporarily discontinued, and follow-up testing should be conducted as clinically indicated
!
If the absolute lymphocyte count returns to 800 / mm3 (i.e. returns to Grade 2), the 
Investigator may re-initiate study intervention (see Section 7.1.1).
!
If there is persistent Grade 4 lymphopenia, permanently discontinue study 
intervention and inform the Medical Monitor.
• For any other laboratory increase/decrease (as relevant) from Baseline to a clinically 
significant higher severity grade, temporarily discontinue study intervention and recheck 
the value within 72 hours of receipt (and no later than 1 week). The Investigator may re-
initiate study intervention if an improving trend is observed.
For other reasons:
• At the first sign or symptom suggestive of PML, or brain MRI suggestive of PML, 
temporarily discontinue the study intervention and check for CSF JCV PCR. If positive, 
permanently withdraw the study intervention.
The SoA specifies the data to collect at study intervention discontinuation and follow-up, 
and any additional evaluations that need to be completed.
7.1.1
Temporary Discontinuation
See Section 7.1 for specific criteria for temporary discontinuation related to abnormal 
laboratory values. The Investigator should inform the Medical Monitor upon re-initiation of 
study intervention following temporary discontinuation.
7.1.2
Rechallenge
See Section 7.1 for specific criteria for rechallenge following temporary discontinuation for 
abnormal laboratory values. 
7.2
Participant Discontinuation/Withdrawal from the Study
! A participant may withdraw from the study at any time, at his/her own request or 
may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons.
! If a participant is permanently withdrawn from study intervention due to stopping 
rules (see Section 7.1), the participant should also be withdrawn from the study.
! At the time it is determined that a participant is withdrawing from the study, the 
participant should if possible, return for an Early Discontinuation Visit, as listed in 
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the SoA. The SoA specifies the data to collect at study discontinuation and follow-
up, and any additional evaluations that need to be completed.
! If the participant withdraws consent for future involvement in the study, any data 
collected up to that point may still be used, but no future data can be generated, and 
any biological samples collected will be destroyed.
! Subsequent to the Early Discontinuation Visit, the participant should, if possible, 
enter the 4-week Safety Follow-Up Period. At the end of that 4-week period, the 
participant should return for the 4-week Safety Follow-Up Visit. After completing 
this visit, the participant would be discontinued from the study.
! A participant has the right at any time to request destruction of any biological 
samples taken. The investigator must document this in the site study records.
Participants who have discontinued after randomization (e.g., due to AEs or lack of efficacy) 
will not be replaced and will not be eligible to participate in the OLE (see Section 7.1). 
Participants who discontinue from the study should return for the Early Discontinuation Visit 
and the Safety Follow-up visit 4 weeks from the day of discontinuation of study interventions.  
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
! The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain if the participant wants to or should continue 
in the study.
! Before a participant is deemed “lost to follow-up”, the Investigator or designee must 
make every effort to regain contact with the participant: 1) where possible, make 3 
telephone calls; 2) if necessary, send a certified letter (or an equivalent local method) 
to the participant’s last known mailing address, and 3) if a participant has given the 
appropriate consent, contact the participant’s general practitioner for information.
These contact attempts should be documented in the participant’s medical record.
! Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8
Study Assessments and Procedures
! Study assessments and procedures and their timing are summarized in the SoA.
! No protocol waivers or exemptions are allowed.
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! Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.
! Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
! All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all participants screened, to confirm eligibility, and if 
applicable, record reasons for screening failure.
! Prior to performing any study assessments that are not part of the participant’s routine 
medical care, the Investigator will obtain written informed consent as specified in 
Appendix 2 Study Governance.
! Procedures conducted as part of the participant’s routine medical care (e.g., blood 
count) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
The following data will be collected: 
! Demography: date of birth, sex (gender), ethnicity, and race, as permitted by local 
regulations
! Medical history (including diagnosis and duration of MS): previous illness and 
surgeries (e.g., all during the past year and only major ones prior to that), concomitant 
illness, allergies, prior therapies for the target indication and reason for switch (i.e., 
relevant previous medications), therapies stopped or changed at entry into the study 
(includes use of drugs, alcohol, tobacco, and caffeine), special diets and, for women, 
menstrual status and date of last menstrual period.
! Participants will be asked to record the following information daily in a paper
participant diary: dosing date and time and food intake around time of dosing.
All blood and urine tests will be analyzed by a central laboratory, with the following 
exceptions:
! Urine testing for β-human chorionic gonadotropin will be conducted at the local 
laboratories.
! Urine dipstick results will be interpreted locally. Please see the SoA (Section 1.3)
and Appendix 5 for information regarding abnormal dipstick results. 
will be analyzed by the analytical laboratories 
specified by the Sponsor.
! HIV testing should be conducted and analyzed locally.
! In addition, ECG results will be interpreted locally by the Investigator (see 
Section 8.2.3).
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Screening
See the SoA (Section 1.3.1) for a list of assessments completed at Screening.
The Screening packet will be reviewed by the Medical Monitor. See Appendix 2 for further 
details.
The Screening Period may be extended (but cannot exceed 8 weeks) for participants who have 
used systemic corticosteroids for their MS before Screening. For a participant to be eligible, 
systemic corticosteroids should not have been administered between Screening and Baseline.
See Appendix 2 for details of the steps to be performed.
Retesting before Baseline
In case the Screening laboratory samples are rejected by the central laboratory or the results 
are not assessable or abnormal, the tests need to be repeated once within 4 weeks. Any 
abnormal Screening laboratory value that is clinically relevant should be retested once in order 
to rule out any progressive or uncontrolled underlying condition. The last value before 
randomization must meet study criteria. In such circumstances, the Screening Period may 
need to be prolonged but should not exceed 8 weeks and only after approval by the Medical
Monitor.
For screen failures, see Section 5.5.
Rescreening
Participants who are considered screen failures after a first Screening Period may undergo 
rescreening once, after approval by the Medical Monitor. If a participant is rescreened, all 
Screening tests will need to be repeated except as follows:
a.
Documented CXR and TB testing if occurred within 3 months prior to the 
rescreening visit.
b.
Hepatitis and HIV testing if occurred within 1 month prior to the rescreening visit.
Unscheduled Visit 
Participants should be instructed that if, at any point during the trial, they suspect that they 
are experiencing new or worsening neurological symptoms, including possible relapse, they 
should contact the Investigator as soon as possible after the onset of symptoms. If necessary, 
the participant should be evaluated by the Investigator within the clinic and every effort should 
be made to complete this evaluation within 1 week after the start of symptoms. Any 
assessments needed to confirm the relapse should be performed at the discretion of the 
Investigator. Details should be documented within the relevant section(s) of the eCRF. The 
definition of a qualifying and nonqualifying relapse is provided in Section 8.1.1.1.
If an MRI scan is indicated at an Unscheduled Visit for Neurological Worsening and Relapse 
Assessment, it should be performed prior to initiating corticosteroid therapy, where possible. 
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In addition, care should be taken to avoid the participant being exposed to gadolinium more 
than once in a 4-week period, i.e. it may be necessary to cancel the MRI scan at the next 
scheduled visit (all other assessments should be completed at the visit as normal). If the 
Unscheduled Visit is conducted for a safety concern the assessments described below should 
be completed and any additional assessments and further management will be at the discretion 
of the Investigator.
The following will be performed at an Unscheduled Visit:
! Review of concomitant medications and procedures, evaluation of AEs, disease 
activity assessment (relapse assessment, EDSS), complete physical examination, 
vital signs, and a neurologic exam
! Blood sample collection for safety assessments (hematology, chemistry, 
coagulation).
! Urine collection for urinalysis, and, if necessary, microscopy and protein:creatinine 
ratio
! Additional assessments can be performed at the discretion of the Investigator.
Open-label Extension Period
After completing the Treatment Period (Weeks 1 through 96), participants will be offered the 
opportunity to participate in an OLE Period where all participants will receive evobrutinib. 
Signed consent will also be obtained prior to participation in the optional OLE Period. 
Scheduled assessments will be performed according to the SoA (Section 1.3.2) before 
administration of the study intervention. All scheduled visits during the OLE Period may take 
place within the visit windows specified in the SoA. Participants who discontinue early must 
return for the OLE End of Treatment Visit (Week 144/Visit 26). For further details see 
Sections 1.3.2 and 4.
8.1
Efficacy Assessments and Procedures
8.1.1
Neurological Assessment
The examining neurologist (i.e., the assessor) will perform the neurological examination, 
document the functional system scores (FSS) and assess EDSS scores. 
 
 
He or she will have 
access only to data from assessments listed above. The examining neurologist will not be 
involved with any aspect of medical management of the participant and will not have access 
to participant data. Every effort will be made to ensure that there is no change in the examining 
neurologist throughout the course of the study for any individual participant. The examining 
neurologist will be trained and instructed not to discuss what adverse effects (if any) the 
participant is experiencing from their medication. The examining neurologist will receive 
training in performing EDSS assessments prior to the beginning of the study and must have 
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successfully passed an examination on performance of the Neurostatus EDSS examination 
within 24 months of participation. All examining neurologists will receive ongoing training 
on performance of the Neurostatus EDSS examination throughout the course of the study.
Prior to being examined by the examining neurologist. treating neurologists and/or study 
coordinators should remind participants not to discuss what (if any) adverse effects they may 
be experiencing; this should be documented in the source documents.
8.1.1.1
Qualified Relapse
A qualifying relapse is the occurrence of new or worsening neurological symptoms 
attributable to MS (for > 24 hours, no fever, infection, injury, AEs, and preceded by a stable 
or improving neurological state for ≥30 days). The relapse should be accompanied by an 
increase of ≥0.5 EDSS, or 2 points increase on 1 of the FSS, or 1-point increase on ≥2 of the 
FSS. The increase in FSS scores must be related to the neurological symptoms which were 
reported as new or worsening. The change must affect the selected FSS (i.e., pyramidal, 
ambulation, cerebellar, brainstem, sensory, or visual, excluding bladder or bowel).
Episodic spasms, sexual dysfunction, fatigue, and mood change will not suffice to establish a 
relapse.
The annualized relapse rates over 96 weeks will be calculated based on qualified relapses.
8.1.1.2
Disability progression and Expanded Disability Status 
Scale
Disability progression is defined as an increase of ≥1.0 point from the Baseline EDSS score 
that is not attributable to another etiology (e.g., fever, concurrent illness, or concomitant 
medication) when the Baseline score is 5.0 or less and an increase of ≥0.5 when the Baseline 
score is 5.5. Disability progression is considered sustained when the initial increase in the 
EDSS is confirmed at a regularly scheduled visit at least 12 weeks or 24 weeks, after the initial 
documentation of neurological worsening.
Confirmed disability progression, sustained for 12 and 24 weeks after the initial 
documentation of neurological worsening, will be analyzed as secondary endpoints.
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8.1.3
Patient Reported Outcomes
PRO data will be collected at the study visit with an electronic 
 device at specified study 
visits (see the SoA for details, Section 1.3.1). The 
 with the PRO instruments will be 
distributed by the Investigator staff and completed in their entirety by the participant.
PROs should be administered prior to administration of study intervention and prior to any 
other study assessment(s) to ensure the validity of the instruments is not compromised, and 
data quality meet requirements of the Guidance for Industry Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims (FDA 2009).
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PRO data will be elicited from participants in this study to better characterize the clinical 
profile of evobrutinib. These PRO measurements are described in Sections 8.1.3.1,
 
