Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis American College of Rheumatology High-sensitivity C-reactive protein Bruton's tyrosine kinase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 390
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the efficacy, dose response, and safety of M52951 in participants with Rheumatoid Arthritis (RA), and to consider a dose to took forward into Phase III development.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: M2591 25 mg QD intervention 2: M2951 75 mg QD intervention 3: M2951 50 mg BID intervention 4: Placebo
Intervention descriptions: intervention 1: Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks. intervention 2: Participants received 75 mg of M2951 orally QD for 12 weeks. intervention 3: Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks. intervention 4: Participants received placebo matched to M2951 orally for 12 weeks.

Protocol document:
Prot_000.pdf: 
Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
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Clinical Trial Protocol
Clinical Trial Protocol Number
MS200527-0060
Title
A Phase IIb, Randomized, Double-blind Study in 
Subjects with Rheumatoid Arthritis Evaluating the 
Safety and Efficacy of Evobrutinib Compared with
Placebo in Subjects with an Inadequate Response to 
Methotrexate
Phase
IIb
IND Number
EudraCT Number
2017-000384-32
Coordinating Investigator
Sponsor
For all countries except the USA and Japan:
Merck KGaA, Frankfurter Str. 250
64293 Darmstadt, Germany
For Japan only: 
Merck Serono Co., Ltd.
(Affiliate of Merck KGaA, Darmstadt, Germany)
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
And
For the USA 
EMD Serono Research & Development Institute, 
Inc. 
45A Middlesex Turnpike
Billerica, MA 01821
USA
Medical Responsible:
EMD Serono Research & Development Institute
45A Middlesex Turnpike, Billerica, MA 01821, 
USA
Telephone: 
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
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Clinical Trial Protocol Version
12 July 2018/Version 3.0 (Amendment 4)
Replaces Version
13 December 2017/Version 2.0
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
11 May 2017
1.1
Amendment specific for US
03 July 2017
2.0
Global Amendment
13 December 2017
2.1
Amendment specific for US
16 November 2017
3.0
Global Amendment
12 July 2018
Protocol Version [3.0] (12-July-2018)
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study.
After receiving feedback from multiple regulatory agencies, the Sponsor has decided not to initiate 
the Open-label Extension (OLE) Period.
Section # and 
Name
Description of Change
Brief Rationale
Throughout
All mention of OLE and related 
procedures, objectives, and duration
estimates were removed
Implementing Sponsor decision to not initiate the 
OLE Period
Synopsis
Removed Table 2 and Table 3
No longer required given Sponsor decision to not 
initiate the OLE Period
8.6. Planned 
Analysis
Removed 12-week analysis and moved 
consistency analysis to be part of the 
final analysis
Without the OLE, there is no need to run an 
interim analysis before the final analysis
Synopsis
Added text to explain removal of OLE 
Period and provide procedure for 
subjects already in the OLE Period
Give guidance for subjects who enroll in the OLE 
Period prior to implementation of Protocol Version 
3.0.
7.1.3. Open-
label Extension 
Period
Added text to explain removal of OLE 
Period and provide procedure for 
subjects already in the OLE Period
Give guidance for subjects who enroll in the OLE 
Period prior to implementation of Protocol version 
3.0.
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 © 2018 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Amendment Summary of Changes........................................................................3
Protocol History
..............................................................................................................3
Protocol Version [3.0] (12-July-2018).................................................................................3
Protocol Table of Contents ..................................................................................................4
Table of In-Text Tables .......................................................................................................8
Table of In-Text Figures......................................................................................................8
List of Abbreviations .........................................................................................................10
1
Synopsis..............................................................................................14
2
Sponsor, Investigators and Trial Administrative Structure ................30
3
Background Information.....................................................................31
3.1
Rheumatoid Arthritis ..........................................................................31
3.2
Evobrutinib .........................................................................................31
3.4
Risk/Benefit ........................................................................................34
4
Trial Objectives ..................................................................................35
4.1
Primary Objective...............................................................................35
4.2
Key Secondary Objective ...................................................................35
4.3
Other Secondary Objectives ...............................................................36
5
Investigational Plan ............................................................................36
5.1
Overall Trial Design and Plan ............................................................36
5.2
Discussion of Trial Design .................................................................40
5.2.1
Scientific Rationale for the Trial ........................................................40
5.2.3
Rationale for Endpoints......................................................................45
5.2.4
Inclusion of Special Populations ........................................................52
5.3
Selection of Trial Population..............................................................52
5.3.1
Inclusion Criteria ................................................................................53
5.3.2
Exclusion Criteria...............................................................................55
5.4
Criteria for Randomization and Initiation of Trial Treatment............60
5.5
Criteria for Subject Withdrawal..........................................................61
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5.5.1
Withdrawal from Trial Therapy..........................................................61
5.5.2
Withdrawal from the Trial..................................................................64
5.6
Premature Termination of the Trial ....................................................64
5.7
Definition of End of Trial...................................................................65
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................65
6.1
Description of the Investigational Medicinal Product........................65
6.2
Dosage and Administration ................................................................66
6.3
Assignment to Treatment Groups.......................................................66
6.4
Noninvestigational Medicinal Products to be Used............................67
6.5
Concomitant Medications and Therapies ...........................................67
6.5.1
Permitted Medicines...........................................................................67
6.5.2
Prohibited Medicines..........................................................................68
6.5.3
Other Interventions.............................................................................70
6.6
Packaging and Labeling of the Investigational Medicinal Product....71
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................72
6.8
Investigational Medicinal Product Accountability.............................72
6.9
Assessment of Investigational Medicinal Product Compliance .........73
6.10
Blinding ..............................................................................................73
6.11
Emergency Unblinding.......................................................................74
6.12
Treatment of Overdose .......................................................................74
6.13
Medical Care of Subjects after End of Trial.......................................75
7
Trial Procedures and Assessments......................................................75
7.1
Schedule of Assessments....................................................................75
7.1.1
Screening Period.................................................................................76
7.1.2
Treatment Period ................................................................................76
7.1.3
Open-label Extension Period (Only Applicable Prior to Protocol 
Version 3.0) ........................................................................................76
7.1.4
Safety Follow-up Visit........................................................................77
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7.2
Demographic and Other Baseline Characteristics ..............................77
7.2.1
Demography .......................................................................................77
7.2.2
Medical History ..................................................................................77
7.3
Efficacy Assessments .........................................................................78
7.3.1
Disease Activity Assessments ............................................................78
7.3.2
Physical Function Assessments..........................................................82
7.3.3
Prevention of Joint Structural Damage Progression...........................83
7.4
Assessment of Safety..........................................................................84
7.4.1
Adverse Events ...................................................................................84
7.4.2
Pregnancy and In Utero Drug Exposure.............................................89
7.4.3
Clinical Laboratory Assessments .......................................................90
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............92
7.7
Assessment of Symptoms and Health Related Quality of Life 
(HRQoL).............................................................................................96
7.7.1
Medical Outcomes Study 36-item Short-Form Health Survey...........96
7.7.2
Functional Assessment of Chronic Illness Therapy-Fatigue..............96
7.8
Other Assessments..............................................................................97
8
Statistics..............................................................................................97
8.1
Sample Size ........................................................................................97
8.2
Randomization....................................................................................98
8.3
Endpoints............................................................................................99
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8.3.1
Primary Endpoint................................................................................99
8.3.2
Secondary Endpoints ..........................................................................99
8.4
Analysis Sets.....................................................................................102
8.4.1
Subgroups .........................................................................................102
8.5
Description of Statistical Analyses...................................................103
8.5.1
General Considerations.....................................................................103
8.5.2
Analysis of Primary Endpoint ..........................................................104
8.5.3
Analysis of Secondary Endpoints.....................................................104
8.5.4
Analysis of Safety and Other Endpoints...........................................105
8.6
Planned Analysis ..............................................................................107
9
Ethical and Regulatory Aspects........................................................107
9.1
Responsibilities of the Investigator ..................................................107
9.2
Subject Information and Informed Consent .....................................108
9.3
Subject Identification and Privacy....................................................109
9.4
Emergency Medical Support and Subject Card................................109
9.5
Clinical Trial Insurance and Compensation to Subjects...................110
9.6
Independent Ethics Committee or Institutional Review Board........110
9.7
Health Authorities.............................................................................110
10
Trial Management.............................................................................111
10.1
Case Report Form Handling.............................................................111
10.2
Source Data and Subject Files..........................................................111
10.3
Investigator Site File and Archiving.................................................112