and
. Please note that the methods for collecting and analyzing PRO data are different 
from those for the ascertainment of observed or volunteered adverse events. Due to these 
differences, PRO data will not be reported as adverse events and no attempt will be made to 
resolve any noticeable severe symptoms or functional status.
To ensure missing data are minimized, all participants will be given detailed information and 
training about the nature of the PRO assessments and importance of such information for the 
trial, at or prior to study start (based on materials provided). 
Further guidance/information for study sites on procedures for collecting electronic PROs 
(ePROs), as well as strategies to ensure complete and high-quality PRO data will be provided 
in the study manual of operations.
8.1.3.1
Patient Reported Outcomes Measurement Information 
System 
The National Institute of Health Patient Reported Outcomes Measurement Information 
System (NIH PROMIS) comprises an extensive set of item banks and short-form measures 
created from the item banks that assess physical, mental, and social aspects of health in adults 
and children, including symptoms such as pain, fatigue, and sleep disturbance, and health 
domains such as physical function (PF) (Cella 2007).
The PROMIS physical function (PF) item bank was identified as having great potential for 
the evobrutinib program due to several factors, despite limited previous use in MS 
(Amtmann 2018), and lack of an MS-specific short form. First, the content includes all key 
aspects of physical function domain, such as IADL, lower extremity (mobility), back and neck 
(central), and upper extremity functioning domains (Rose 2014). Second, the development 
process of PROMIS items included a rigorous development and calibration process, ensuring 
the technical quality of items. Further, items capture the full continuum of PF, from low to 
high levels, which is a useful characteristic for capturing changes over time. A short form 
specific to MS has recently been derived with input from MS patients (n = 57) and is currently 
undergoing validation (Kamudoni 2018). Measures from the PF item bank are scored on a 
T-score metric (higher scores = higher PF). The minimal clinically important difference 
(MCID) score cut-off for the short form is yet to be established. A provisional MCID estimate 
of 5 points is proposed, based on previous research on the PF item bank (Yost 2011, Amtmann 
2018).
The PROMIS Fatigue item bank includes 95 items assessing the experience (frequency, 
duration and intensity) as well as the impacts of fatigue on physical, mental and social 
activities (Lai 2011). Psychometric properties of this bank have been established across 
different clinic populations (Cella 2016). An 8-item short-form specific to MS, derived based 
on input from clinicians (n = 36) and participants with MS (n = 48), is available (Cook 2012). 
This short form is currently undergoing further validation. Measures from the fatigue item 
bank are scored on a T-score metric (higher scores = higher fatigue); a provisional MCID 
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estimate of 4 points is proposed based on previous research on the fatigue item bank 
(Yost 2011, Amtmann 2018).
The PROMIS approach offers flexibility in the selection of items and how these are 
administered, including use of bespoke measures, fixed short forms, or computerized adaptive 
testing. PROMIS based short forms for physical functioning and fatigue are currently in 
preparation for FDA qualification as a drug development tool (DDT) in MS (MS Working 
Group, 2018; DDT COA, 2018).
Physical function deterioration is defined as a reduction in PROMIS PF T-score ≥5.0 
compared to Baseline PROMIS PF T-score sustained for at least 12 weeks.
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8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting 
and analysis of baseline medical conditions, adverse events (AEs), physical examination 
findings, vital signs, electrocardiograms, and laboratory tests including Ig and subclass 
concentration.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1.
8.2.1
Physical Examinations
! A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
! A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).
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! Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Any physical exam abnormality findings, which are identified as clinically significant before 
the ICF is signed, will be captured on the Medical History eCRF. After the ICF is signed, any 
new physical exam abnormality findings will be captured on the Adverse Event form.
8.2.2
Vital Signs
! Height at Screening and weight will also be measured and recorded. Weight will be 
measured and recorded at each visit where vital signs are recorded as noted in the 
SoA.
! Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
! Blood pressure and pulse measurements will be assessed semisupine with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
! Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones).
! Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and respiratory 
rate.
8.2.3
Electrocardiograms
! Triplicate 12-lead ECG will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
intervals.
! At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes and should 
occur in a resting state without prior procedure such as blood draw.
! The 12-lead ECG recordings will be obtained after 10 minutes of rest in a semisupine 
position.
! ECG results will be interpreted locally by the Investigator. In the event of findings 
that could represent clinically relevant cardiac issues (including but not limited to 
new or worsening arrhythmia, significant changes in ECG parameters, signs and/or 
symptoms that could represent cardiac events such as syncope, chest pain, etc.), 
additional evaluations can be performed per the Investigator’s clinical judgement. 
(including but not limited to repeat ECGs, echocardiography, evaluation by a 
cardiologist).
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8.2.4
Clinical Safety Laboratory Assessments
! Blood and urine samples will be collected for the clinical laboratory tests listed in 
Appendix 5, at the time points listed in the SoA. All samples should be clearly 
identified. 
! Additional tests may be performed at any time during the study, as determined 
necessary by the Investigator or required by local regulations.
! The tests will be performed by the central laboratory. See Appendix 5 for exceptions.
! Local laboratory results are only required when central laboratory results are not 
available in time for study intervention administration and/or response evaluation. If 
a local sample is required, it is important that the sample for central analysis is 
obtained at the same time. Additionally, if the local laboratory results are used to 
make a study intervention decision or response evaluation, the results must be entered 
in the CRF.
! The Sponsor must receive a list of the local laboratory normal ranges before shipment 
of study intervention(s). Any changes to the ranges during the study must be 
forwarded to the Sponsor or designated organization.
! The Investigator must review each laboratory report, document their review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents.
! Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
! Pregnancy testing (serum or highly sensitive urine, as required by local regulations) 
will be conducted at monthly intervals during study intervention administration.
! Pregnancy testing (serum or highly sensitive urine, as required by local regulations) 
will be conducted at the end of relevant systemic exposure of the study intervention 
and correspond with the time frame for female participant contraception in 
Section 5.1.
8.2.5
Pregnancy
Pregnancy testing (urine or serum as required by local regulations) should be conducted as 
summarized in the SoA (Section 1.3) during intervention.
Urine pregnancy testing will be performed at home or at the site. Urine pregnancy test kits 
will be provided to the participants at site visits. The Investigator and/or delegated site staff 
will train the relevant participants to self-administer the urine pregnancy test, and will contact 
the participant by telephone to confirm completion of urine pregnancy testing and discuss 
results.
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8.2.6
Immunoglobulin levels
Blood samples for Ig levels (IgM, IgA, IgG, and IgE) will be collected as noted in the SoA
(Section 1.3).
Samples will be analyzed by the central laboratory selected by the Sponsor. Samples will be 
collected, labeled, processed, stored, and shipped according to the instructions in the 
Laboratory Manual.
Results will not be disclosed to the sites, Sponsor, or representative prior to database lock to 
avoid unblinding. However, the IDMC will have access to these data as applicable.
8.2.7
Chest X-ray
Posteroanterior CXRs will be performed as noted in the SoA (Section 1.3) according to local 
standard practice. Participants who had a CXR performed for clinical reasons within 3 months 
prior to Day 1 do not need to have the CXR repeated. The CXR should show no evidence of 
active infective process, or any other clinically significant abnormalities. The overall 
evaluation (normal/abnormal) will be recorded on the eCRF, and if abnormal, the specific 
abnormality will be recorded. Abnormal evaluations will be judged as clinically significant 
or not clinically significant by the Investigator. The CXR will be performed and read locally.
8.2.8
Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used for prospective 
suicidality assessment. C-SSRS is a tool used to assess the lifetime suicidality of a participant 
and to track suicidal events through the treatment. The structured interview prompts 
recollection of suicidal ideation, including the intensity of the ideation, behavior and attempts 
with actual/potential lethality.
The scale will be administered by the Treating Physician at the timepoints indicated in the 
SoA (Section 1.3). The C-SSRS “Screening/Baseline” will be collected at Screening and 
Baseline and the C-SSRS “since last visit” will be collected at subsequent visits.
Subjects who answer “yes” to any suicidal behavior questions or to suicidal ideation questions 
4 or 5 on the C-SSRS during the study should be referred for appropriate psychiatric care and 
the Medical Monitor notified.
Please note: assessing the risk of suicide is a difficult and complex task when applied to the 
individual participant. Certainly, no single clinical scale can replace a thorough medical 
examination and suicide risk assessment. Ultimately, the determination of the presence of 
suicidality depends on clinical judgment.
8.2.9
Independent Data Monitoring Committee, Endpoint
Adjudication Committee, and Study Steering Committee
Independent Data Monitoring Committee
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An IDMC will be formed for this study to monitor interim safety and disease activity data on 
a regular basis to ensure ongoing surveillance of participant safety and to monitor the conduct 
of the study to protect its integrity, including recommendations about additional monitoring 
measures or risk mitigation procedures that may be deemed necessary to protect the study 
participants. After consideration, the Sponsor will inform the IDMC of any decision that will 
be taken in response to the IDMC recommendations. The IDMC will consist of a minimum 
of at least 3 expert members who are independent of the Sponsor. The members will be 
appointed by the Sponsor based on their expertise in biostatistics, MS and additional members 
with expertise in hepatology who are available on an ad hoc basis. All IDMC members will 
have experience in the conduct of clinical studies. Members will not be Investigators in the 
study, nor will they have any conflict of interest with the Sponsor. Sponsor representatives 
and study Investigators are not eligible for membership on the IDMC. Details regarding 
IDMC roles, responsibilities, activities, and possible recommendations will be provided in a 
separate IDMC charter.
The IDMC will review 
. The recommendations of the IDMC will not 
contain unblinded data or other information that could lead to Investigators or Sponsor 
representatives becoming unblinded. An independent statistician, who is not involved with 
study conduct and not a member of IDMC, is responsible for producing the 
 
 for IDMC review.
Study Steering Committee
A Study Steering Committee (SSC) will provide direction and oversight to the study from an 
Investigator’s perspective, including protocol creation and amendments, study execution, and 
evaluation of study results at the end of study. Investigators in this clinical study and other 
experts who are not otherwise involved in the trial may serve on this committee.
8.3
Adverse Events and Serious Adverse Events
The definitions of an Adverse Event (AE) and a Serious Adverse Event (SAE) are in 
Appendix 4.
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8.3.1
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially 
included in the study (date of first signature of informed consent/date of first signature of first 
informed consent) and continues until the Safety Follow-up Visit.
Any SAE assessed as related to study intervention must be recorded and reported, as indicated 
in Appendix 4, whenever it occurs, irrespective of the time elapsed since the last 
administration of study intervention.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and 
the procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. During 
the reporting period, any unfavorable changes in the participant’s condition will be recorded 
as AEs, regardless if reported by the participant or observed by the Investigator.
Complete, accurate and consistent data on all AEs experienced for the duration of the 
reporting period (defined below) will be reported on an ongoing basis in the appropriate 
section of the CRF. All SAEs and nonserious AESIs must be additionally documented and 
reported using the appropriate Report Form as specified in Appendix 4.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
AEs are recorded and assessed continuously throughout the study, as specified in Section 
8.3.1 and are assessed for their outcome at the Safety Follow-up Visit. All SAEs ongoing at 
the Safety Follow-up Visit must be monitored and followed up by the Investigator until 
stabilization or until the outcome is known, unless the participant is documented as “lost to 
follow-up”. Reasonable attempts to obtain this information must be made and documented. It 
is also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. Further information on follow-up 
procedures is given in Appendix 4.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance 
with applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the IEC/IRB that 
approved the study.
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In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of findings 
that could adversely affect the safety of participants, impact the conduct of the study or alter 
the IEC’s/IRB’s approval/favorable opinion to continue the study. In line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious 
and unexpected and considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator should place copies of 
Safety Reports in the Investigator Site File. National regulations regarding Safety Report 
notifications to Investigators will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records 
of these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by the Sponsor/designee and of filing copies of all 
related correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
8.3.5
Pregnancy
Only pregnancies the Investigator considers to be related to the study intervention (e.g., 
resulting from a drug interaction with a contraceptive method) are AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 8.3.1 
(Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) must be recorded in the AE page/section of the CRF for both pregnancies in 
female participants and pregnancies in female partners of male participants. The Investigator 
must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted by the same process specified for SAE 
reporting in Appendix 4, section on Reporting Serious Adverse Events and Adverse Events
of Special Interest.
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy 
Report Form. If an abnormal outcome occurs, the SAE Report Form will be used if the 
participant sustains an event and the Parent-Child/Fetus Adverse Event Report Form if the 
child/fetus sustains an event. Any abnormal outcome (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) must be reported in an expedited manner, 
as specified in Section 8.3.1, while normal outcomes must be reported within 45 days after 
delivery.
In the event of a pregnancy in a participant occurring during the study, the participant must 
be discontinued from study intervention. The Sponsor/designee must be notified without 
delay and the participant must be followed as indicated above.
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8.3.6
Medical Device Incidents (Including Malfunctions)
! Medical devices are being provided for use in this study as Avonex and Avonex 
placebo are supplied in single-use prefilled syringes. To fulfill regulatory reporting 
obligations worldwide, the Investigator is responsible for the detection and 
documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices.
! The definition of a Medical Device Incident is in Appendix 6.
! Incidents meeting the definition of an AE or a SAE will also follow the processes 
outlined in Section 8.3 (Adverse Events and Serious Adverse Events) and 
Appendix 6.
8.3.6.1
Time Period for Detecting Medical Device Incidents
! Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented, and reported during all periods of the study in which the 
medical device is used.
! If the Investigator learns of any incident at any time after a participant has ended
study participation, and such incident is considered reasonably related to a medical 
device provided for the study, the Investigator will promptly notify the Sponsor.
! The method of documenting Medical Device Incidents is provided in Appendix 6.
8.3.6.2
Follow-up of Medical Device Incidents
! All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs, as specified in Section 8.3.3. This applies to all 
participants, including those who discontinue study intervention.
! The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
! New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the Investigator.
8.3.6.3
Prompt Reporting of Medical Device Incidents to Sponsor
! Medical device incidents will be reported to the Sponsor within 24 hours after the 
Investigator determines that the event meets the protocol definition of a medical 
device incident.
! The investigator/site will send the Medical Device Incident Report Form to the 
Sponsor. The investigator/site will complete the IMP Complaint receipt form and 
send to Clinical Trial Supplies (CTS). If the server is unavailable, then use site 
communication with the Sponsor.
! The Sponsor will be the contact for the receipt of medical device reports and SAE.
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8.3.6.4
Regulatory Reporting Requirements for Medical Device 
Incidents
! The Investigator will promptly report all incidents occurring with any medical device 
provided for use in the study for the Sponsor to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
! The Investigator or responsible person per local requirements (e.g., the head of the 
medical institution) will comply with the applicable local regulatory requirements 
relating to the reporting of incidents to the IRB/IEC.
8.4
Treatment of Overdose
For this study, any dose of study intervention greater than the highest total daily dose included 
in the protocol or planned for a participant in the study within a 24-hour time period ± 6 hours 
will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose, but assistive/supportive 
measures, as necessary, should be provided.
Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and 
reported to drug safety in an expedited manner. Overdoses are reported on a SAE Report 
Form, following the procedure in Appendix 4, section on Reporting Serious Adverse Events
and Adverse Events of Special Interest.
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9
Statistical Considerations
9.1
Statistical Hypotheses
9.1.1
Statistical Hypotheses related to Primary Objective
The primary endpoint, ARR based on 96 weeks of follow-up and qualified relapse events 
from participants enrolled in the present study, will be assessed for superiority via a 1-sided 
test of the null hypothesis H0: rRR ≥1, where rRR denotes qualified relapse rate ratio 
comparing evobrutinib to Avonex. The alternative hypothesis is H1: rRR < 1. The rRR effect 
measure will be estimated from a negative binomial (NB) model for qualified relapse count 
that adjusts for covariates based on stratification factors. 
9.1.2
Statistical Hypotheses related to Secondary Objectives
There are four efficacy secondary endpoints and two HRQoL secondary endpoints: time to 
first occurrence of 12-week confirmed disability progression (CDP) over 96 weeks (pooled), 
time to first occurrence of 24-week CDP over 96 weeks (pooled), Change from Baseline 
(CFB) in PROMIS Physical Function (PF) score at 96 weeks (pooled), CFB in PROMIS 
Fatigue score at 96 weeks (pooled), total number of T1 Gd+ lesions based on assessments at 
Week 24, 48, and 96, and total number of new or enlarging T2 lesions based on assessments 
at Week 24, 48, and 96.
The secondary endpoint, time to 12-week CDP (pooled), will be assessed for superiority via 
a 1-sided stratified logrank test of the null hypothesis H0: Se(t) ≤Sc(t), where Se(t) denotes the 
survival function for time to 12-week CDP in the experimental (evobrutinib) arm, Sc(t) 
denotes the survival function for time to 12-week CDP in the control (Avonex) arm, and the 
variable t denotes time since randomization. The alternative hypothesis is H1: Se(t) > Sc(t). 
Strata in the logrank test will be based on randomization strata and study ID. The secondary 
endpoint time to 24-week CDP (pooled) will be analyzed similarly, with a similar null 
hypothesis tested.
The secondary endpoint, CFB in PROMIS PF score at 96 weeks (pooled), will be assessed 
for superiority via a 1-sided test of the null hypothesis H0: ΔPF ≤0, where ΔPF denotes 
difference in PROMIS Physical Function score Change From Baseline (CFB) at 96 weeks 
least-squares mean, comparing evobrutinib to Avonex, based on pooled data (higher score 
corresponds to improved physical function). The alternative hypothesis is H1: ΔPF > 0.
Covariates in the model used to model CFB will be based on randomization strata and study 
ID. The secondary endpoint CFB in PROMIS Fatigue score at 96 weeks (pooled) will be 
analyzed similarly, with a similar null hypothesis tested.
The secondary endpoint, total number of T1 Gd+ lesions based on scans at Weeks 24, 48, and 
96, from participants enrolled in the present study, will be assessed for superiority via a 
1-sided test of the null hypothesis H0: lRR ≥1, where lRR denotes lesion rate ratio comparing 
evobrutinib to Avonex. The alternative hypothesis is H1: lRR < 1. The lRR effect measure 
will be estimated from a NB model for total number of T1 Gd+ lesions that adjusts for 
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covariates based on stratification factors. The secondary endpoint total number of active T2 
lesions based on scans at Weeks 24, 48, and 96, will be analyzed similarly, with a similar null 
hypothesis tested.
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9.3
Populations for Analyses
The analysis populations are specified below. The final decision to exclude participants 
from any analysis population will be made during a blinded data review meeting prior to 
database lock and unblinding.
Analysis Set
Description
Screening (SCR) 
All participants, who provided informed consent, regardless of the participant’s 
randomization and study intervention status in the study.
Full Analysis Set 
(FAS)
All participants who were randomized to study intervention. Participants will be 
analyzed per the intervention group to which they were randomized (i.e., 
intention-to-treat principle).
Per-Protocol (PP)
All FAS participants, who comply with the protocol in meeting criteria that could 
impact the proper evaluation of key objectives of the study. Clinically important 
protocol deviations that would lead to a participant being excluded from the PP 
Analysis Set will be finalized prior to database lock. Participants will be 
analyzed per the intervention group to which they were randomized.
Safety (SAF)
All participants, who were administered any dose of any study intervention. 
Participants will be analyzed per the actual study intervention they received. 
Quality of life (QoL)
All FAS participants who have received at least one dose of any study 
intervention and have at least one Baseline and one post Baseline QoL 
assessment (among the following: SF-36, EQ-5D-5L, etc). Participants will be 
analyzed according to randomized treatment.
Open Label Extension 
(OLE) 
All participants who receive at least 1 dose of evobrutinib during the OLE.
The following subgroups of the FAS will be considered for efficacy analyses:
! sex, age, region, severity of disease, ethnic origin, prior treatment history (including 
but not limited to type, number and duration of prior treatments as well as reason for 
switch), EDSS.
9.4
Statistical Analyses
This section provides a description of the statistical methods to be used to analyze efficacy, 
safety, and other endpoints. Prior to locking the database, a detailed Integrated Analysis Plan 
(IAP) will be finalized. 
Unless otherwise specified, the FAS will be the PA set for all efficacy analyses, PRO analyses, 
and reporting of demographic and Baseline characteristics. The Safety analysis set will be 
used for all safety data reporting.
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The secondary objectives based on disability progression and patient reported symptoms and 
functional status will be evaluated based on pooled data from the present study and the second 
Phase III study (i.e., MS200527_0073).
9.4.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
ARR over 96 weeks
Primary analysis based on NB model of qualified relapse count over 96 weeks, 
adjusted for Baseline covariates defined by randomization strata; test based on 
adjusted relapse rate ratio (evobrutinib versus comparator) from the model. 
Estimation of treatment effect (and 95% 2-sided CI) based on adjusted relapse 
rate ratio from NB model. In the primary analysis of ARR, missing data assumed 
to be missing at random, with missing data status noninformative for qualified 
relapse.
Secondary efficacy and HRQoL
Time to 12-week CDP
Analyzed for participants pooled from both Phase III studies. Primary analysis 
based on stratified logrank test of distribution of time to 12-week CDP with strata 
defined by randomization strata and study ID (i.e., study 0073 or 0074),
 