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................112
10.5
Changes to the Clinical Trial Protocol..............................................113
10.6
Clinical Trial Report and Publication Policy....................................113
10.6.1
Clinical Trial Report.........................................................................113
10.6.2
Publication........................................................................................113
11
References Cited in the Text.............................................................114
12
Appendices .......................................................................................119
Appendix I:
Contraceptive Guidance and Woman of Childbearing Potential......120
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Appendix II:
Joint Count Assessment Forms (66/68 Joint Evaluation).................122
Appendix III:
Signature Pages and Responsible Persons for the Trial....................124
Signature Page – Protocol Lead.......................................................................................125
Signature Page – Coordinating Investigator ....................................................................126
Signature Page – Principal Investigator...........................................................................127
Sponsor Responsible Persons not Named on the Cover Page .........................................128
Appendix IV:
Protocol Amendment History...........................................................129
Table of In-Text Tables
Table 1
Schedule of Assessments – Screening to Safety Follow-up Visit......24
Table 2 
Trial Study Population........................................................................37
Table 3 
Treatment Groups and Regimens .......................................................37
Table 5
Disease Activity Cutoffs for Select American College of 
Rheumatology - Recommended Disease Activity Measures..............47
Table 6 
Scoring Method for the Hybrid American College of 
Rheumatology Response Measure......................................................49
Table 7 
Categorization of Subject Responses as No Response, Moderate 
Response, or Good Response Based on EULAR Response Criteria..49
Table 8 
Dosage and Administration of Evobrutinib........................................66
Table 9 
Examples of Inhibitors or Inducers of CYP3A Enzymes or 
Substrates with Narrow Therapeutic Range .......................................70
Table 10
Clinical Safety Laboratory Evaluations..............................................90
Table of In-Text Figures
Figure 1
Schematic of the Trial Design – Screening to Safety Follow-up 
Visit.....................................................................................................40
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List of Abbreviations
ACR
American College of Rheumatology
ACR20
American College of Rheumatology 20% Response Criteria
ACR50
American College of Rheumatology 50% Response Criteria
ACR70
American College of Rheumatology 70% Response Criteria
AE
Adverse event
ALT
Alanine aminotransferase
APRIL
A proliferation-inducing ligand
AST
Aspartate aminotransferase
AUC
Area under the curve
β-hCG
Beta-human chorionic gonadotropin
bDMARD
Biologic disease-modifying anti-rheumatic drugs
bDMARD-IR
RA subjects with inadequate response to methotrexate and ≥1 bDMARD
BID
Twice daily
BlyS
B lymphocyte stimulator (also called B-cell activating factor or BAFF)
BTK
Bruton’s tyrosine kinase
C
Collect
CARLOS
Cartilage Loss Scale
CAT
Computer adaptive testing
CCP
Cyclic citrullinated protein
CDAI
Clinical Disease Activity Index
CI
Confidence interval
Cmax
Maximum plasma concentration
CRO
Contract research organization
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical trial report
CXR
Chest X-ray
CYP
Cytochrome P450
CYP3A
Cytochrome P450 isozyme 3A
CYP3A4/5
Cytochrome P450 isozyme 3A4/5
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DAS
Disease Activity Score
DAS28
Disease Activity Score Based on a 28 Joint Count
DMARD
Disease-modifying anti-rheumatic drugs
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ESR
Erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-Glutamyl-transferase
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL-C
High-density lipoprotein cholesterol
HIV
Human Immunodeficiency Virus
HRQoL
Health-related quality of life
hsCRP
High-sensitivity C-reactive protein
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IMP
Investigational Medicinal Product
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IRB
Institutional Review Board
ITT
Intent-to-treat
IWRS
Interactive Web Response System
JAK
Janus kinase
JSN
Joint space narrowing
LDA
Low disease activity
LDL-C
Low-density lipoprotein cholesterol
LFT
Liver Function Test
LLN
Lower limit of normal
LTBI
Latent tuberculosis infection
MAR
Missing at random
MCP
Metacarpophalangeal
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
MOP
Manual of Procedures
MRI
Magnetic resonance imaging
mRNA
Messenger Ribonucleic Acid
MTX
Methotrexate
MTX-IR
RA subjects with inadequate response to methotrexate
NIH
National Institute of Health
NSAID
Nonsteroidal anti-inflammatory drug
OLE
Open-label extension
OMERACT
Outcome Measures in Rheumatology Clinical Trials
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PK
Pharmacokinetics
PO
Orally
PP
Per-Protocol
Q2W
Every 14 days
QD
Once daily
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R
Review
RA
Rheumatoid arthritis
RAMRIQ
Rheumatoid Arthritis Magnetic Resonance Image Quantification
RAMRIS
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System
RF
Rheumatoid factor
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDAI
Simplified Disease Activity Index
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
SJC
Swollen joint count
SLE
Systemic lupus erythematosus
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TJC
Tender joint count
TNF
Tumor necrosis factor
tsDMARD
Targeted synthetic disease-modifying anti-rheumatic drugs
ULN
Upper limit of normal
VAS
Visual analog scale
WOCBP
Women of childbearing potential
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1
Synopsis
Clinical Trial Protocol Number
MS200527-0060
Title
A Phase IIb, Randomized, Double-blind Study in 
Subjects with Rheumatoid Arthritis Evaluating 
the Safety and Efficacy of Evobrutinib Compared 
with Placebo in Subjects with an Inadequate 
Response to Methotrexate
Trial Phase
IIb
IND Number
FDA covered trial
Yes
EudraCT Number
2017-000384-32
Coordinating Investigator
Telephone: 
E-mail: 
Sponsor
For all countries except the USA and Japan:
Merck KGaA, Frankfurter Str. 250
64293 Darmstadt, Germany
For Japan only:
Merck Serono Co., Ltd.
(Affiliate of Merck KGaA, Darmstadt, Germany)
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
And
For the USA:
EMD Serono Research & Development
Institute, Inc.
45A Middlesex Turnpike
Billerica, MA 01821, USA
Medical Responsible:
EMD Serono Research & Development Institute
45A Middlesex Turnpike, Billerica, MA 01821, 
USA
Telephone: 
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Trial centers/countries
Approximately 160 sites in 17 countries
Planned trial period
(first subject in-last subject out)
June 2017 to June 2020
Trial Registry
ClinicalTrials.gov, EudraCT
Objectives:
Primary objective: 
∀To evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib
compared with placebo in subjects with rheumatoid arthritis (RA) with inadequate response 
to methotrexate (MTX-IR) on stable MTX therapy by assessment of the signs and symptoms 
of RA, as measured by American College of Rheumatology (ACR) 20% (ACR20) response 
assessed using high-sensitivity C-reactive protein (hsCRP) at Week 12.
Key secondary objectives:
∀To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib
in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and 
symptoms of RA, as measured by DAS28-hsCRP low disease activity (DAS28 < 3.2) rate 
at Week 12 
∀To further evaluate the efficacy of 12 weeks of treatment with evobrutinib compared to 
placebo in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs 
and symptoms of RA, as measured by DAS28-hsCRP remission (DAS28 < 2.6) rate at 
Week 12 
∀To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib
in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and 
symptoms of RA, as measured by ACR50 and ACR70 at Week 12 
∀To evaluate the safety of evobrutinib in MTX-IR subjects with RA on stable MTX therapy.
Other secondary objectives: 
∀To further evaluate the efficacy of evobrutinib on the signs and symptoms of RA with 
inadequate response to MTX
∀To evaluate the effect of evobrutinib on joint structures and inflammation, at Weeks 4 
and 12 in the MRI substudy, as assessed by magnetic resonance imaging (MRI)
∀To evaluate the effect of evobrutinib on physical function in RA subjects
∀To evaluate the effect of evobrutinib on subject-reported health-related quality of life 
(HRQoL)
∀To evaluate the effect of evobrutinib on subject-reported fatigue (using Functional 
Assessment of Chronic Illness Therapy [FACIT]-Fatigue).
Exploratory objectives: 
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Methodology:
This is a Phase IIb, multicenter, international, randomized, double-blind, placebo-controlled 
parallel-arm trial, designed to determine the efficacy, dose response, and safety of evobrutinib
(also known as M2951) in subjects 18 to 75 years of age with moderate to severe RA, and to 
consider a dose to take forward into Phase III development.
Enrollment will include approximately 360 MTX-IR subjects with no prior treatment with 
biologic disease-modifying anti-rheumatic drugs (bDMARD) or targeted synthetic DMARD 
(tsDMARD).
Approximately 50% of the subjects will participate in a substudy using MRI to evaluate the 
ability of evobrutinib to prevent the progression of joint structural damage.
Eligible subjects will be randomly assigned in a 1:1:1:1 ratio to receive, in combination with 
their stable background MTX therapy, evobrutinib 25 mg once daily, evobrutinib 75 mg once 
daily, evobrutinib 50 mg twice daily, or placebo.
Randomization will be stratified by whether or not subjects are in the MRI substudy and by 
region.
The trial is composed of a Screening Period of 4 weeks, a Treatment Period of 12 weeks, and 
a Safety Follow-up Period of 4 weeks. After completing the 12-week Treatment Period, 
subjects will enter into safety follow up period.
In Protocol version 2.0, subjects completing the Treatment Period could have entered an 
optional Open-label Extension (OLE) Period, but the Sponsor made the decision to not initiate
the OLE Period. As of the effective date of Protocol version 3.0 at study sites, all subjects 
completing the Treatment Period will enter the Safety Follow-up Period, and any subjects 
already participating in the OLE Period at that time will be immediately withdrawn from the 
study following the protocol-specified withdrawal procedures: subjects would return for an 
End of Treatment Visit and return 4 weeks later for an End of Study/Safety Follow-up Visit.
During the trial, clinical efficacy endpoints will be evaluated using assessments of clinical 
response, disease activity and remission, prevention of joint structural damage progression, 
physical function, fatigue, and HRQoL. Safety will be evaluated through the nature, 
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occurrence, severity and outcome of adverse events (AEs), and assessment of physical 
examination findings, electrocardiograms (ECGs), hematology and chemistry laboratory 
assessments, vital signs, and absolute values and change from Baseline in serum total 
immunoglobulin (Ig) levels (IgG, IgA, and IgM) and total B cell counts.
Planned number of subjects: 360 subjects with RA (to achieve 320 evaluable subjects)
Primary endpoint:
Primary efficacy endpoint: ACR20 response assessed using hsCRP (ACR20) at Week 12.
Key secondary endpoints:
Key secondary efficacy endpoints:
∀DAS28-hsCRP low disease activity (DAS28 < 3.2) rate at Week 12
∀DAS28-hsCRP remission (DAS28 < 2.6) rate at Week 12
∀ACR 50% (ACR50) response assessed using hsCRP at Week 12
∀ACR 70% (ACR70) response assessed using hsCRP at Week 12.
Key secondary safety endpoints:
∀The nature, severity, and occurrence of AEs and serious AEs (SAEs)
∀Absolute values and change from Baseline in:
o
Vital signs
o
ECG parameters including RR interval, PR interval, QRS duration, QT interval, and 
QTcF interval
o
Serum Ig levels (IgG, IgA, IgM)
o
Total B cell counts
o
Clinical laboratory parameters.
Other secondary efficacy endpoints: 
At Week 12:
∀Achieving American College of Rheumatology/European League Against Rheumatism 
(EULAR) Boolean remission
∀Achieving Clinical Disease Activity Index (CDAI) score ≤2.8 (CDAI remission)
∀Achieving Simplified Disease Activity Index (SDAI) score ≤3.3 (SDAI remission)
∀EULAR Responder Index (based on DAS-hsCRP)
∀ACR hybrid scores computed using hsCRP
∀Change from Baseline in DAS28-hsCRP
∀Change from Baseline in CDAI and SDAI
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∀Changes and percentage changes from Baseline of individual components of the ACR Core 
Set
∀Imaging:
o
Change from Baseline in Outcome Measures in Rheumatology Clinical Trials 
(OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System 
(RAMRIS)
scores
(designated 
hand, 
minimal 
assessed 
joints: 
wrist, 
metacarpophalangeal [MCP] joints #1 to #5) for subjects in the MRI substudy:

Synovitis score

Bone marrow edema (osteitis) score.
∀Changes from Baseline of Physical Function:
o
Health Assessment Questionnaire – Disability Index (HAQ-DI).
∀Changes from Baseline of HRQoL:
o
Medical Outcomes Study 36-item Short Form Health Survey (SF-36)
o
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue.
Exploratory endpoints:
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Diagnosis and key inclusion and exclusion criteria:
Key inclusion criteria (all subjects):
The current trial will enroll subjects who fulfill the following key inclusion criteria:
∀Consenting male or female subjects, 18 to 75 years of age (In Japan, if a subject is 
< 20 years, the written informed consent from the subject’s parent or guardian will be 
required in addition to the subject’s written consent.)
∀Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at 
least 6 months duration prior to Screening
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∀Persistently active moderate to severe RA at both Screening and Randomization (if 
significant surgical treatment of a joint has been performed, that joint cannot be counted for 
entry or enrollment purposes), as defined by:
o
≥6 swollen joints (of 66 assessed) and
o
≥6 tender joints (of 68 assessed).
∀An hsCRP ≥5.0 mg/L (≥0.50 mg/dL) at Screening
∀Treatment for ≥16 weeks with 7.5 to 25 mg/week MTX at a stable dose and route of 
administration (oral or parenteral) for at least 8 weeks prior to dosing with the IMP and 
maintained throughout the trial
∀For subjects entering the trial on MTX doses < 15 mg/week (< 10 mg/week in Japan), there 
must be clear documentation in the medical record that higher doses of MTX were not 
tolerated or that the dose of MTX is the highest acceptable dose based on local clinical 
practice guidelines.
MRI Substudy Subjects:
In addition to meeting the inclusion criteria for the study, subjects must have palpable synovitis 
of the wrist and/or ≥1 of MCP joints #1 to #5, defined as loss of bony contours with palpable 
joint effusion and/or swelling, in the MRI-designated hand (ie, the hand being used in MRI 
assessments).
Key exclusion criteria (all subjects):
Subjects who fulfill any of the following key exclusion criteria should not be enrolled into this 
trial:
∀ACR functional class IV as defined by the ACR classification of functional status or 
wheelchair/bedbound
∀Use of oral corticosteroids > 10 mg daily prednisone equivalent, or change in dose of 
corticosteroids within 2 weeks prior to Screening or during Screening
∀Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular 
hyaluronic acid within 4 weeks prior to Screening or during Screening
∀Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) (including 
low-dose aspirin and COX-2 inhibitors) within 2 weeks prior to dosing with the IMP
∀High potency opioid analgesics are prohibited within 2 weeks prior to Screening and during 
the trial; other analgesics are allowed (eg, acetaminophen, codeine, hydrocodone*,
propoxyphene*, or tramadol), although not within 24 hours of study visits with clinical 
assessments (*not approved in Japan).
∀Current or prior treatment with ANY of the following:
o
Biologic DMARDs (approved or investigational), including but not limited to:

TNF antagonists or biosimilars of these agents (approved or investigational), or any 
investigational TNF antagonist
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
Interleukin-6 antagonists

Abatacept (CTLA4-Fc)

Anakinra* (IL-1 receptor antagonist) (*not approved in Japan)