 Estimation of treatment effect (and 95% 2-sided CI) based on hazard 
ratio from stratified Cox model of 12-week CDP hazard rate. Cumulative 
distribution function for time to 12-week CDP will be estimated via Kaplan-Meier 
method by treatment group. In the primary analysis of time to 12-week CDP, 
censoring assumed to be noninformative for 12-week CDP.
Time to 24-week CDP
Analyzed for participants pooled from both Phase III studies. Primary analysis 
based on stratified logrank test of distribution of time to 24-week CDP with strata 
defined by randomization strata and study ID. Estimation of treatment effect (and 
95% 2-sided CI) based on hazard ratio from stratified Cox model of 24-week CDP 
hazard rate. Cumulative distribution function for time to 24-week CDP will be 
estimated via Kaplan-Meier method by treatment group. In the primary analysis of 
time to 24-week CDP, censoring assumed to be noninformative for 24-week CDP.
PROMIS physical 
function (PF) score CFB 
at Week 96
Analyzed for participants pooled from both Phase III studies. Primary analysis 
based on MMRM analysis where score CFB at Week 96 is modeled, with 
adjustment for baseline PROMIS PF score and covariates defined by 
randomization strata and study ID; test based on difference (evobrutinib versus 
comparator) in least squares means of Week 96 CFB from the model. Estimation 
of treatment effect (and 95% 2-sided CI) based on adjusted difference in least-
squares means from the model. Cumulative distribution function for Week 96 CFB 
will be estimated by treatment group. In the primary analysis of PROMIS PF CFB, 
missing data assumed to be missing at random, with missing data status 
noninformative for CFB.
PROMIS fatigue score 
CFB at Week 96
Analyzed for participants pooled from both Phase III studies. Primary analysis 
based on MMRM analysis where score CFB at Week 96 is modeled, with 
adjustment for baseline PROMIS Fatigue score and covariates defined by 
randomization strata and study ID; test based on difference (evobrutinib versus 
comparator) in least squares means of Week 96 CFB from the model. Estimation 
of treatment effect (and 95% 2-sided CI) based on adjusted difference in least-
squares means from the model. Cumulative distribution function for Week 96 CFB 
will be estimated by treatment group. . In the primary analysis of PROMIS Fatigue 
CFB, missing data assumed to be missing at random, with missing data status 
noninformative for CFB.
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Endpoint
Statistical Analysis Methods
Total T1 Gd+ lesions 
over scans at Weeks 
24, 48, and 96 
Primary analysis based on NB model of total lesion count, adjusted for Baseline 
lesion activity and covariates defined by randomization strata; test based on 
adjusted lesion rate ratio (evobrutinib versus comparator) from model. Estimation 
of treatment effect (and 95% 2-sided CI) based on adjusted lesion rate ratio from 
NB model. In the primary analysis of lesion rate, missing data assumed to be 
missing at random, with missing data status noninformative for lesion count.
Total new or enlarging 
T2 lesions over scans 
at Weeks 24, 48, and 
96
Primary analysis based on NB model of total lesion count, adjusted for Baseline 
lesion activity and covariates defined by randomization strata; test based on 
adjusted lesion rate ratio (evobrutinib versus comparator) from model. Estimation 
of treatment effect (and 95% 2-sided CI) based on adjusted lesion rate ratio from 
NB model. In the primary analysis of lesion rate, missing data assumed to be 
missing at random, with missing data status noninformative for lesion count.
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, CDP = Confirmed disability 
progression, CFB = change from baseline,
, CI = confidence interval, CUA = 
combined unique active, EDSS = Expanded Disability Status Scale, EQ-5D-5L = EuroQoL 5 Dimension 5 
Levels, Gd = gadolinium, HRQoL = health-related quality of life,
 
MMRM = Mixed Effect model for repeated measures, NB = negative binomial, 
 
 PROMIS = Patient Reported Outcomes Measurement Information System, SD = 
standard deviation,
 