B cell-depleting 
antibodies 
(eg,
rituximab, 
ocrelizumab*, 
ofatumumab, 
obinutuzumab*, ocaratuzumab*, veltuzumab*, or any biosimilars of these agents 
[approved or investigational]) (*not approved in Japan)

Anti-BLyS (B lymphocyte stimulator) agents (eg, belimumab, tabalumab*) (*not 
approved in Japan)

Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (eg,
atacicept*, RCT-18*) (*not approved in Japan).
o
Targeted synthetic DMARDs (approved or investigational), specifically:

Janus kinase inhibitors

Other Bruton’s tyrosine kinase (BTK) inhibitors
o
Alkylating agents (eg, chlorambucil*, cyclophosphamide) (*not approved in Japan).
∀The following restrictions on nonbiologic DMARD must be followed, otherwise the subject 
is excluded:
o
Auranofin (Ridaura®), minocycline, penicillamine,
sulfasalazine, cyclosporine, 
mycophenolate
(mycophenolate sodium not approved in Japan), tacrolimus, 
azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP
o
Leflunomide (Arava®) must have been discontinued 12 weeks prior to dosing with the 
IMP if no elimination procedure is followed. Alternately, it should have been 
discontinued with the following elimination procedure at least 4 weeks prior to dosing 
with the IMP: Cholestyramine at a dosage of 8 g 3 times a day for at least 24 hours, or 
activated charcoal at a dosage of 50 g 4 times a day for at least 24 hours.
o
Injectable Gold (aurothioglucose* or aurothiomalate): must have been discontinued for 
8 weeks prior to dosing with the IMP (*not approved in Japan)
o
Anti-malarials (hydroxychloroquine, chloroquine*) will be allowed in this trial. Subjects 
may 
be 
taking 
oral 
hydroxychloroquine 
(≤400 mg/day) 
or 
chloroquine*
(≤250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with 
the IMP, and will need to be continued at that stable dose for the duration of the trial. If 
discontinued prior to this trial, they must have been discontinued for 4 weeks prior to 
dosing with the IMP (*not approved in Japan).
MRI Substudy Subjects:
∀Inability to comply with MRI scanning, including contraindications to MRI such as known 
allergy to gadolinium contrast media, claustrophobia (if the site does not have ability to scan 
extremities only), presence of a pacemaker, cochlear implants, ferromagnetic devices or 
clips, intracranial vascular clips, insulin pumps, and nerve stimulators.
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∀More than 25% of applicable joints of the target hand and wrist having had prior surgery or 
showing maximum Genant-modified Sharp erosion (3.0) or joint-space narrowing (4.0) 
scores, based on single posteroanterior radiographs of target hand and wrist read centrally.
Investigational Medicinal Product: dose/mode of administration/dosing schedule:
Subjects randomized into the trial will receive 1 of 3 doses of evobrutinib (also known as 
M2951) (25 mg once daily, 75 mg once daily, or 50 mg twice daily) or placebo, taken orally.
Reference therapy: dose/mode of administration/dosing schedule:
Not applicable.
Planned trial and treatment duration per subject:
Total duration of subject participation is approximately 5 months (approximately 20 weeks) 
which includes:
∀Screening: 28 days (4 weeks)
∀Treatment: 84 days (12 weeks)
∀Safety Follow-up: 28 days (4 weeks).
Statistical methods:
A sample size of 80 evaluable subjects per group will provide adequate (approximately 90%) 
power to detect a difference in ACR20 response proportion at Week 12 between evobrutinib
and placebo-treated subjects at an α = 0.05 2-sided significance level, assuming a placebo 
response proportion of 30% to 45% and an expected treatment benefit of 30%, after adjusting 
for multiple comparisons of 3 dose comparisons with placebo. For the same range of placebo 
response rate, the sample size of 80 evaluable subjects per group will also provide adequate 
power (approximately 80%) for the expected difference of 25%. To account for reduced
information provided by the Modified Intent-to-Treat (mITT) analysis set, due to subject 
dropout and protocol noncompliance, occurring at a rate of approximately 11% over a 12-week 
period, approximately 90 subjects per group will be enrolled. The study includes a Japanese 
cohort: 32 evaluable Japanese subjects total, increased to 36 randomized Japanese subjects 
total to protect against loss of information.
For the evaluation of MRI data, assuming an effect size of 0.7 for change from Baseline in the 
OMERACT RAMRIS individual scores for osteitis or synovitis at Week 12, at a 2-sided 
α = 0.05, a sample size of 40 evaluable subjects per group with MRI data will provide 
approximately 80% power using the Wilcoxon rank-sum test. To account for approximately 
11% dropout and nonevaluable MRI data, approximately 45 subjects per arm will be enrolled 
in the MRI study.
There is 1 planned analysis from this study. The final analysis will be triggered when 100% of 
subjects randomized complete the safety follow-up or discontinue prematurely from the study, 
the protocol violations are determined, and the database is locked. All data collected up to and 
including the Safety Follow-up Visit will be included in this analysis. A consistency analysis 
is also planned to be performed as part of the final analysis to evaluate the consistency of 
efficacy at Week 12 between the Japan and non-Japan subjects. If the Japanese cohort 
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enrollment is too slow to have n = 32 to 36 evaluable subjects included in the consistency
analysis, then the consistency analysis will not occur.
For the primary and key secondary efficacy analyses, ACR20 (ACR50/ACR70) response rate, 
the estimate of the odds ratio (OR), together with the associated 2-sided 95% CI and p-value, 
comparing each evobrutinib dose group to placebo, is based on a logistic regression model for 
the odds of ACR20 (ACR50/ACR70) response, with evobrutinib dose group or placebo as a 
factor and adjustment for covariates based on randomization strata (region, MRI-substudy 
participation).
The dose response will be assessed via a modeling approach as an additional supportive 
analysis.
Analysis of the change from Baseline scores of the MRI data will be performed on the 
appropriate analysis sets (eg, MRI analysis set for the RAMRIS scores) using a mixed-effect 
model for repeated measures, with treatment arm as factors, and randomization strata, and 
Baseline as covariates.
Analyses of all other secondary endpoints will be exploratory in nature.
Safety data will be listed and summarized using descriptive statistics.
 
 
 
 
 
a 
 
 
 
 
 
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Table 1
Schedule of Assessments – Screening to Safety Follow-up Visit
Activity/Assessment
Screening
Treatment Period
Safety
Follow-upa/End 
of Trial Visit
Trial Visit Number
1a
1b
1c
2
3
4
4a
5
5a
6/End of 
Treatment/Early 
Withdrawal
Trial Week
1
(Baseline)
2
4
6
8
10
12
16
Trial Day
-28 to -1
1
14
28
42
56
70
84
112
Visit Window (Days)
+ 7
± 2
± 2
± 2
± 2
± 2
- 5
+ 5
Informed consent
X
Inclusion/Exclusion criteria
X
Xb
Demographics
X
Medical historyc
X
Physical examination
X
X
X
X
Abbreviated physical 
examination
X
X
X
Vital signsd
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
Chest X-rayf
X
Concomitant medicines and 
proceduresg
X
X
X
X
X
X
X
X
X
Tuberculosis test
X
HIV/Hepatitis B/
Hepatitis C test
X
Reflex testing for HBV DNAh
X
X
X
X
X
MRIi
X
X
X
Posteroanterior radiograph of 
target hand and wristj
X
TSH
X
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Activity/Assessment
Screening
Treatment Period
Safety
Follow-upa/End 
of Trial Visit
Trial Visit Number
1a
1b
1c
2
3
4
4a
5
5a
6/End of 
Treatment/Early 
Withdrawal
Trial Week
1
(Baseline)
2
4
6
8
10
12
16
Trial Day
-28 to -1
1
14
28
42
56
70
84
112
Visit Window (Days)
+ 7
± 2
± 2
± 2
± 2
± 2
- 5
+ 5
Pregnancy test (serum 
β-hCG) and FSHk
X
Highly sensitive urine 
pregnancy test
X
X
X
X
X
Serum β-D-glucanl
X
Randomization
X
Dispense/review/collect 
subject diary
D
R
R
R
R/C
SF-36m
X
X
X
X
FACIT-Fatiguem
X
X
X
X
IMP dispensationo
X
X
X
X
X
IMP administrationp
X
Daily administration of evobrutinib or placebo
IMP complianceq
X
X
X
X
Patient’s Assessment of 
Arthritis Pain VASr,m
X
X
X
X
X
X
Patient’s Global Assessment 
of Disease Activity VASr,m
X
X
X
X
X
X
Tender/Swollen Joint Count 
(68/66 joints)r
X
X
X
X
X
X
Physician’s Global 
Assessment of Disease 
Activity VASr
X
X
X
X
X
X
HAQ-DIr
X
X
X
X
X
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Activity/Assessment
Screening
Treatment Period
Safety
Follow-upa/End 
of Trial Visit
Trial Visit Number
1a
1b
1c
2
3
4
4a
5
5a
6/End of 
Treatment/Early 
Withdrawal
Trial Week
1
(Baseline)
2
4
6
8
10
12
16
Trial Day
-28 to -1
1
14
28
42
56
70
84
112
Visit Window (Days)
+ 7
± 2
± 2
± 2
± 2
± 2
- 5
+ 5
AE evaluations
X
X
X
X
X
X
X
X
X
IgG, IgA, IgM, and IgG 
subclasses
X
X
X
X
X
X
X
Total B cell countst
X
X
X
X
X
X
X
Hematologyv
X
Xu
X
X
X
X
X
Biochemistry
X
Xu
X
X
X
X
X
Coagulation
X
Lipid panelx
X
Urinalysis, Urine Microscopyy
X
X
X
X
hsCRPr
Xz
Xz
X
X
X
X
X
X
ESRr
X
X
B cell subsetst
Xu
X
X
X
Whole blood/T cells, NK cells, 
monocytes, and T cell 
subsetst
Xu
X
Anti-CCP
X
Xu
X
RF
X
X
X
14-3-3!
X
X
Whole blood RNAbb
X
X
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Activity/Assessment
Screening
Treatment Period
Safety
Follow-upa/End 
of Trial Visit
Trial Visit Number
1a
1b
1c
2
3
4
4a
5
5a
6/End of 
Treatment/Early 
Withdrawal
Trial Week
1
(Baseline)
2
4
6
8
10
12
16
Trial Day
-28 to -1
1
14
28
42
56
70
84
112
Visit Window (Days)
+ 7
± 2
± 2
± 2
± 2
± 2
- 5
+ 5
ACR = American College of Rheumatology, AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, β-hCG = beta-human 
chorionic gonadotropin, C = collect, CAT = Computer adaptive testing, CCP = cyclic citrullinated protein, CXR = chest X-ray, D = Dispense, 
DNA = deoxyribonucleic acid, ECG = electrocardiogram, ESR = erythrocyte sedimentation rate, FACIT = Functional Assessment of Chronic Illness Therapy, 
FSH = follicle-stimulating hormone, GGT = γ-Glutamyl-transferase, HAQ-DI = Health Assessment Questionnaire – Disability Index, HBsAg = hepatitis B surface 
antigen, HBV = hepatitis B Virus; HIV = Human Immunodeficiency Virus, 
, hsCRP = high-sensitivity C-reactive protein,
ICF = Informed Consent Form, Ig = immunoglobulin, IMP = investigational medicinal product, LFT = liver function test, MRI = magnetic resonance imaging, 
NK = natural killer, 
, R = review, 
R/C = review/collect, RA = rheumatoid arthritis, RF = rheumatoid factor, RNA = ribonucleic acid, SF-36 = Medical Outcomes Study 36-item Short Form Health 
Survey, TSH = thyroid stimulating hormone, US = United States, VAS = visual analog scale, WOCBP = women of childbearing potential.
a The Safety Follow-up Visit will be performed 28 days (+ 5-day window) after the Week 12/End of Treatment Visit. Subjects who discontinue the IMP or withdraw 
from the trial early will attend the Safety Follow-up Visit according to procedures described in Sections 5.5.1 or 5.5.2, respectively. 
b Subject eligibility to be confirmed on Day 1 prior to randomization. For WOCBP, the highly sensitive urine pregnancy test on Day 1 must be negative prior to 
randomization. 
c Medical history includes documentation of general medical history, RA classification criteria, RA medical history, medications, and surgery/procedures.
d Vital signs including height, weight, oral temperature, seated blood pressure, pulse rate, and respiratory rate will be assessed predose at each indicated visit 
(height measured only at Screening), including the Safety Follow-up Visit.
e At visits where assessment time points coincide with each other, the following procedure should be followed: perform vital signs assessments slightly before the 
specific time point, ECG assessment as close to protocol-specified time as possible, and 
 blood sampling immediately following ECG.
f Subjects who have previously had a normal CXR for clinical reasons within the last 3 months prior to Screening do not need to have the CXR repeated. In 
Germany, only subjects with CXR taken within 3 months of screening with results available and normal will be considered for this study. See Section 7.4.4.3 for 
details.
g Concomitant medications will be recorded at Screening and Day 1, and any changes solicited/recorded at every trial visit, and during any ad hoc telephone 
contacts.
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h For subjects who are negative for HBsAg but are anti-hepatitis B surface antibody positive and/or anti-hepatitis B core antibody positive at Screening, an HBV 
DNA PCR reflex test will be completed at Screening. If the subject is able to enter the study (ie, subject is either HBV DNA-negative OR has detectable HBV DNA 
< 20 IU/mL only), additional HBV DNA PCR testing must be performed (see Exclusion Criterion 17 in Section 5.3.2). 
i For subjects participating in the MRI substudy, MRI of wrist and hand must to be completed within 7 days prior to Day 1 (Baseline), and at the Weeks 4 and 12 
study visit. All other inclusion/exclusion criteria should be verified prior to completing the baseline MRI image (including the second hsCRP test). 
j For subjects participating in the MRI substudy, a posteroanterior radiograph of target hand and wrist must to be completed at least 7 days before the Baseline
MRI. In Germany, only subjects with posteroanterior radiographs taken within 3 months of screening with radiograph available for submission to central reader 
will be considered for this study. All radiographs must be read centrally.
k For women who are postmenopausal, see Appendix I. A sample for FSH must be drawn at Screening to confirm postmenopausal status.
l For Japan only.
o The IMP will be dispensed after randomization on Day 1 and thereafter at each indicated trial visit during the Treatment Period. All remaining IMP will be 
collected at Week 12 for all subjects.
p At the indicated visits, the IMP will be administered during the trial visit after trial visit procedures are completed (other than postdose 
 sampling); 
otherwise, the IMP will be self-administered at a set time each day (± 2 hours).
q At the indicated visits after Day 1, IMP compliance for the intervals since the previous visit will be documented using pill counts.
r These assessments are part of the American College of Rheumatology Core Set of Disease Activity Measures for Rheumatoid Arthritis Clinical Trials 
(Felson 1993), commonly referred to as the ACR Core Set (see Sections 7.3.1 and 7.3.2).
s Any AEs occurring during the Screening Period (for subjects who have signed the ICF) will be recorded, and AEs will be solicited/recorded at all remaining trial 
visits and during any ad hoc contacts (eg, telephone calls).
t For visits including subsets, flow cytometry will be performed on the same sample for counts of: total T cell, total B cell, total NK cell, monocytes, B cell subsets, 
and T cell subsets – total B cells will not be counted separately (see Section 7.6.1). For visits where only total B cell counts are being performed, flow cytometry 
for the other cell types and subsets, including B-cell subsets, will not be performed.
u Blood samples on Day 1 are to be collected predose for hematology, chemistry, coagulation (partial thromboplastin time and international normalized ratio), 
hsCRP, ESR, samples for exploratory 
, anti-CCP and RF are to be collected predose on Day 1. See Table 10 for detailed assessments.
v Hemoglobin A1C evaluated only for subjects with a diagnosis of diabetes; only at Screening.
x Lipid panel includes HDL-C, LDL-C, total cholesterol, and triglycerides (see Table 10). Subjects are required to fast for a minimum of 8 hours prior to lipid panel.
y Microscopy will be performed if urinalysis results are abnormal for blood, protein, or nitrite.
z During the Screening Period, two hsCRP level measurements must be obtained and both results must meet the inclusion criterion in the study (see 
Section 5.3.1). The second hsCRP must be collected: a) at least 7 days after the initial screening hsCRP and b) at least 7 days prior to randomization or baseline 
MRI (for subjects in the MRI substudy), and c) no more than 14 days prior to randomization (21 days for MRI sites that are not able to transfer X-rays 
electronically) or baseline MRI (for subjects in the MRI substudy).
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2
Sponsor, Investigators and Trial Administrative Structure
This clinical trial will be sponsored by:
∀EMD Serono Research & Development Institute, Inc., Billerica, Massachusetts, USA, in the 
USA.
∀Merck Serono Co., Ltd., (Affiliate of Merck KGaA, Darmstadt, Germany) in Japan.
∀Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany in countries outside the USA
and Japan.
Study Organization in Japan: Refer to Study Organization in Japan in supporting documentation 
for additional information.
The trial will be conducted at approximately 160 sites in the USA (15 sites), Europe, South 
America, Africa, and Japan. The Coordinating Investigator,
 