 
9.4.1.1
Efficacy Analyses related to Primary Objective 
Analysis of the primary efficacy endpoint, ARR over 96 weeks, will be based on the Full 
Analysis set (FAS) and include all available data during the 96-week Treatment Period, as 
well as data from participants assigned to an additional 12 weeks of treatment. ARR will be 
analyzed via a NB model for qualified relapse count, with offset equal to the log of time on 
study in years, and adjustment for covariates defined by randomization strata. The adjusted 
qualified relapse rate ratio (RR) comparing evobrutinib to Avonex will be estimated from the 
NB model. The adjusted RR, 95% 2-sided CI, and 1-sided p-value will be reported, together 
with adjusted ARR for each intervention group from the model, unadjusted ARR for each 
intervention group calculated nonparametrically, and associated 95% 2-sided CI. The analysis 
of ARR will be based on data from this study alone. In the primary analysis of ARR, missing 
data will be assumed missing at random, with missing data status noninformative for qualified 
relapse.
Unadjusted annualized relapse rate over 96 weeks is calculated by dividing the total number 
of qualified relapse events experienced by all participants in a given arm through week 96 by 
the person-time (in years) observed for those participants through week 96, based on 
participants in the Full Analysis Set (FAS).
Adjusted annualized relapse rate over 96 weeks in each arm will be estimated using a NB 
model that adjusts for region (4 levels: North America, Western Europe, Eastern Europe, 
Rest of World) and baseline EDSS (< 4.0 versus ≥4.0), based on participants in the FAS. 
This NB model assumes a common dispersion parameter for all patients, independent of 
treatment or baseline covariates. The adjusted relapse rate ratio estimate is given by 
exponentiation of the estimate for the treatment coefficient from the NB model. In the primary 
analysis, only observed events and observation time will be included in the analysis; there 
will be no imputation of events for patients discontinuing study early.
Sensitivity analyses are specified in Section 9.4.1.3.
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9.4.1.2
Efficacy Analyses related to Secondary Objectives 
The hypotheses tested in support of secondary efficacy objectives are described, and the 
inheritance of alpha graphically depicted, in Section 9.4.4.4.
Analysis of the secondary efficacy endpoint, time to 12-week CDP, will be based on the PA 
sets pooled from the present study and the second Phase III study, and include all 12-week 
CDP events where the initial disability event occurred during the first 96 weeks of treatment 
with subsequent confirmation, at least 12 weeks later, occurring on treatment. For participants 
assigned to an additional 12 weeks of treatment, for a total of 108 weeks of treatment, 
confirmation (or lack thereof) at Week 108 will be included in the analysis. Participants who 
did not have onset of CDP by completion of assigned treatment, by the time of early 
discontinuation of treatment, or who are lost to follow up, will be censored at the date of the 
last EDSS assessment during the 96-week Treatment Period. In the primary analysis of time 
to 12-week CDP, censoring will be assumed noninformative for 12-week CDP.
The PA of time to 12-week CDP will report the hazard ratio comparing evobrutinib to Avonex 
estimated via a stratified Cox model, 95% 2-sided CI, and 1-sided p-value for the 
 test,
together with a Kaplan-Meier estimate of cumulative probability of experiencing 12-week 
CDP over time for each intervention group. In general, a participant not experiencing a 12-
week CDP event while on treatment will have time to 12-week CDP censored at the last EDSS 
assessment. Prior to pooling, the validity of pooling data across the present study and the 
second Phase III study will be assessed by ensuring consistency of demographics, Baseline 
characteristics, ARR and 12-week CDP results.
The secondary endpoint, time to 24-week CDP, will be analyzed only at the time of the PA, 
so a conventional stratified logrank test will be used, not the 
 test. In all other respects, 
the analysis of the 24-week CDP endpoint will be the same as that of the 12-week CDP 
endpoint.
The secondary efficacy endpoint, Change from Baseline (CFB) in PROMIS Physical Function 
(PF) score at Week 96, will be analyzed based on pooled data via Mixed-Effect Model for 
Repeated Measures (MMRM), with adjustment for Baseline score and covariates defined by 
randomization strata and study ID. The difference (comparing evobrutinib and Avonex) in 
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least-squares mean CFB, 95% 2-sided CI, and 1-sided p-value will be reported. For each 
intervention group, the adjusted least-squares mean Week 96 score CFB and associated 95% 
2-sided CI will be reported, as will the estimated cumulative distribution function for Week 
96 score CFB. In the primary analysis of PROMIS PF CFB, missing data will be assumed 
missing at random, with missing data status noninformative for CFB. The CFB in PROMIS 
Fatigue score at Week 96 endpoint will be analyzed in the same manner as CFB in PROMIS 
PF score at Week 96.
The secondary efficacy endpoint, total number of T1 Gd+ lesions over scans at Weeks 24, 48, 
96, will be analyzed via a NB model for total T1 Gd+ lesion count, with offset equal to the 
log of number of scans, and adjustment for Baseline lesion activity and covariates defined by 
randomization strata. The adjusted lesion RR comparing evobrutinib to Avonex estimated 
from the NB model, 95% two-sided CI, and 1-sided p-value will be reported, together with 
adjusted lesion rate for each intervention group and associated 95% 2-sided CI. The analysis 
of total number of T1 Gd+ lesions will be based on data from the present study only. In the 
primary analysis of lesion rate, missing data will be assumed missing at random, with missing 
data status noninformative for lesion count. The total number of new or enlarging T2 lesions 
endpoint will be analyzed in the same manner as total number of T1 Gd+ lesions.
9.4.1.3
Sensitivity Analyses
The following sensitivity analyses for the primary endpoint ARR over 96 weeks will be 
considered and detailed in the IAP:
1. analysis in which multiple imputation is used to evaluate the potential influence of 
informative drop-outs according to drop-out reason. For each imputed data set, 
participants who discontinued treatment early during the 96-week Treatment Period 
without qualified relapse in the 30 days prior to discontinuation will be (a) imputed to 
relapse according to the control ARR if the drop-out reason was unrelated to treatment 
(i.e., unrelated to lack of efficacy or safety issues), and (b) assumed to have a qualified 
relapse event at the date of discontinuation if the drop-out reason was related to 
treatment;
2. analysis in which 100% of participants who discontinued treatment early during the 
96-week Treatment Period without qualified relapse in the 30 days prior to 
discontinuation, are assumed to have a qualified relapse event at the date of 
discontinuation
3. analysis including all available data during the 96-week Treatment Period, data from 
participants assigned to an additional 12 weeks of treatment, and data from the Safety 
Follow-up;
4. analysis based on PP analysis set, to be performed if at least 10% of FAS participants 
are excluded from the PP analysis set; 
5. analysis restricted to participants in FAS set who received study intervention, to be 
performed if at least 1% of FAS participants did not receive study intervention; 
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6. analysis with additional covariates in the NB model, such as number of relapses 
occurring within 2 years prior to study entry, baseline presence/absence of T1 Gd+ 
lesions, prior MS treatment, and age;
7. analysis of time to qualified relapse, with qualified relapse considered a recurrent 
event, and qualified relapse hazard ratio, comparing evobrutinib to Avonex, estimated 
from the time to recurrent event model.
The following sensitivity analyses for the secondary efficacy endpoint time to 12-week CDP 
will be considered and detailed in the IAP:
1. analysis in which multiple imputation is used to evaluate the potential influence of 
informative initial progression events that could not be confirmed due to drop-out, 
according to drop-out reason. For each imputed data set, participants who discontinued 
treatment early during the 96-week Treatment Period after having an initial 
progression event, but prior to 12-week confirmation, will be (a) imputed to have a 
12-week CDP event according to the control distribution for 12-week CDP if the drop-
out reason was unrelated to treatment (i.e., unrelated to lack of efficacy or safety 
issues), and (b) assumed to have a 12-week CDP event at the date of initial progression 
if the drop-out reason was related to treatment;
2. analysis in which 100% of participants who discontinued treatment early during the 
96-week Treatment Period after having an initial progression event, but prior to 12-
week confirmation, are assumed to have a 12-week CDP event at the date of initial 
progression;
3. analysis based on PP analysis set, to be performed if at least 10% of FAS participants 
are excluded from the PP analysis set;
4. analysis with additional covariates in the stratified Cox model, such as number of 
relapses occurring within 2 years prior to study entry, baseline presence/absence of T1 
Gd+ lesions, prior MS treatment, and age.
Sensitivity analyses for time to 24-week CDP will be similar.
The following sensitivity analyses for the secondary HRQoL endpoint PROMIS Physical 
Function (PF) score CFB at Week 96 will be considered and detailed in the IAP:
1. analysis in which multiple imputation is used to evaluate the potential influence of 
informative drop-outs. For each imputed data set, participants who discontinued 
treatment early during the 96-week Treatment Period will be imputed to have a score 
CFB value at a given timepoint according to the control score CFB distribution at that 
timepoint;
2. analysis based on PP analysis set, to be performed if at least 10% of FAS participants 
are excluded from the PP analysis set;
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Sensitivity analyses for PROMIS Fatigue score CFB at Week 96 will be similar.
The following sensitivity and supplemental analyses for the secondary efficacy endpoint total 
T1 Gd+ lesions (or new/enlarging T2 lesions) will be considered and detailed in the IAP:
1. analysis in which multiple imputation is used to evaluate the potential influence of 
informative drop-outs. For each imputed data set, participants who are missing one or 
more scans planned during the 96-week Treatment Period will be imputed to have a 
lesion count at the missing scans according to the control lesion rate;
2. (supplemental) lesion count at a single scan modeled as Poisson-distributed, with a 
random effect for participant, and adjustment for Baseline lesion activity and 
covariates defined by randomization strata. This model will compare treatment on the 
basis of conditional adjusted lesion rate ratio, where conditioning is on the random 
effect.
3. (supplemental) total lesion count compared between arms on the basis of distribution 
location shift (Hodges-Lehmann estimate) and Wilcoxon rank sum test, stratified 
according to randomization strata, and baseline lesion activity.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis population.
Endpoint
Statistical Analysis Methods
Primary
Not applicable.
Secondary
Adverse Events
Descriptive statistics, AESI summaries, 3-Tier AE summaries
Clinical Laboratory Test 
Values
Descriptive statistics, shift tables, boxplots, individual participant line 
plots, Kaplan-Meier analyses of time to event, Evaluation of Drug-
Induced Serious Hepatotoxicity (eDISH) figures
ECG Parameters
Descriptive statistics
Vital Signs
Descriptive statistics
9.4.2.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). All treatment-emergent AEs (TEAEs) will be summarized by intervention group. 
Treatment-emergent AEs are defined as AEs that occurred or worsened on or after the first 
dose of study intervention. The number and percentage of participants who experienced at 
least 1 TEAE will be summarized by SOC and preferred term. The percentage will be based 
on the number of participants in each intervention group. Treatment-emergent AEs will also 
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be summarized by relationship to intervention and by severity within each intervention group. 
Deaths, SAEs, AESIs, and AEs leading to study discontinuation will be tabulated and 
presented in data listings. Participant level data listings of all AEs will be presented.
Summary and analysis of AEs will be performed based on the 3-tier approach (Crowe 2009) 
as further detailed in the IAP. Tier 1 AEs and AESIs will be pre-defined in the IAP.
9.4.2.2
Clinical Laboratory Test Values
Clinical laboratory results (chemistry, hematology, and urinalysis) will be summarized using 
descriptive statistics for each visit by intervention group. Observed values at each visit and 
changes from Baseline to each post-baseline visit will be presented. For clinical laboratory 
parameters with associated normal ranges, number and percentage of participants having 
high/low/normal findings for worst on-treatment laboratory value will be summarized by 
intervention group; shift tables will be used to summarize changes from Baseline finding to 
worst on-treatment finding. For clinical laboratory parameters with National Cancer Institute 
(NCI)- Common Terminology Criteria for Adverse Events (CTCAE) grades, shift tables will 
be used to summarize changes from Baseline grade to worst on-treatment grade. The 
distribution of selected laboratory parameters by time point and intervention group will be 
displayed via boxplots. All laboratory data will be provided in participant data listings.
Analyses of liver enzyme tests will include Kaplan-Meier estimates of time to ALT or AST 
events, plots supporting evaluation of Drug-Induced Serious Hepatotoxicity (eDISH), and 
individual participant profiles.
9.4.2.3
Vital Signs
Observed values at each visit and changes from Baseline to each post-baseline visit in vital 
signs (blood pressure, pulse rate, respiratory rate, and temperature) will be summarized by 
time point and intervention group using descriptive statistics. Similar summaries of 
descriptive statistics will be provided for the vital signs collected before and after the first 
dose of study intervention. Out-of-range values of vital signs will be tabulated as appropriate. 
All vital signs will be provided in participant data listings.
9.4.2.4
Electrocardiogram Parameters
Observed values at each visit and change from Baseline to Week 96 in ECG parameters (e.g., 
PR, HR, QRS, RR, QT, and QTc) will be summarized by intervention group using descriptive 
statistics. QTc will be reported based on Fridericia’s method. Percentage and counts of 
participants with normal and abnormal ECG findings will be summarized by intervention 
group. Out-of-range values of ECG parameters will be tabulated as appropriate. All ECG data 
will be provided in participant data listings.
For all ECG parameters, the results for categorical analysis will be summarized by 
intervention group and visit (or time point) in frequency tables with counts and percentages 
of participants.
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Categories will cover absolute values and changes from Baseline:
HR:
! Absolute < 50 bpm, < 40 bpm, < 30 bpm
! Change from Baseline > 20 bpm, > 30 bpm, > 40 bpm
PR:
! Absolute > 200 msec and > 220 msec
! Change from Baseline
QRS:
! Absolute > 110 msec
QTc:
! Absolute > 450 msec, > 480 msec, and > 500 msec
! Change from Baseline > 30 msec and > 60 msec
Electrocardiogram parameters will be summarized using descriptive statistics for continuous 
variables such as QTc intervals, and frequency counts and percentages for categorical 
variables.
9.4.2.5
Concomitant Medication and Procedures
Prior and concomitant medications will each be categorized by therapeutic class and preferred 
term using World Health Organization (WHO) Drug coding dictionary. The number and 
percent of participants using each prior and concomitant medication will be summarized by 
therapeutic class and preferred drug name for each intervention group. Participants who 
reported more than 1 medication for a particular preferred term will be counted once for each 
preferred term and therapeutic class.
Concomitant procedures will be classified by medical review. The number of and percent of 
participants experiencing each prior and concomitant procedure will be summarized by type 
of procedure for each intervention group.
9.4.2.6
Columbia-Suicide Severity Rating Scale
Results of the C-SSRS will be listed for each visit by participant.
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9.4.3.2
Demographics, Baseline Characteristics, Disposition, and 
Compliance
Participant demographics, such as age, sex, race, will be summarized by intervention group 
using descriptive statistics. Baseline disease characteristics (including MS history and MRI 
characteristics), such as Baseline EDSS, number of relapses in the 1 year and 2 years prior to 
randomization, time (in years) since onset of MS symptoms, time (in years) since MS 
diagnosis, Baseline number of T1 Gd+ lesions, Baseline number of T2 lesions, and Baseline 
T2 lesion volume, prior MS study treatment will also be summarized.
Disposition of participants (i.e., discontinuation from treatment by reason, discontinuation 
from study by reason) and compliance of participants to intervention will be summarized by 
intervention group using descriptive statistics.
9.4.3.3
Patient Reported Outcome Analyses
The endpoint change from Baseline (CFB) in PRO score at a given time point (Week 48 or 
Week 96), will be compared between evobrutinib and Avonex via a Mixed-Effect Model for 
Repeated Measures (MMRM) based on pooled data, adjusted for Baseline PRO score and 
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covariates defined by randomization strata and study ID. The adjusted difference in least-
squares mean change from Baseline at a given time point (Week 48 or Week 96), comparing 
evobrutinib to Avonex, 2-sided 95% CI, and 1-sided p-value will be reported. A similar 
analysis will be performed for all PRO score change from Baseline endpoints.
 
 
9.4.3.5
Analysis of Open Label Extension Period Endpoints
Efficacy and HRQoL data collected during the 144-week OLE Period will be summarized. 
Details will be provided in the IAP. 
Safety data collected during the 144-week OLE Period will be analyzed as described in 
Section 9.4.2.
9.4.4
Sequence of Analyses
Three analyses are planned for the study: 
 
 
 
 
 