, represents all Investigators for decisions and discussions regarding 
this trial, consistent with the International Council for Harmonisation (ICH) Topic E6 Good 
Clinical Practice (GCP; hereafter referred to as ICH GCP). The Coordinating Investigator will
provide expert medical input and advice relating to trial design and execution and is responsible 
for the review and signoff of the clinical trial report (CTR).
Trial Sites in Japan: Refer to the Trial Sites in Japan supporting documentation.
An Independent Data Monitoring Committee (IDMC) will be established to continually review 
available data and safeguard the interests of trial subjects. The IDMC will be composed of a 
minimum of 3 members who do not have any conflicts of interest with the trial Sponsor, and are 
not Investigators for this study, or any other study of evobrutinib in rheumatoid arthritis, including 
2 clinicians and a biostatistician. The full membership, mandate, and processes of the IDMC will 
be detailed in the IDMC Charter. 
In addition, the trial will be advised and monitored by a Study Steering Committee, chaired by the 
Coordinating Investigator and comprised of, at minimum, 3-5 Study Investigators, the Clinical 
Program Lead, and the Medical Responsible. Recommended optional members of the Study 
Steering Committee include the Study Statistician and the Operational Lead from the contract 
research organization (CRO). Signature pages for the Protocol Lead and the Coordinating 
Investigator as well as a list of Sponsor responsible persons are provided in Appendix III.
The trial will appear in the following clinical trial registries: clinicaltrials.gov and 
www.clinicaltrialsregister.eu.
The Sponsor will enlist the support of 
, a CRO, to conduct the clinical part of the trial 
including trial set-up, coordination, monitoring, medical oversight, data capture, data management, 
statistical analysis, and clinical trial reporting. 
, 
will undertake operational aspects in Japan. The Sponsor will also make use of the CRO’s central 
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laboratory for sample analyses, storage, and shipment to specialized bioanalytical laboratories. 
The Sponsor will supervise all outsourced activities.
The investigational medicinal product (IMP) will be supplied by the Clinical Trial Supply 
Department of the Sponsor, and packaged, labeled and distributed by a designated contract 
manufacturing organization. 
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader.
3
Background Information
3.1
Rheumatoid Arthritis
Conventional rheumatoid arthritis (RA) therapy consists of treatment with nonsteroidal 
anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying anti-rheumatic drugs 
(DMARD). Methotrexate (MTX) represents one of the most widely used DMARD for RA, yet 
less than half of patients with RA show substantial and sustained clinical improvement in disease 
signs and symptoms (Blumberg 2001).
The emergence of biologic therapies for RA, such as tumor necrosis factor (TNF)-α inhibitors, 
represent treatment options that mitigate the clinical manifestations of RA by selectively targeting 
key inflammatory mediators. Approximately 30% of patients with RA, usually those with more 
severe disease, will not experience satisfactory clinical improvement with use of currently 
available therapies (Rindfleisch 2005). Patients with RA prefer the oral route of administration, 
with some refusing injected therapies, despite the benefit (Louder 2016). Janus kinase (JAK) 
inhibitors are efficacious, but are associated with adverse reactions including increased risk of 
infections and malignancies, which cause concern (Nakayamada 2016). Accordingly, a significant 
unmet need remains for more effective treatments for RA.
3.2
Evobrutinib
Evobrutinib (also known as M2951) is a novel inhibitor of Bruton’s tyrosine kinase (BTK). 
Ibrutinib, the only approved molecule in this class, is used in the treatment of hematological 
malignancies. Several BTK inhibitors have been evaluated in preclinical models of RA, with some 
of these advancing to clinical development for treatment of RA (Akinleye 2013, Norman 2016, 
Whang 2014). Evobrutinib is being developed for the treatment of RA due to the known role of 
B cells and autoantibodies in RA. As inhibition of BTK has been shown to inhibit key B cell
functions (eg, antigen presentation, proliferation, differentiation and cytokine production), and has 
also been shown to inhibit signaling via autoantibody/antigen engagement of the Fc receptor on 
non-B cells—all factors felt to contribute to RA disease biology—blockade of BTK is expected to 
provide clinical benefit to patients with RA. The expectation that BTK inhibition will be beneficial 
in RA is supported by recently reported data showing clinical efficacy in a small, early clinical 
trial of another BTK inhibitor, CC-292 (Kivitz 2016). As BTK inhibition is a different mechanism 
of action than currently available treatments for RA, the expectation is that treatment with 
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evobrutinib will help patients that are not responsive to current therapies. Additionally, as 
evobrutinib is a highly selective BTK inhibitor, it may have a more favorable safety profile than 
ibrutinib.
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Refer to the Investigator’s Brochure (IB) for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, the 
Japanese ministerial ordinance on GCP (for Japan only), and any additional applicable regulatory 
requirements.
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Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable. 
3.4
Risk/Benefit
No identified risks or new potential risks have emerged from the completed 
Studies EMR200527-001 
or 
MS200527-0019 
in 
healthy 
volunteers
or 
SLE 
Study EMR200527-002. No new safety signals have been confirmed from ongoing Study 
MS200527-0081 as of an IDMC data review meeting on 24 October 2017.
Important potential risks to subjects are based on nonclinical safety data of evobrutinib and clinical 
data on adverse drug effects associated with compounds of a similar pharmacological class. They 
include infection, leukopenia, thrombocytopenia, hemorrhage, gastrointestinal intolerance, renal 
toxicity, hepatocellular injury, atrial fibrillation, and embryo-fetal toxicity. The potential risk of 
infection relates to the immunomodulatory actions of evobrutinib. Women of childbearing 
potential participating in clinical studies with evobrutinib must agree to adhere to the use of highly 
effective contraception as specified in the clinical study protocol. 
 