(2) a primary analysis (PA), performed by the Sponsor, with timing 
and endpoint evaluation as described in Section 9.4.4.2, and (3) a final analysis (FA), 
performed by the Sponsor, triggered when 100% of participants enrolled in the OLE complete 
the OLE, or discontinue prematurely from the OLE. The IA will not be performed for futility.  
If the sample size is not increased at the time of the IA, and the PA of the present study occurs 
prior to the PA of the second Phase III study, there will be an analysis of endpoints based on 
data pooled from the two studies at the time of the PA of the second Phase III study.
In addition, analyses will be performed at regular intervals for the purpose of safety 
monitoring by the IDMC, as described in the IDMC Charter.
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9.4.4.2
Primary Analysis
If the sample size is not increased when the IA is performed, the PA of the present study will 
be triggered when the last participant reaches 96 weeks of treatment or discontinues from 
treatment prematurely during the blinded Treatment Period, and completes Safety Follow-up, 
or discontinues from the study prematurely during the blinded Treatment Period. Given that 
the primary analyses of this study and the second Phase III study are unlikely to coincide, 
endpoints based on data pooled from both studies will be evaluated at the time of the last 
study-specific PA. 
If the sample size is increased when the IA is performed, the PA will be triggered when the 
recalculated number of events from the pooled studies is reached based on events occurring 
during the blinded Treatment Period, or when the last participant from both studies reaches 
96 weeks of treatment or discontinues from treatment prematurely during the blinded 
Treatment Period, and completes Safety Follow-up or discontinues from study prematurely
during the blinded Treatment Period, whichever occurs first.
After protocol deviations are determined, and the database is locked for the primary analysis, 
the drug codes will be broken and made available for the primary data analysis. All endpoints 
based on Baseline to Week 96 data will be evaluated. 
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9.4.4.3
Final Analysis
The final analysis will occur only when the last participant enrolled in the OLE completes the 
OLE or discontinues prematurely, the protocol deviations are determined, and the database is 
locked for the final analysis. All endpoints based on OLE data will be evaluated.
9.4.4.4
Multiplicity
To control trial-wise and family-wise type I error at the 1-sided 0.025 level in the presence of 
multiple endpoint testing, a graphical approach to sequentially rejective multiple testing will 
be employed (Bretz 2009, Hung 2013). The 1-sided null hypotheses in the graph are as 
follows, where “Study 1” denotes the present study, and “Study 2” denotes the second 
Phase III study:
Primary Endpoint Null Hypotheses:
H011: rRR1 ≥1, where rRR1 denotes qualified relapse rate ratio comparing evobrutinib to 
Avonex in Study 1
H012: rRR2≥1, where rRR2 denotes qualified relapse rate ratio comparing evobrutinib to 
Avonex in Study 2
Secondary Endpoint Null Hypotheses:
H02: S12e(t) ≤S12c(t), where S12e(t) denotes the survival function for time to 12-week CDP in 
the experimental (evobrutinib) arm based on pooled data, S12c(t) denotes the survival function 
for time to 12-week CDP in the comparator (Avonex) arm based on pooled data, and the 
variable t denotes time since randomization. 
H03: S24e(t) ≤S24c(t), where S24e(t) and S24c(t) denote the survival functions for time to 24-
week CDP based on pooled data
H04: ΔPF ≤0, where ΔPF denotes difference in PROMIS Physical Function score Change From 
Baseline (CFB) at 96 weeks least-squares mean, comparing evobrutinib to Avonex, based on 
pooled data (higher score corresponds to improved physical function) . 
H05: ΔFatigue ≤0, where ΔFatigue denotes difference in PROMIS Fatigue score CFB at 96 weeks 
least-squares mean, comparing evobrutinib to Avonex, based on pooled data (higher score 
corresponds to reduced fatigue). 
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H061: lRR61 ≥1, where lRR61 denotes T1 Gd+ lesion rate ratio comparing evobrutinib to 
Avonex in Study 1
H062: lRR62 ≥1, where lRR62 denotes T1 Gd+ lesion rate ratio comparing evobrutinib to 
Avonex in Study 2
H071: lRR71 ≥1, where lRR71 denotes new or enlarging T2 lesion rate ratio comparing 
evobrutinib to Avonex in Study 1
H072: lRR72 ≥1, where lRR72 denotes new or enlarging T2 lesion rate ratio comparing 
evobrutinib to Avonex in Study 2.
At the primary analysis, the primary efficacy endpoint, ARR, will be tested at the 0.025 – α1/2 
(1-sided) level in each study, assuming α1 (1-sided) is spent in the conduct of the IA of 12-
week CDP based on pooled data. Figure 2 shows the multiple testing procedure (MTP) 
involving study-specific endpoints and pooled endpoints, with the simplifying assumption 
that α1= 0.
At the primary analysis, the 12-week CDP pooled endpoint will be tested at the 0.025 – α1
level, 1-sided, only if ARR is significant in both studies at the 0.025 – α1/2 level, 1-sided.
If the 12-week CDP pooled endpoint is significant at the 0.025 – α1 level, 1-sided, the 
subsequent pooled endpoints (24-week CDP, PROMIS PF CFB at Week 96, PROMIS 
Fatigue CFB at Week 96) will be tested in a hierarchical order at 0.025 – α1 level, 1-sided.
If all the pooled endpoints (12-week CDP, 24-week CDP, PROMIS PF CFB at Week 96, 
PROMIS Fatigue CFB at Week 96) are significant at the 0.025–α1 level, 1-sided, then the T1 
Gd+ endpoint will be tested within each study at the 0.025– α1/2 level, 1-sided.
If the T1 Gd+ endpoint within a study is significant at the 0.025– α1/2 level, 1-sided, then the
active T2 endpoint for that study will be tested at the same level.
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Figure 2
Multiplicity Graph
ARR = Annualized Relapse Rate, CDP = Confirmed Disability Progression, CFB = change from baseline, 
Gd+ = gadolinium positive, PROMIS = Patient Reported Outcomes Measurement Information System, T1 and 
T2 = type of Magnetic Resonance Image, Wk = Week.
10
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Appendices
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Appendix 1
Abbreviations 
AE
Adverse Event
AESI
Adverse Event of Special Interest 
ALT
Alanine aminotransferase 
ARR
Annualized Relapse Rate
AST
Aspartate aminotransferase 
AUC
Area under the curve
AV
Atrioventricular
BEA
Blinded Extension Analysis
BID
Twice daily
CDP
Confirmed disability progression
CFB
Change from baseline
CI
Confidence interval
CNS
Central nervous system
CP
Conditional power
CRF
Case Report Form
CRO
Contract Research Organization 
CSF
Cerebrospinal fluid
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTCAE
Common Terminology Criteria for Adverse Events
CTS
Clinical Trial Supplies
CUA
Combined unique active
CXR
Chest X-ray
CYP3A
Cytochrome P450 3A 
DAC
Data Analysis Center
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DMD
Disease-modifying drugs
EAC
Endpoint Adjudication Committee 
ECG
Electrocardiogram
EDC
Electronic Data Capture
EDSS
Expanded Disability Status Scale
eGFR
Estimated glomerular filtration rate
FA
Full Analysis
FAS
Full Analysis Set
F/D
Follow-up/Discontinuation 
FDA
Food and Drug Administration 
FLAIR
Fluid-attenuated inversion recovery
FSH
Follicle-stimulating hormone
FSS
Functional system scores
GCP
Good Clinical Practice
Gd
Gadolinium
HCV
Hepatitis C virus
HFE
High Iron Fe (human hemochromatosis protein)
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
HRT
Hormonal replacement therapy
IA
Interim analysis
IAP
Integrated Analysis Plan
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IRB
Institutional Review Board
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IWRS
Interactive Web Response System
LFT
Liver function test
LTBI
Latent TB infection
MCID
Minimal clinically important difference
MedDRA
Medical Dictionary of Regulatory Activities 
MRI
Magnetic Resonance Imaging
MMRM
Mixed effect model for repeated measures
MS
Multiple sclerosis
NB
Negative binomial
NCI
National Cancer Institute
NYHA
New York Heart Association
OLE
Open Label Extension
PA
Primary Analysis
PF
Physical function
PML
Progressive multifocal leukoencephalopathy
PP
Per-Protocol
PRO
Patient Reported Outcomes
PROMIS
Patient Reported Outcomes Measurement Information System
QD
Once a day
QoL
Quality of Life
RA
Rheumatoid arthritis
RMS
Relapsing multiple sclerosis
RR
Rate ratio
SAE
Serious Adverse Event
SCR (or S)
Screening
SD
Standard deviation
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SLE
Systemic lupus erythematosus
SoA
Schedule of activities
SOC
System Organ Class
SPMS
Secondary progressive multiple sclerosis
SSC
Study Steering Committee
SSR
Sample size re-estimation
SUSAR
Suspected Unexpected Serious Adverse Reaction
 