 
 
Risk minimization measures routinely implemented in early phase clinical trials, including 
exclusion criteria for hematological cytopenias and stopping rules based on grade changes in 
specific laboratory parameters, are considered adequate for planned clinical trials in patients with 
autoimmune diseases. No additional risk minimization measures are proposed.
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Taking the above information into account, benefit-risk considerations support the proposed 
clinical trial of evobrutinib in patients with RA.
For the Japanese population, a Phase I trial (MS200527-0017) has been conducted to evaluate 
safety, pharmacokinetics (PK), and pharmacodynamics (PD) of evobrutinib as a bridging trial
between Japanese and non-Japanese healthy subjects.
Refer to the Investigator’s Brochure for more details of each trial.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, the 
Japanese ministerial ordinance on GCP (for Japan only), and any additional applicable regulatory 
requirements.
4
Trial Objectives
4.1
Primary Objective
The primary objective is:
∀To evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib compared 
with placebo in subjects with rheumatoid arthritis (RA) with inadequate response to 
methotrexate (MTX-IR) on stable MTX therapy by assessment of the signs and symptoms of 
RA, as measured by American College of Rheumatology (ACR) 20% (ACR20) response 
assessed using high-sensitivity C-reactive protein (hsCRP) at Week 12.
4.2
Key Secondary Objective
The key secondary objectives are:
∀To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib
in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms 
of RA, as measured by DAS28-hsCRP low disease activity (DAS28 < 3.2) rate at Week 12 
∀To further evaluate the efficacy of 12 weeks of treatment with evobrutinib compared to placebo 
in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms 
of RA, as measured by DAS28-hsCRP remission (DAS28 < 2.6) rate at Week 12 
∀To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib
in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms 
of RA, as measured by ACR50 and ACR70 at Week 12 
∀To evaluate the safety of evobrutinib in MTX-IR subjects with RA on stable MTX therapy.
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4.3
Other Secondary Objectives
The other secondary objectives are:
∀To further evaluate the efficacy of evobrutinib on the signs and symptoms of RA with 
inadequate response to MTX
∀To evaluate the effect of evobrutinib on joint structures and inflammation, at Weeks 4 and 12 
in the MRI substudy, as assessed by magnetic resonance imaging (MRI)
∀To evaluate the effect of evobrutinib on physical function in RA subjects
∀To evaluate the effect of evobrutinib on subject-reported health-related quality of life (HRQoL)
∀To evaluate the effect of evobrutinib on subject-reported fatigue (using Functional Assessment 
of Chronic Illness Therapy [FACIT]-Fatigue).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase IIb, multicenter, international, randomized, double-blind, placebo-controlled 
parallel-arm trial, designed to determine the efficacy, dose response, and safety of evobrutinib in 
subjects with RA, and to consider a dose to take forward into Phase III development. 
Approximately 360 total subjects 18 to 75 years of age with RA planned to be randomized (to 
obtain 320 evaluable subjects). The study includes a Japanese cohort (approximately 36 Japanese 
subjects). This trial will be conducted at approximately 160 sites across 17 countries. Schematic 
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presentations of the trial design are presented in Figure 1. A detailed schedule of trial 
procedures/assessments is provided in Table 1. Details of the study population are presented in 
Table 2.
Table 2
Trial Study Population
Diagnosis:
Moderate to severe RA
Methotrexate Therapy:
MTX-IR, on a stable dose of methotrexate
Prior exposure to bDMARD? 
(eg, TNF antagonists, IL-6 
antagonists, anakinraa, 
abatacept, rituximab, etc.)
No prior exposure to approved or investigational bDMARD allowed.
Prior exposure to 
tsDMARD? (eg, JAK 
inhibitors, BTK inhibitors)
No prior treatment with investigational or approved tsDMARD(s) allowed.
bDMARD = biologic disease-modifying anti-rheumatic drug, BTK = Bruton’s tyrosine kinase, IL = interleukin, 
JAK = Janus kinase, MTX-IR = inadequate response to methotrexate, RA = rheumatoid arthritis, TNF = tumor 
necrosis factor, tsDMARD = targeted synthetic disease-modifying anti-rheumatic drug.
a
Not approved in Japan.
Approximately 50% of subjects will participate in a substudy using magnetic resonance imaging 
(MRI) to evaluate the ability of evobrutinib to prevent the progression of joint structural damage. 
These subjects will have hand and wrist MRI images and X-rays at the times indicated in the 
Schedule of Assessments (Table 1).
Treatment Sequences
Eligible subjects will be randomly assigned in a 1:1:1:1 ratio to 1 of the 4 parallel treatment groups
(N = 90/group), as detailed in Table 3, in combination with their stable background MTX therapy. 
Subjects and Investigators will be blinded to the initial treatment assignment.
Table 3
Treatment Groups and Regimens
Treatment Group
Regimena,b
1
Evobrutinib 25 mg QD
2
Evobrutinib 75 mg QD
3
Evobrutinib 50 mg BID
4
Placebo
MTX = methotrexate.
a All subjects will continue to take their MTX background therapy along with trial treatment per treatment group. 
b To maintain the study blind, all subjects will receive BID treatment. For subjects with QD treatment assignments, 
1 dose a day will be study drug and 1 will be placebo.
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Trial Duration
Total duration of subject participation is approximately 5 months (approximately 20 weeks), 
which includes:
∀Screening: 28 days (4 weeks)
∀Treatment: 84 days (12 weeks)
∀Safety Follow-up: 28 days (4 weeks).
The trial will be conducted on an outpatient basis. Subjects will attend clinic visits at regular 
intervals as indicated in the Schedule of Assessments (Table 1).
Screening Period
The first visit will be a Screening Visit and will include a review of the inclusion/exclusion criteria 
(see Section 5.3). Subjects should undergo the Day 1 visit as soon as possible after eligibility for 
the trial has been confirmed. Subjects who do not meet all inclusion criteria or meet one or more 
of the exclusion criteria within the first Screening Period and are considered screen failures. If 
inclusion/exclusion criteria are not met at the end of the 28-day Screening Period (+ 7-day 
window), either the initial Screening Period or the single Rescreening Period, based on the results 
of the repeated tests, the subject should be considered a screen failure and not be enrolled in the 
study.
Rescreening:
Subjects who are considered screen failures after a first Screening Period may undergo rescreening 
once, after approval by the Medical Monitor (see Section 5.3). If a subject is rescreened, all 
screening tests will need to be repeated except as follows:
a.
Documented chest X-ray (CXR), hand and wrist X-ray if applicable, and TB testing must have 
occurred within 3 months of the initial rescreening visit, or need to be repeated during the 
Rescreening Period.
b. Hepatitis and Human Immunodeficiency Virus (HIV) testing must have occurred within 
1 month of the initial rescreening visit, or need to be repeated during the Rescreening Period.
Retesting:
During the initial Screening Period, or single Rescreening Period, testing may be repeated for 
subjects if test results, would preclude enrollment in the study, and are thought to represent a 
laboratory error or a reversible, clinically insignificant intermittent condition, or are inconsistent 
with the subject’s historical values (see Inclusion Criteria 12 and 13 for specifics regarding 
tuberculosis [TB] testing), after discussion with the Medical Monitor. When a test needs to be 
repeated during the Screening Period, the Screening Period can be extended to 8 weeks after 
discussion with the Medical Monitor. 
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In addition, if the initial MRI quality check at Screening indicates a repeat MRI is necessary, the 
Screening Period may be extended up to 7 days after discussion with the Medical Monitor. 
Treatment Period (Double-blind Placebo-controlled)
The duration of the Treatment Period will be 12 weeks starting at randomization (Day 1). The 
Day 1 visit will be considered the Baseline for disease activity assessments (eg, ACR20/50/70, 
ACR hybrid, Disease Activity Score Based on a 28 Joint Count [DAS28], Clinical Disease Activity 
Index [CDAI], Simplified Disease Activity Index [SDAI]). Subject eligibility and a negative 
pregnancy test (if applicable) must be reviewed on Day 1 prior to randomization, and the first dose 
of IMP will be given while the subject is still on site for Day 1. Subjects must then return to the 
site for trial visits as indicated in the Schedule of Assessments Table 1.
Treatment decisions will be made by Investigator assessment for the purpose of subject 