TB
Tuberculosis
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal
US
United States of America 
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information, as requested, for the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. This 
information is required during the study and for 1 year after completion of the study.
Informed Consent Process
! The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions on the study.
! Participants must be informed that their participation is voluntary.
! Participants will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50; local regulations; International Council for 
Harmonisation (ICH) guidelines; Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable; and the IRB/IEC or study center.
! The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
! If the ICF is updated during their participation in the study, participants must be re-
consented to the most current, approved version.
! A copy of the ICF(s) must be provided to the participant.
! The original signed and dated consent will remain at the Investigator’s site and must 
be safely archived so that it can be retrieved at any time for monitoring, auditing and 
inspection purposes.
! As this study includes optional pharmacogenetic examinations, including collection 
and storage of biological samples, participants may consent to a separate 
pharmacogenetic analysis, the process of which will need to be documented in the 
participant’s medical records.
! Participants who are rescreened are required to sign a new ICF.
! Consenting participant will enter the 4-week screening period to be evaluated for 
eligibility. Please see the SoA (Section 1.3.1) for details. Participants must fulfill all 
entry criteria for participation in the study.
! The screening period can be extended to a total period of 8 weeks. The following 
should be performed:
o
An Eligibility Screening Form [ESF] documenting the Investigator’s 
assessment of each screened participant with regard to the protocol’s 
inclusion and exclusion criteria is to be completed by the Investigator.
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o
Each participant screened must be registered in the IWRS by the 
Investigator or the Investigator’s research staff at Screening. A screen 
failure record must be maintained by the Investigator, and reasons must 
be captured in the IWRS.
o
It should be stated in the medical record that the participant is 
participating in this clinical study.
o
Eligibility will be evaluated and confirmed by the study eligibility team. 
Sites will be required to submit an eligibility packet to the Medical 
Monitor
(consisting of an eligibility checklist and appropriate 
documentation) for potential eligible participants.
Data Protection
! The Sponsor will assign a unique identifier to participants after obtaining their 
informed consent. All participant records or datasets transferred to the Sponsor will 
contain the identifier only; participant names or any identifiable information will not 
be transferred.
! The Sponsor must inform participants that their personal study-related data will be 
used per local data protection and privacy laws. The level of disclosure must also be 
explained to the participant.
! The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other Sponsor-appointed, authorized 
personnel, by appropriate IRB/IEC members, and by regulatory authority inspectors. 
All such persons will strictly maintain participants’ confidentiality.
Study Administrative
This clinical study will be sponsored by Merck Healthcare KGaA Darmstadt, Germany for 
sites outside of the US and Canada and EMD Serono Research & Development Institute, Inc., 
Billerica, MA, US for sites in the US and Canada.
The study will be conducted at approximately 198 global sites anticipated from approximately 
25 to 30 countries (approximately 30 sites in the US). Sites will be a mixture of academic 
centers and outpatient clinics.
The Coordinating Investigator listed on the title page represents all Investigators for decisions 
and discussions on this study, per ICH Good Clinical Practice (GCP). The Coordinating 
Investigator will provide expert medical input and advice on the study design and execution 
and is responsible for the review and signoff of the clinical study report.
An Independent Data Monitoring Committee (IDMC), Endpoint Adjudication Committee 
(EAC), and Study Steering Committee (SSC) will perform specific study related activities as 
detailed in each committee’s charter (see Section 8.2.9).
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The study will appear in the following clinical studies registries: ClinicalTrials.gov and 
EudraCT.
Details of structures and associated procedures will be defined in a separate Study Reference 
Manual.
Regulatory and Ethical Considerations
! This study will be conducted in accordance with the protocol and the following:
o
Consensus ethical principles derived from international guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations
! The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an 
IRB/IEC and the IRB/IEC must review and approve them before the study is 
initiated.
! Any protocol amendments (i.e., changes to the protocol) will be documented in 
writing and require IRB/IEC approval before implementation of changes, except for 
changes necessary to eliminate an immediate hazard to study participants. When 
applicable, amendments will be submitted to the appropriate Health Authorities.
! The Investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently per the IRB’s/IEC’s requirements, policies, 
and procedures.
o
Notifying the IRB/IEC of SAEs or other significant safety findings, as 
required by IRB/IEC procedures
o
Providing oversight of the study conduct at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
! The protocol and any applicable documentation will be submitted or notified to the 
Health Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
! The Sponsor or designee will provide Emergency Medical Support cards to 
participants for use during the study. These provide the means for participants to 
identify themselves as participating in a clinical study. Also, these give health care 
providers access to any information about this participation that may be needed to 
determine the course of medical treatment for the participant. The information on the 
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Emergency Medical Support card may include the process for emergency unblinding 
(if applicable).
! The first point of contact for all emergencies will be the clinical study Investigator 
caring for the participant. Consequently, the Investigator agrees to provide his or her 
emergency contact information on the card. If the Investigator is available when an 
event occurs, they will answer any questions. Any subsequent action (e.g., 
unblinding) will follow the standard process established for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact 
a Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a 
call center, whereby the health care providers will be given access to the appropriate Sponsor 
(or designee) physician to assist with the medical emergency and to provide support for the 
potential unblinding of the participant concerned.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
Clinical Study Report
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator.
Publication
! The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows Merck to protect proprietary information 
and to provide comments. 
! The Sponsor will comply with the requirements for publication of study results. Per 
standard editorial and ethical practice, the Sponsor will generally support publication 
of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating Investigator will be designated by agreement.
! Authorship will be determined by agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
After completion of the study, a clinical study report will be written by the Sponsor in 
consultation with the Coordinating Investigator following the guidance in ICH Topic E3, and 
will be submitted in accordance with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
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information to any third party except to such of the Investigator’s employees and staff as have 
been made aware that the information is confidential and who are bound to treat it as such and 
to whom disclosure is necessary to evaluate that information. The Investigator shall not use 
such information for any purpose other than for determining mutual interest in performing the 
study and, if the parties decide to proceed with the study, for the purpose of conducting the 
study.
The Investigator understands that the information developed from this clinical study will be 
used by the Sponsor in connection with the development of the study drug and therefore may 
be disclosed as required to other clinical Investigators, to the US Food and Drug 
Administration, and to other government agencies. The Investigator also understands that, to 
allow for the use of the information derived from the clinical study, the Investigator has the 
obligation to provide the Sponsor with complete test results and all data developed in the 
study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement.
Data Quality Assurance
! All participant study data will be recorded on printed or electronic CRFs or 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are complete, accurate, 
legible, and timely by physically or electronically signing the CRF. Details for 
managing CRFs are in the Study Reference Manual.
! For PRO data (e.g., QoL and pain assessments), ePRO will be used.
! The Investigator must maintain accurate documentation (source data) that supports 
the information in the CRF.
! The Investigator must permit study-related monitoring, quality assurance audits, 
IRB/IEC review, and regulatory agency inspections and provide direct access to the 
study file and source data.
! Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are in the Monitoring Plan.
! The Sponsor or designee is responsible for data management of this study, including 
quality checking of the data and maintaining a validated database. Database lock will 
occur once quality control and quality assurance procedures have been completed. 
PDF files of the CRFs will be provided to the Investigators at study completion.
! Study monitors will perform ongoing source data verification to confirm that data in 
the CRF are accurate, complete, and verifiable; that the safety and rights of 
participants are being protected; and that the study is being conducted per the 
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currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.
! Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 15 years after study completion, unless 
local regulations, institutional policies, or the Sponsor requires a longer retention. No 
records may be destroyed during the retention period without the Sponsor’s written 
approval. No records may be transferred to another location or party without the 
Sponsor’s written notification.
Source Documents
! Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.
! The Investigator must keep a paper or electronic file (medical file and original 
medical records) at the site for each study participant. The file must identify each 
participant, contain the following demographic and medical information for the 
participant, and should be as complete as possible:
o
Participant’s full name, date of birth, sex, height, and weight
o
Medical history and concomitant diseases
o
Prior and concomitant therapies (including changes during the study)
o
Study identifier (i.e., the Sponsor’s study number) and participant’s 
study number.
o
Dates of entry into the study (i.e., signature date on the informed consent) 
and each visit to the site
o
Any medical examinations and clinical findings predefined in the 
protocol
o
All AEs
o
Date that the participant left the study, including any reason for early 
withdrawal from the study or study intervention, if applicable.
! All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and 
laboratory results). Each document must have the participant number and the 
procedure date; ideally, printed by the instrument used for the procedure. As 
necessary, medical evaluation of these records should be performed, documented, 
signed and dated by the Investigator. 
! Data recorded on printed or electronic CRFs that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.
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! The study monitors will use printouts of electronic files for source data verification. 
These printouts must be signed and dated by the Investigator and kept in the study 
file.
! Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the 
Sponsor’s written approval.
! Definition of what constitutes source data is found in the eCRF guidelines.
Study and Site Closure
! The Sponsor reserves the right to close the study site or terminate the study at any 
time and for any reason. Study sites will be closed upon study completion. A study 
site is considered closed when all required documents and study supplies have been 
collected and a site closure visit has been completed.
! The Investigator may initiate site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
! Reasons for the early closure of a study site by the Sponsor or Investigator may 
include:
o
Failure of the Investigator to comply with the protocol, the requirements 
of the IRB/IEC or local health authorities, the Sponsor’s procedures, or 
GCP guidelines
o
Inadequate recruitment of participants by the Investigator
o
Discontinuation of further development of the Sponsor’s compound
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical 
records, medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Müllerian agenesis, androgen insensitivity), investigator discretion 
applies to determine study entry.
3. A postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
!
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, more than 1 FSH measurement is 
required in the postmenopausal range.
!
A female on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if she 
wishes to continue her HRT during the study. Otherwise, she must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulationa
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS) a
!
Bilateral tubal occlusion
!
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationa
!
Oral
!
Intravaginal
!
Transdermal
!
Injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulationa
!
Oral
!
Injectable
!
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study. Abstinence is only acceptable as a contraceptive method for study 
purposes if it is in line with the preferred and usual lifestyle of the participant as evaluated by the Investigator.
Barrier Methods 
!
Male or female condom with or without spermicide
!
Cap, diaphragm, or sponge with spermicide
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Evobrutinib has been characterized as both an inducer and a time-dependent inhibitor of CYP3A4/5 in vitro, an 
enzyme involved in the metabolism of estrogen and progestin. Although it is a low risk, it is possible that 
co-administration with evobrutinib results in increased metabolism of estrogen, progestin, and other hormones 
used for contraception, increasing the likelihood that hormonal contraception methods, marked above with a, 
might fail. However, all participants that are WOCBP are required to use a barrier method as backup (see 
Inclusion Criterion 6) in part to mitigate this potential risk.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction).
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Appendix 4
Adverse 
Events: 
Definitions 
and 
Procedures 
for 
Recording, Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product, regardless of causal relationship with this treatment. Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, regardless if it is considered 
related to the medicinal product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute - Common Terminology Criteria for 
AEs (CTCAE), version 4.03 (publication date: 14 June 2010), a descriptive terminology that 
can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use 
the general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening 
Grade 5 or Death 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only 
if the condition meets one of the serious criteria specified below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death 
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will not be recorded as separate event. Only, if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to study 
intervention (including any other non-study interventions, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to 
the study interventions (evobrutinib and Avonex) include, but may not be limited to, temporal 
relationship between the AE and the study interventions, known side effects of study 
interventions, medical history, concomitant medication, course of the underlying disease, and 
study procedures.
Unrelated:
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. A reasonable alternative explanation 
must be available.
Related:
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to study intervention discontinuation or are considered otherwise medically 
important by the Investigator. If a laboratory abnormality fulfills these criteria, the identified 
medical condition (e.g., anemia or increased ALT) must be reported as the AE rather than the 
abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. Life-threatening refers to an event in which the participant is at 
risk of death at the time of the event, not an event that hypothetically might have 
caused death if it was more severe.
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be 
considered as SAEs when, based upon appropriate medical judgment, they may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
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dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs and AESIs.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., 
an overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all 
events leading to unplanned hospitalizations or unplanned prolongation of an elective 
hospitalization (i.e., undesirable effects of any administered treatment) must be documented 
and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions, and are not to be considered 
AEs.
Other Adverse Events to be Reported Following a Specialized Procedure 
The following procedures should be followed for reporting overdoses (see eCRF guidelines 
for further details):
! Overdoses without an AE should be reported using the paper SAE form only, stating 
if the overdose was accidental or intentional.
! Overdoses associated with a nonserious AE should be recorded on the AE eCRF and 
also the paper SAE form.
! Overdoses associated with an SAE should be recorded on the AE eCRF and the SAE 
reporting procedure outlined below should be followed.
Recording and Follow-up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of 
AE onset relative to the recorded study intervention administration time), its severity, its 
causal relationship with the study intervention, any other potential causal factors, any 
treatment given or other action taken, including dose modification or discontinuation of the 
study intervention, and its outcome. In addition, serious cases should be identified and the 
appropriate seriousness criteria documented. 
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the 
Sponsor.
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Reporting Serious Adverse Events and Adverse Events of Special Interest
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform 
the Sponsor or its designee using the electronic SAE report form in the Electronic Data 
Capture (EDC) system.
Reporting of SAEs using a paper report form is required as a back-up method only for an EDC 
system failure. Names, addresses, and telephone and fax numbers will be included on the 
paper form. All information from the paper form must be transcribed into the electronic form 
as soon as the system becomes available.
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, an electronic SAE report form must be completed immediately 
thereafter.
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., 
laboratory results, hospital report, autopsy report). 
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for 
initial reports. This is necessary to ensure prompt assessment of the event by the Sponsor or 
designee and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated 
with expedited safety reporting obligations.
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
Adverse Events of Special Interest
In the event of a nonserious AESI, the Investigator will complete the AESI Report Form and 
send it to the Sponsor/designee within 7 days (nonserious AESIs), or 24 hours (AESIs 
classified as serious). Names, addresses, and telephone and fax numbers for AESI reporting 
will be included on the Report Form. Serious AESIs must be reported in an expedited manner 
as SAEs as outlined above.
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Appendix 5
Clinical Laboratory Tests
Table 1
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Mean Corpuscular Volume
(MCV)
White Blood Cell 
(WBC) Count with 
Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Hemoglobin
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular hemoglobin 
concentration (MCHC)
Hematocrit
Coagulation
International 
normalized 
ratio
Partial 
thromboplastin 
time
Supplementary LFT 
visits
Aspartate aminotransferase
γ-Glutamyl-transferase
Total Bilirubin
Alanine aminotransferase
Alkaline phosphatase
Biochemistry
Blood Urea 
Nitrogen
Potassium
Aspartate Aminotransferase
Bilirubin
Creatinine 
and eGFR 
calculation
Sodium
Alanine Aminotransferase
Protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Chloride
Lactate 
dehydrogenase
Lipase
Amylase
Magnesium
Total carbon dioxide
Phosphate
γ-Glutamyl-
transferase
Immunoglobulin and subclass 
concentrations (as specified in 
the SoA, Section 1.3)a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.
Routine Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick
!
Microscopic examination (if blood or protein is abnormal). 
!
βhCG (women only)
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Laboratory 
Assessments
Parameters
Reflex Testing for 
HBV DNA
!
HBV DNA PCR
Other Screening 
Tests
!
Serology (HCV antibodies, HBV antibodies, HIV testingb, HBsAg, HCV RNA PCR, 
QuantiFERON tuberculosis test)
!
FSH and estradiol (as needed if not a WOCBP only)
!
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed for a WOCBP). Note: Local urine testing will be standard for the protocol 
unless serum testing is required by local regulation or the IRB/IEC.
!
Ferritin and transferrin saturation
!
All study-required laboratory assessments will be performed by a central laboratory, 
except for urine dipstick, urine pregnancy, ESR, PPD, and T-SPOT.
βhCG = β-Human Chorionic Gonadotropin, CMV = Cytomegalovirus, DNA = deoxyribonucleic acid, EA = Early 
Antigen, EBNA = Epstein-Barr Nuclear Antigen, eGFR = Estimated Glomerular Filtration Rate, 
ESR = Erythrocyte Sedimentation Rate, FSH = Follicle Stimulating Hormone, HAV = Hepatitis A Virus, 
HBc = Hepatitis B Core Antigen, HBsAg = Hepatitis B Surface Antigen, HBV = Hepatitis B Virus, 
HCV = Hepatitis C Virus, HEV = Hepatitis E Virus, HFE = High Iron Fe (human hemochromatosis protein), 
HIV = Human Immunodeficiency Virus, hsCRP = High Sensitivity C Reactive Protein, IDMC = Independent Data 
Monitoring Committee, IEC = Independent Ethics Committee, IRB = Institutional Review Board, 
Ig = Immunoglobulin, PCR = polymerase chain reaction, VCA = Viral Capsid Antigen, MCH = mean corpuscular 
hemoglobin, MCHC = mean corpuscular hemoglobin concentration; PPD = purified protein derivative, 
WBC = White Blood Cell, WOCBP = Women of Childbearing Potential.
a Results will not be disclosed to the sites, Sponsor, or representative, to avoid unblinding. However, the IDMC 
will have access to these data as applicable.
b HIV testing will be done at Screening and will be analyzed locally.
c Focused genetic testing for variants that confer risk for liver diseases and/or drug-related liver injury, including 
but not limited to testing for variants in the HFE gene (C282Y, H63D) in the setting of abnormal 
ferritin/transferrin saturation values as defined in Exclusion Criterion 10.
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Appendix 6
Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definitions of a Medical Device Incident
The detection and documentation procedures specified in this protocol apply to all Sponsor 
medical devices provided for use in the study. See Section 6.1.1 for the list of Sponsor medical 
devices.
Medical Device Incident Definition
! A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for 
use which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health.
! Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such 
a result might have been due to other fortunate circumstances or to the intervention of 
health care personnel.
It is sufficient that:
! An incident associated with a device happened.
AND
! The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:
! Life-threatening illness
! Permanent impairment of body function or permanent damage to body structure
! Condition necessitating medical or surgical intervention to prevent one of the above 
! Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of Incidents
! A participant, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.
! A participant’s study intervention is interrupted or compromised by a medical device 
failure.
! A misdiagnosis due to medical device failure leads to inappropriate treatment.
! A participant’s health deteriorates due to medical device failure.
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Documenting Medical Device Incidents
Medical Device Incident Documenting
! Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the Investigator’s normal clinical 
practice, and on the appropriate form of the CRF.
! For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF 
page will be completed as specified in Appendix 4.
! The CRF will be completed as thoroughly as possible and signed by the Investigator before 
transmittal to the Sponsor or designee.
! It is very important that the Investigator provides his/her assessment of causality 
(relationship to the medical device provided by the Sponsor) at the time of the initial AE 
or SAE report and specify any corrective or remedial actions taken to prevent recurrence 
of the incident.
! A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes 
any amendment to the device design to prevent recurrence.
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Appendix 8
Guidance for Diagnosis of PML 
The safety monitoring algorithm presented in Figure 3 will be implemented in this study.
Comprehensive neurological assessments will be performed every 12 weeks at the regular 
study visits. Additionally, telephone interviews will be conducted to assess for new or 
worsening neurological symptoms and a neurological evaluation will be conducted if 
clinically indicated. This neurological exam will include calculation of an Expanded 
Disability Status Scale (EDSS) score at the scheduled 12-week visit or in the event of 
new/worsening symptoms. This exam requires that Functional System Score (FSS) also be 
determined. The examination to calculate the FSS includes cognitive, visual and motor 
assessments, as well as assessments of other neurological systems. These neurological 
systems are often affected by PML, and by MS as well.
Should a non-MS etiology, such as PML, be considered as a differential etiology for any 
change in the clinical picture (neurological symptoms and/or exam), further assessments 
should be done. The evaluation of PML may include a brain MRI scan and CSF analysis per 
the proposed treatment algorithm (Figure 3).
Action Steps if PML is suspected:
If the clinical presentation is suggestive of PML, further investigations should include brain 
MRI evaluation as soon as possible. If MRI evaluation reveals lesions suspicious for PML a 
lumbar puncture with evaluation of the cerebrospinal fluid (CSF) for the detection of JCV 
DNA should be undertaken. A diagnosis of PML can potentially be made by evaluating 
clinical and MRI findings plus the identification of JCV in the CSF.   
MRI Assessments
Although there are no pathognomonic findings that differentiate PML from MS, a brain MRI 
scan that includes fluid-attenuated inversion recovery (FLAIR) and T2-weighted and 
T1-weighted sequences, with and without Gadolinium (Gd), should be performed to assess 
patients with neurological changes suggestive of PML.
CSF Assessment
! The detection of JCV DNA in the CSF of a participant with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML.
! If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, a 
repeat lumbar puncture should be performed.
! If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy 
may be considered to establish a definitive diagnosis.
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Figure 3
Diagnostic Algorithm for PML – Suggested Diagnostic Algorithm
Clinical assessment of new neurological 
symptoms if suggestive of non-MS-related 
disease
SUSPEND DOSING
MRI assessment
Treat as PML
Dosing may be resumed
Repeat assessment
CSF assessment
PML excluded
Cannot 
exclude 
PML
JCV not 
detected 
and low 
clinical 
suspicion
JCV not 
detected and 
high clinical 
suspicion 
JCV detected
If PML is suspected based on clinical 
presentation and an MRI is not readily 
available, CSF assessment to exclude 
PML should be considered prior to MRI
Dosing may 
be resumed
Treat as 
clinically indicated
If no clinical 
suspicion of PML 
High clinical 
suspicion of PML 
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Appendix 9
Protocol Amendment History
The information for the current amendment is on the title page.
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Appendix 12
Principal Investigator Signature Page
Study Title:
A Phase III, Multicenter, Randomized, Parallel Group, 
Double Blind, Double Dummy, Active Controlled 
Study of Evobrutinib Compared with an Interferon 
Beta 1a (Avonex®), in Participants with Relapsing 
Multiple Sclerosis to Evaluate Efficacy and Safety.
Regulatory Agency Identifying 
Numbers:
EudraCT: 2018-004700-19
Clinical 
Study 
Protocol 
Version:
Version 2.0 / 05 Sep 2019
Site Number:
I am responsible for the conduct of the study at this site, and understand and will conduct it 
per the clinical study protocol, any approved protocol amendments, International Council on 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain 
and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such 
information solely for complying with the regulatory requirements. Therefore, I agree to 
supply the Sponsor with any necessary information regarding ownership interest and financial 
ties including those of my spouse and dependent children, and to provide updates as necessary 
to meet Health Authority requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Integrated Analysis Plan
Clinical Study Protocol 
Identification No.
MS200527-0074
Title
A Phase III, Multicenter, Randomized, Parallel Group, Double 
Blind, Double Dummy, Active Controlled Study of Evobrutinib 
Compared with an Interferon Beta 1a (Avonex®), in Participants 
with Relapsing Multiple Sclerosis to Evaluate Efficacy and 
Safety
Study Phase
III
Investigational Medicinal 
Product(s)
Evobrutinib
Clinical Study Protocol 
Version
05 September 2019 / Version 2.0 (18 July 2019 / Version 1.1 US 
only)
Integrated Analysis Plan 
Author
Coordinating Author
 Merck
Function
Author(s) / Data Analyst(s)
Integrated Analysis Plan
Date and Version
28 May 2020 / Version 1.0
Integrated Analysis Plan 
Reviewers
Merck/EMD-Serono Reviewers:
Function
Name
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without 
express permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2020 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Approval Page
Integrated Analysis Plan: MS200527-0074
A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active 
Controlled Study of Evobrutinib Compared with an Interferon Beta 1a (Avonex®), in 
Participants with Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety
Approval of the Integrated Analysis Plan (IAP) by all Merck Data Analysis Responsible has to be 
documented within Electronic Document Management System (EDMS) via eSignature. With the 
approval, the Merck responsible for each of the analysis also takes responsibility that all reviewers’ 
comments are addressed adequately.
By using eSignature, the signature will appear at the end of the document.
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Table of Contents
Approval Page
2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ............................................................................8
4
Purpose of the Integrated Analysis Plan...............................................8
5
Objectives and Endpoints .....................................................................8
7
Changes to the Planned Analyses in the Clinical Study Protocol ......12
8
Analysis Populations and Subgroups..................................................12
8.1
Definition of Analysis Populations.....................................................12
8.2
Subgroup Definition and Parameterization ........................................12
9
General Specifications for Data Analyses ..........................................13
9.1
Definition of Baseline.........................................................................13
9.2
Study Day / Study Treatment Day......................................................13
9.3
Definition of Duration and ‘time since’ Variables .............................13
9.4
Conversion Factors.............................................................................14
9.5
Definition of Body Mass Index (BMI) (kg/m²)..................................14
9.6
Repeated and Unscheduled Measurements ........................................14
9.7
Definition of On-treatment Period......................................................14
9.8
Imputation of Missing Data................................................................14
9.9
Software..............................................................................................15
9.10
Unblinding..........................................................................................15
10
Study Participants ...............................................................................15
10.1
Disposition of Participants and Discontinuations...............................15
10.2
Protocol Deviations / Exclusion from Analysis Populations..............15
10.2.1
Important Protocol Deviations............................................................15
10.2.2
Reasons Leading to the Exclusion from an Analysis Population.......16
11
Demographics and Other Baseline Characteristics.............................16
11.1
Demographics.....................................................................................16
11.2
Other Baseline Characteristics............................................................16
12
Previous or Concomitant Medications/Procedures.............................17
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12.2
Prior or Concurrent Procedures ..........................................................18
13
Study Treatment Exposure .................................................................19
13.1
Exposure Calculation..........................................................................19
14
Efficacy Analyses ...............................................................................20
15
Safety Analyses ..................................................................................20
15.1
Adverse Events...................................................................................20
15.1.1
All Adverse Events.............................................................................20
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events...................................................................................20
15.2.1
Deaths .................................................................................................20
15.2.2
Serious Adverse Events......................................................................20
15.2.3
Other Significant Adverse Events ......................................................21
15.3
Clinical Laboratory Evaluation...........................................................21
15.4
Vital Signs ..........................................................................................22
15.5
12-Lead Electrocardiogram (ECG).....................................................23
15.6
Immunoglobulin levels.......................................................................23
16
Analyses of Other Endpoints..............................................................23
16.4
Patient Reported Outcomes ................................................................23
17
References...........................................................................................24
18
Appendices .........................................................................................25
18.1
AEs of Special Interest .......................................................................25
18.2
Laboratory Parameters to be Listed....................................................26
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Table of In-Text Tables
Table 1: Objective and Endpoints........................................................................................8
Table 2: Analysis Sets........................................................................................................12
Table 4: Definition of previous/concomitant medication..................................................18
Table 6: Laboratory Parameters to be Listed.....................................................................26
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2
List of Abbreviations and Definition of Terms
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
ARR
Annualized Relapse Rate
AST
Aspartate aminotransferase
AUC
Area under the curve
BID
Twice per day
BMI
Body mass index
BTK
Bruton’s Tyrosine Kinase
CDP
Confirmed Disability Progression
CFB
Change from Baseline
CL/F
Apparent plasma clearance following oral administration
Cmax
Maximum plasma concentration
(e)CRF
(electronic) Case Report Form
CSR
Clinical Study Report
CUA
Combined Unique Active
DBP
Diastolic Blood Pressure
DRM
Data Review Meeting
ECG
Electrocardiogram
EDMS
Electronic Document Management System
EDSS
Expanded Disability Status Scale
EEA
European Economic Area
FA
Final Analysis
HRQOL
Health Related Quality of Life
IA
Interim Analysis
IAP
Integrated Analysis Plan
IDMC
Independent Data Monitoring Committee
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Ig
Immunoglobulin
LFT
Liver Function Tests
Mean
Arithmetic Mean
MedDRA
Medical Dictionary for Regulatory Activities
MS
Multiple Sclerosis
NA
Not Applicable
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse Events
OLE
Open Label Extension
PF
Physical Function
PROMIS
Patient Reported Outcomes Measurement Information System
PT
Preferred Term
RMS
Relapsing Multiple Sclerosis
RRMS
Relapsing-remitting Multiple Sclerosis
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAS
Statistical Analysis System
SBP
Systolic Blood Pressure
SCR
Screening Analysis Population
SDTM
Study Data Tabulation Model
SFU
Safety Follow-up
SOC
System Organ Class
SPMS
Secondary Progressive Multiple Sclerosis
SSR
Sample Size Re-estimation
TEAE
Treatment-Emergent Adverse Event
Vz/F
Apparent volume of distribution
WHO-DD
World Health Organization Drug Dictionary
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3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
1.0
28May2020
Initial Version
4
Purpose of the Integrated Analysis Plan
The purpose of this IAP is to document technical and detailed specifications for the final analysis
of data collected for protocol MS200527-0074. Results of the analyses described in this IAP will 
be included in the synoptic Clinical Study Report (CSR). Any post-hoc, or unplanned analyses 
performed to provide results for inclusion in the CSR but not identified in this prospective IAP 
will be identified in the CSR.
5
Objectives and Endpoints
Objectives and endpoints are summarized in Table 1.
Table 1: Objective and Endpoints
Objectives
Endpoints (Outcome Measures)
IAP 
Section
Primary
To demonstrate superior efficacy 
with evobrutinib compared to 
Avonex in terms of annualized 
relapse rate (ARR)
ARR based on qualified relapses at Week 96 in participants with 
relapsing multiple sclerosis (RMS)
NA
Secondary
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex on disability progression
!
Time to first occurrence of 12-week confirmed Expanded 
Disability Status Scale (EDSS) progression over 96 weeks
!
Time to first occurrence of 24-week confirmed EDSS 
progression over 96 weeks
NA
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex on patient reported 
symptoms and functional status
!
Change from Baseline (CFB) in Patient Reported Outcomes 
Measurement 
Information 
System 
[PROMIS] 
Physical 
Function (PF) score at 96 weeks
!
CFB in PROMIS Fatigue score at 96 weeks
NA
To demonstrate the efficacy of 
evobrutinib relative to that of 
Avonex on magnetic resonance 
imaging (MRI) lesion parameters
!
Total number of T1 Gd+ lesions based on assessments at 
Week 24, Week 48, and Week 96
!
Total number of new or enlarging T2 lesions based on 
assessments at Week 24, Week 48, and Week 96
NA
To characterize the safety and 
tolerability of evobrutinib.
Safety as assessed by the nature, severity, and occurrence of 
adverse events (AEs) and adverse events of special interest 
(AESIs); vital signs; electrocardiograms (ECGs); absolute 
concentrations and change from Baseline in immunoglobulin (Ig) 
levels; and clinical laboratory safety parameters up to Week 108
15
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Open Label Extension (OLE) Period
To evaluate the long-term safety, 
efficacy, and HRQoL of evobrutinib 
for an additional 144 weeks
!
Efficacy and HRQoL endpoints at Weeks 48, 96, and 144
o
ARR, based on protocol-defined qualified relapses
o
Change from Baseline in PROMIS PF score
o
Change from Baseline in PROMIS fatigue score
o
Change from Baseline in Medical Outcomes Study 36 
Item Short Form Health Survey (SF-36v2) 
!
Efficacy and HRQoL endpoints over 144 weeks
o
Time to first occurrence of 12-week confirmed EDSS 
progression over 144 weeks
o
Time to first occurrence of 24-week confirmed EDSS 
progression over 144 weeks
o
Time to first occurrence of 12-week confirmed PF 
deterioration compared to Baseline over 144 weeks
!
Efficacy endpoints at Weeks 24, 48, 96, and 144
o
Total number of new or enlarging T2 lesions 
o
Total number of T1 Gd+ lesions
!
Safety as assessed by the nature, severity, and occurrence of 
AEs and AESIs; vital signs; ECGs; absolute concentrations 
and change from Baseline in Ig levels; clinical laboratory 
safety parameters up to Week 144
NA
NA: Not applicable; see Section 7.
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This IAP covers the final analysis of data after early database lock. See section 7.
7
Changes to the Planned Analyses in the Clinical Study
Protocol
Following analysis of open label extension (OLE) data from the RMS phase 2 study (MS200527-
0086), it was determined that a change in active comparator was warranted in the phase 3 RMS 
program comprised of trials MS200527-0073 and MS200527-0074. Consequently, trial 
MS200527-0074 was terminated early
. Only one subject 
was randomized/treated in this trial. 
Due to early termination, changes to the Clinical Trial Protocol (CTP) statistical section (Section 
9 “Statistical Considerations” Trial Protocol MS200527-0074) are required. None of the planned 
analyses described in Section 9 of this protocol will be performed and data collected on subjects 
will be listed only, after the database has been locked. The listings were chosen to satisfy the 
requirements of a Clinical Study Synopsis Report.
8
Analysis Populations and Subgroups
8.1
Definition of Analysis Populations
The analysis populations are specified in Table 2 below. 
Table 2: Analysis Sets
Analysis Set
Description
Screening (SCR) 
All participants, who provided informed consent, regardless of the participant’s 
randomization and study intervention status in the study.
Safety (SAF)
All participants, who were administered any dose of any study intervention. 
Participants will be analyzed according to the actual treatment they receive. If a 
participant receives more than one study treatment, the participant will be classified 
according to the treatment he/she has been most exposed to.
The SAF analysis set will be the only population for reporting in this study.
As no efficacy analyses will be performed, neither a Full Analysis Set nor a Per Protocol Analysis 
Set will be defined. Similarly, no analysis sets need to be defined for analysis of HRQOL, 
 or 
 endpoints. 
8.2
Subgroup Definition and Parameterization
Not applicable.
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9
General Specifications for Data Analyses
This section describes any general specifications not included in subsequent sections. 
Treatment groups and study intervention
Treatment groups in the double blind, double dummy period are defined as indicated in
:
9.1
Definition of Baseline
For the purpose of statistical analysis, baseline is defined as the last non-missing measurement 
(including those collected at an Unscheduled visit) prior to the first dose of study. If baseline 
cannot be defined, then the baseline value will be treated as missing.
9.2
Study Day / Study Treatment Day
Study day is defined relative to the date of randomization. Treatment day is defined relative to the 
date of start of treatment.  
The day before the start date of treatment is defined as treatment day -1, i.e., there is no treatment 
day zero.
9.3
Definition of Duration and ‘time since’ Variables
Duration will be calculated as the difference between start and stop dates plus 1 (eg, AE duration
(days) = AE end date - AE start date + 1). Durations will be calculated only when both dates are 
available (imputed dates cannot be used for the duration computation) unless otherwise specified.
The time since an event will be calculated as:
!
reference date minus date of event +1 (eg, days in study at onset of AE = AE start date - date 
of randomization + 1) if date of event is equal or greater than reference date
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!
reference date minus date of event (eg, days in study at onset of AE = AE start date - date of 
randomization) otherwise.
9.4
Conversion Factors
The following conversion factors will be used to convert days into months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
9.5
Definition of Body Mass Index (BMI) (kg/m²)
BMI will be computed as weight / (height²), where weight is expressed in kg and height in m.
9.6
Repeated and Unscheduled Measurements
Repeated and unscheduled measurements are included in the listings. 
9.7
Definition of On-treatment Period
On-treatment values are results of assessments done from the first study intervention
administration on Day 1 until End of Study (completion or early termination).
9.8
Imputation of Missing Data
Presentation of missing data
In all participant data listings, partial dates, which are not to be imputed according to this IAP, will 
be presented using the format “_____YYYY”. When presented, imputed dates will be flagged (ie, 
D for day, M for month).
In case of zero records available for presentation in a given listing, an empty output with a sentence 
stating that there are no data will be provided.
Handling of missing or partial adverse events dates
For defining the TEAE flag, missing or partial adverse event dates will be imputed as follows:
! In case the onset date is missing completely or missing partially but the onset month and year, 
or the onset year are equal to the start of study intervention, then the onset date will be replaced 
by the minimum of start of study intervention and AE resolution date. 
! In all other cases the missing onset day or missing onset month will be replaced by 1.
! Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of participant's death. In the latter case the date of death 
will be used to impute the incomplete stop date. 
Imputed dates will be used for defining the TEAE flag only. 
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Handling of partially missing multiple sclerosis (MS) first attack or diagnosis date
For time since MS first attack or MS diagnosis, a missing onset day/month will be replaced by 1 
for the duration derivation.
9.9
Software
All statistical analyses will be performed using SAS® (Statistical Analysis System, SAS-Institute, 
Cary, North Carolina Windows Version 9.4 or higher).
9.10
Unblinding
Details regarding the unblinding process are available in the unblinding plan (MS200527-
0074_unblinding_plan_final_v1.0_19May2020.pdf).
10
Study Participants
The subsections in this section include specifications for reporting participant disposition and 
study treatment/study discontinuations. Additionally, procedures for reporting protocol deviations 
are provided.
10.1
Disposition of Participants and Discontinuations
Participants’ information on informed consent, screening and randomization will be listed. 
Participants discontinued from treatment or study will be listed with their reason for withdrawal
(from treatment or study).
10.2
Protocol Deviations / Exclusion from Analysis Populations
As no efficacy analysis sets are required for the primary analysis of this study, protocol deviations 
are not used to exclude subjects from an analysis set. 
10.2.1
Important Protocol Deviations
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. Important protocol deviations are defined in a separate 
document (latest version of MS200527-0074_List_of_IPDs).
All deviations will be identified by either site monitoring, medical review processes or 
programming and confirmed prior to or at the Data Review Meeting (DRM), which will occur 
before the database lock. 
Important protocol deviations will be documented in Clinical Data Interchange Standards 
Consortium SDTM whether identified through sites monitoring or medical, and provided in a 
participant data listing.
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10.2.2
Reasons Leading to the Exclusion from an Analysis 
Population
Not applicable.
11
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be listed on SAF. 
11.1
Demographics
! Demographic characteristics 
-
Sex: male, female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Multiple (Combinations reported with ‘/’), Not collected 
at this site, Other
-
Ethnicity: Hispanic or Latino, Not Hispanic or Latino
-
Age (years) at informed consent: summary statistics
! Geographic Region: North America, Western Europe, Eastern Europe, ROW from IWRS
! European Economic Area (EEA)
! Baseline EDSS (<4.0, ≥4.0) from IWRS
Specifications for computation:
! Age (years): 
o
(date of given informed consent - date of birth + 1) / 365.25
o
In case of missing day for date of birth, but month and year available: 
o
For the derivation of age, the day of birth will be set to 1 and the formula above will be 
used
o
In case of missing month for at date of birth, but year available: 
o
For the derivation of age, the day and the month of birth will be set to 1 and the formula 
above will be used
11.2
Other Baseline Characteristics
Information on MS baseline disease characteristics, based on data collected on Day 1 predose and 
during screening, will be listed:
!
Type of MS, either relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS)
!
Conversion date from RRMS to SPMS (for participants with SPMS)
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!
Initial MS diagnosis date
!
Time (years) since initial MS diagnosis date
!
Time (years) since first attack
!
System(s) affected by first attack
!
Number of relapse(s) in the last two years
!
Number of relapse(s) from last year
!
Fulfills McDonald criteria 2017, fulfills 2017 and 2010 McDonald criteria
!
Was there at least 1 Gadolinium positive T1 lesion within 6 months prior to randomization?
12
Previous or Concomitant Medications/Procedures
12.1
Previous or Concomitant Medications
The ATC-2nd level and PT will be tabulated as given from the World Health Organization Drug 
Dictionary (WHO-DD) current version. In case multiple ATCs are assigned to a drug, all ATC-2nd
level will be used for reporting. 
Previous or concomitant medications will be listed, based on “RELEVANT PREVIOUS 
MEDICATIONS” & “CONCOMITANT MEDICATIONS” eCRF pages. The WHO-DD version 
used will be indicated in footnote.
The definition of previous or concomitant medication is presented in Table 4: 
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Table 4: Definition of previous/concomitant medication
Treatment groups
Definition
Previous medications
are medications, other than study
interventions, which either: 
1.
started and stopped before first administration of any study 
intervention (Avonex or evobrutinib). 
2.
started prior to the first administration of study 
intervention (Avonex or evobrutinib) and are taken by 
participants on or after the first administration of study 
intervention (including safety follow-up (SFU) for early 
discontinued participants).                   
Concomitant medications are medications, other than study
interventions, which either:
1.
started on or after the first administration of any study 
intervention (Avonex or evobrutinib). 
2.
started prior to the first administration of study 
intervention (Avonex or evobrutinib) and are taken by 
participants on or after the first administration of study 
intervention
(including
SFU for early discontinued 
participants).                                     
Partial dates will be handled as follows: 
! For previous medications, in case the date values will not allow a medication to be 
unequivocally allocated to previous medication, the medication will be considered as previous 
medication.
! For concomitant medications, in case the date values will not allow a medication to be 
unequivocally allocated to concomitant medication, the medication will be considered as 
concomitant medication.
12.2
Prior or Concurrent Procedures
Not applicable.
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13
Study Treatment Exposure
Data will be listed by treatment group and participant on SAF.
13.1
Exposure Calculation
Dose interruptions/changes
will not be considered in exposure calculation. Dose 
interruptions/changes with the associated reason will only be listed.
Details describing study therapy dosing and administration are provided in Table 5.
Treatment duration in weeks will be calculated according to the following formula: 
	
 
 
		 (weeks) = 
( 
  
 − 
 	 
 + 1)
7
	
 
 
 (weeks) = 
( 
  
 − 
 	 
 + 7)
7
First dose refers to the first administration of any study intervention. Last dose refers to the last 
administration of any study intervention. Both dates of first and last dose will be retrieved from 
SDTM EC domain [“Evobrutinib / Placebo Administration Details” and “Avonex / Placebo 
Administration Details” eCRF pages]. 
Participant data listings:
Study drug administrations from the 2 eCRF pages will be listed by treatment group, and
participant, with start/end dates of administration, and reason for dose change or no dose (if 
applicable). The duration of treatment will be reported for each participant.
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14
Efficacy Analyses
As a synoptic CSR will be prepared and only 3 participants were randomized, efficacy data will 
not be reported. 
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as adverse events, laboratory tests and vital signs.
Safety listings will be presented on the SAF.
15.1
Adverse Events
All analyses described in this section will be based on TEAEs if not otherwise specified.
TEAEs will be defined as: 
! AEs starting on or after first treatment administration of any study intervention (Avonex or 
evobrutinib) until safety follow-up (end of study),
! or if it was present prior to any study intervention administration but exacerbated after. 
Any AE which started before study first treatment administration of any study intervention
(Avonex or evobrutinib) but improved during treatment period until safety follow up (end of study) 
will not be counted as TEAE.
15.1.1
All Adverse Events
AEs will be coded according to the latest MedDRA version available at the time of analysis. The 
severity of AEs will be graded using NCI-CTCAE version 4.03 toxicity grades. AEs with missing 
classification concerning study intervention relationship will be considered related to the study 
intervention. 
Participant data listings
TEAEs will be listed by treatment group and participant. 
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
Not applicable.
15.2.2
Serious Adverse Events
A participant listing of serious TEAEs will be provided.
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15.2.3
Other Significant Adverse Events
The following events are defined as AEs of Special Interest (AESI):
!
Liver AEs
o
Transaminase and bilirubin elevations, Hy’s law cases
o
Hepatitis non-infectious
o
Hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions
o
Immune-medical hepatitis, alloimmune hepatitis, non-alcoholic fatty liver
!
Severe Infections:
o
Serious AEs or Grade ≥ 3 
o
Opportunistic infections Grade ≥ 3
!
Amylase and Lipase elevations
o
Enzyme elevations Grade ≥ 3
o
Acute pancreatitis SMQ
15.3
Clinical Laboratory Evaluation
The following laboratory parameters will be measured during the study as part of the safety 
evaluation:
!
Hematology,
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!
Urinalysis,
!
Coagulation.
The clinical laboratory safety tests to be measured in this study are provided in the protocol (refer 
to Appendix 5 of the CTP). All available parameters from these 4 categories will be listed (refer 
to Appendix 18.2).
All laboratory data results will be presented using international system of units (SI).
Some laboratory results will be classified according to NCI-CTCAE Version 4.03. In case a 
laboratory parameter has bi-directional toxicities (e.g., Potassium) both directions will be 
presented for the given parameter (i.e., Potassium Low and Potassium High). 
Laboratory results containing a modifier such as “<” or “>=” will be reported as collected in the 
database in participant data listings.
Participant data listings will be provided, with a flag for abnormal values, along with 
corresponding normal ranges:
!
Laboratory gradable parameters part of NCI-CTCAE will be presented according to the 
categories based on normal ranges along with the grade. Abnormal values will be flagged 
according to the direction of toxicity (e.g., for a parameter such as Potassium Low, only values 
below the LLN will be flagged).
!
Laboratory parameters that are not part of NCI-CTCAE will be presented according to the 
categories based on normal ranges: below normal limits (Low), within normal limits (Normal), 
and above normal limits (High). Values that are either above ULN or below LLN will be 
flagged.
In this study, clinically significant lab abnormalities were recorded as adverse events. In lieu of a 
listing of clinically significant lab abnormalities for each domain, the following by-participant lab 
value listings will be provided:
!
Listing of Grade ≥ 3 hematology values
!
Listing of Grade ≥ 3 biochemistry values or Grade ≥ 2 AST, ALT or Bilirubin.
15.4
Vital Signs
Vital signs (height (m), weight (kg), BMI (kg/m²), body temperature (°C), Systolic Blood Pressure 
(SBP) (mmHg), Diastolic Blood Pressure (DBP) (mmHg), respiratory rate (breaths/min) and pulse 
rate (beats/min)) will be listed by treatment group and visit.
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15.5
12-Lead Electrocardiogram (ECG)
Listings of ECG quantitative values, results of ECG and rhythm results will be produced by 
intervention group, participant ID and visit/timepoint.
15.6
Immunoglobulin levels
Listing of absolute value and change from baseline in Immunoglobulin levels will be produced by 
intervention group, participant ID and visit/timepoint.
16
Analyses of Other Endpoints
16.2
Pharmacodynamics
Not applicable.
16.3
Population PK/PD Modeling
Not applicable.
16.4
Patient Reported Outcomes
Not applicable.
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17
References
Crowe BJ, Xia HA, Berlin JA, et al. Recommendations for safety planning, data collection, 
evaluation and reporting during drug, biologic and vaccine development: a report of the safety 
planning, evaluation, and reporting team. Clin Trials. 2009;6(5):430-40.
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18
Appendices
18.1
 
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18.2
Laboratory Parameters to be Listed
Table 6: Laboratory Parameters to be Listed
Names of Clinical Safety 
Laboratory Evaluations in 
Protocol Version 2.0, 05Sep2019 
and Version 1.1, 18Jul2019
If gradable parameter, 
corresponding evaluation names 
in NCI-CTCAE 4.03
Worst on treatment 
value based on normal 
range 
Biochemistry
Albumin
Hypoalbuminemia
LOW
Aspartate aminotransferase
Aspartate aminotransferase 
increased
HIGH
Alanine aminotransferase
Alanine aminotransferase 
increased
HIGH
Alkaline phosphatase
Alkaline phosphatase increased
HIGH
γ-Glutamyl-transferase
GGT increased
HIGH
Lactate dehydrogenase
HIGH
Bilirubin (total)
Blood bilirubin increased
HIGH
Protein (total)
LOW
Creatinine
Creatinine increased
HIGH
eGFR
Chronic kidney disease
LOW
Amylase
Serum amylase increased
HIGH
Lipase
Lipase increased
HIGH
Bicarbonate
LOW
Blood urea nitrogen
HIGH
Glucose
Hyperglycemia
HIGH
Glucose
Hypoglycemia
LOW
Sodium
Hypernatremia
HIGH
Sodium
Hyponatremia
LOW
Potassium
Hyperkalemia
HIGH
Potassium 
Hypokalemia
LOW
Chloride
NA
Calcium
Hypercalcemia
HIGH
Calcium
Hypocalcemia
LOW
Magnesium
Hypermagnesemia
HIGH
Magnesium
Hypomagnesemia
LOW
Phosphate
Hypophosphatemia
LOW
Uric Acid
Hyperuricemia
HIGH
Hematology
Hematocrit
LOW/HIGH
Hemoglobin
Hemoglobin increased
HIGH
Hemoglobin
Anemia
LOW
Red blood cell count
NA
Mean corpuscular volume
NA
Mean corpuscular hemoglobin
NA
Mean corpuscular hemoglobin 
concentration
NA
Reticulocyte count
NA
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Platelet count
Platelet count decreased
LOW
White blood cell count
Leukocytosis
HIGH
White blood cell count
White blood cell decreased
LOW
White blood cell differentials and 
absolute counts: Basophils
NA
White blood cell differentials and 
absolute counts: Eosinophils
NA
White blood cell differentials and 
absolute counts: Lymphocytes
Lymphocyte count increased
HIGH
White blood cell differentials and 
absolute counts: Lymphocytes
Lymphocyte count decreased
LOW
White blood cell differentials and 
absolute counts: Monocytes
NA
White blood cell differentials and 
absolute counts: Neutrophils
Neutrophil count decreased
LOW
Urinalysis
pH
NA
Nitrite
NA
Protein
NA
Blood
NA
Glucose 
NA
Ketones bodies
NA
Urobilinogen
NA
Bilirubin 
NA
leukocyte esterase by disptik
NA
Specific gravity
NA
Coagulation
International normalized ratio
NA
Partial thromboplastin time
NA
Urine 
Microscopy
White blood cells
HIGH
Red blood cells
HIGH
Casts
NA
Crystals
NA
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