management. 
Any subjects permanently withdrawn from IMP will be expected to complete the End of 
Treatment/Early Withdrawal Visit within 5 days of IMP withdrawal, followed by the 
Safety Follow-up Visit.
Safety Follow-up Period
Subjects will enter the Safety Follow-up Period after the Week 12/End of Treatment Visit. For 
subjects who discontinue the Treatment Period (discontinue IMP) during the main study, an End 
of Treatment/Early Withdrawal Visit should occur with the subject then entering the Safety 
Follow-up Period. The Safety Follow-up Visit/End of Trial visit is scheduled 28 days (+ 5-day 
window) after the End of Treatment/Early Withdrawal Visit.
Assessment of Endpoints
During the trial, clinical efficacy endpoints will be evaluated using several assessments, such as 
the ACR20/50/70, hybrid ACR, DAS28, CDAI, SDAI, and others. Efficacy in terms of prevention 
of joint structural damage progression will be assessed using MRI, scored using the Outcome 
Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic 
Resonance Imaging Scoring System (RAMRIS) and other MRI scoring systems. Efficacy in terms 
of physical function will be assessed using the Health Assessment Questionnaire – Disability Index 
(HAQ-DI). Effects of treatment on HRQoL will be examined using subject-reported outcome
measures including but not limited to: Medical Outcomes Study 36-item Short Form Health Survey 
(SF-36v2) and FACIT-Fatigue. 
Safety will be evaluated through the nature, occurrence, severity, and outcome of adverse events 
(AEs), and assessment of physical examination findings, ECGs, hematology and chemistry
laboratory assessments, vital signs, and absolute values and change from Baseline in serum 
immunoglobulin (Ig) levels (IgA, IgG, IgM, and IgG subclasses) and total B cell counts.
Statistical Methods
Statistical methods including sample size justification are provided in Section 8.
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Figure 1
Schematic of the Trial Design – Screening to Safety Follow-up Visit
ACR = American College of Rheumatology, ACR20 = ACR 20% Response Criteria, %ACR20-CRP = Proportion of 
subjects achieving an ACR20 response, where the acute phase reactant criterion is based on hsCRP, D1 = Day 1, 
MTX-IR = RA subjects with inadequate response to methotrexate, PO = Orally, RA = rheumatoid arthritis, SFU = 
Safety Follow-up Visit.
5.2
Discussion of Trial Design
5.2.1
Scientific Rationale for the Trial
The proposed Phase IIb trial design is based on experience with evobrutinib in the Phase IIa trial
for RA (MS200527-0081), studies of other treatments for RA, consensus guidelines for treatment 
of RA (refer to American College of Rheumatology Guideline for the Treatment of Rheumatoid 
Arthritis [2015]), Food and Drug Administration (FDA) draft guidance (refer to FDA Guidance 
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for Rheumatoid Arthritis: Developing Drug Products for Treatment [2013]), and European 
Medicines Agency (EMA) draft guidance (refer to EMA Evaluation of Medicines for Human Use: 
Points to Consider on Clinical Investigation of Medicinal Products Other Than NSAIDs for 
Treatment of Rheumatoid Arthritis [2015]).
Study Population
The proposed trial will evaluate RA subjects with inadequate response to MTX and no prior 
treatment with biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD [eg, JAK 
inhibitors, BTK inhibitors]), which we will refer to as the MTX-IR population. Subjects will be 
randomized to 1 of 3 doses of evobrutinib or placebo.
The MTX-IR population represents a well characterized segment of the total population of 
individuals with RA, and is one of the populations in which efficacy must be evaluated to obtain 
approval in the EU per EMA guidance.
Beyond assessing efficacy on clinical endpoints (eg, ACR20 response at 12 weeks, DAS28, ACR 
core set measures, ACR-EULAR remission), efficacy will also be assessed on physical function 
(HAQ-DI), pain (VAS), fatigue (FACIT-Fatigue), and HRQoL (SF-36), as these patient-reported 
concepts are relevant in patients’ lives and treatment is expected to impact these variables. Efficacy 
in preventing structural damage progression will be assessed using MRI in the MRI substudy.
Other than the inclusion/exclusion criteria for MRI substudy eligibility, participation in the MRI 
substudy is purely random, based on MRI availability at a particular site.
Endpoint Selection
The primary endpoint, ACR20 response at Week 12, is in accordance with FDA and EMA
regulatory guidance documents for dose-ranging studies in RA. Clinical response will also be 
assessed using ACR50 response and ACR 70 response, as well as measures of low disease activity 
(LDA [eg, DAS28-CRP < 2.6]) and remission (eg, ACR/European League Against Rheumatism 
[EULAR] remission). Physical function will be assessed using HAQ-DI. Prevention of structural 
damage progression will be assessed using MRI at Weeks 4 and 12 in the MRI substudy.
Dose Range Finding
As all agents approved since the introduction of TNF antagonists in RA have used the same doses 
in patient populations with inadequate response to either MTX (MTX-IR) or to MTX and at least 
one bDMARD (bDMARD-IR), we will study the efficacy of evobrutinib with 3 doses in the 
MTX-IR to allow the assessment of dose response in this population, and will plan to evaluate the 
dose(s) identified on the basis of this study for subsequent development in all of the RA 
subpopulations to be studied (MTX-IR, bDMARD-IR, DMARD-naïve).
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Stratification Factors at Randomization
Subjects will be stratified by whether or not they are in the MRI substudy and by region to account 
for the impact on study outcomes of these factors.
Use of Magnetic Resonance Imaging to Evaluate Joint Structural Damage Progression
Classically, joint structural damage in RA has been evaluated with radiographic methods, such as 
the modified Total Sharp Score (mTSS) (van der Heijde 2000). However, these methods are 
insensitive to early changes, requiring either 1- and 2-year study durations or large studies of 
shorter duration enriched for patients with documented erosions at Baseline, to assess the ability 
of an agent to prevent progression of joint structural damage. Due to these limitations, OMERACT 
developed the RAMRIS, which evaluates wrist and hand MRI images and scores them for erosions, 
synovitis, tenosynovitis, and osteitis (Ostergaard 2004, Ostergaard 2017). Unlike the mTSS, the 
OMERACT RAMRIS scores have been shown to be sensitive to changes as early as 12 weeks, 
and these changes predict radiographic progression as measured by the mTSS (Baker 2014, 
Baker 2016, Conaghan 2016, Genovese 2016b). Further, these changes have been shown to predict 
efficacy in longer studies using the mTSS. A validated 9-point scale for the assessment of cartilage 
loss (CARLOS) (Peterfy 2012) will also be used.
In the proposed trial, approximately 50% of the subjects will be evaluated using MRI to assess 
treatment effect on the MRI scores at 4 and 12 weeks when compared to Baseline, which we refer 
to as the MRI substudy. Barring subjects with contraindications to MRI imaging (eg, allergy to 
MRI contrast, presence of a non-MRI compatible metal medical device or foreign body), 
participation in the MRI substudy will be required for enrollment at MRI capable sites, in order to 
avoid selection bias. To ensure an adequate sample size in the MRI substudy, enrollment of 
non-MRI subjects may be capped. As the non-MRI subjects are projected to be recruited faster 
than the MRI subjects, capping recruitment of MRI subjects is unlikely to be required. However, 
if during the course of the study, it appears that MRI subjects will reach 45/arm in advance of the 
non-MRI subjects reaching 45/arm, we may limit enrollment of further MRI subjects to prevent 
over enrollment in the MRI substudy.
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5.2.3
Rationale for Endpoints
5.2.3.1
Primary Efficacy Endpoints
The ACR20 response at Week 12 is the primary efficacy endpoint.
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The endpoints and schedule for the efficacy assessments reflect the most updated FDA regulatory 
guidance and evidence-based recommendations for this indication. As the placebo-controlled 
period is limited to the first 12 weeks of the trial, due to ethical concerns regarding longer use of 
placebo in subjects given the availability of other approved, effective therapies (bDMARD and 
tsDMARD) for the MTX-IR population, the primary endpoint, ACR20, is assessed at 12 weeks 
(American College of Rheumatology Clinical Trial Priorities and Design Conference 2010, 
Boers 2009).
Efficacy in RA as evaluated in clinical trials is measured using the American College of 
Rheumatology Core Set of Disease Activity Measures for Rheumatoid Arthritis Clinical Trials 
(Felson 1993), commonly referred to as the ACR Core Set. The ACR Core Set consists of:
1. Swollen Joint Count (of 66 joints assessed)
2. Tender Joint Count (of 68 joints assessed)
3. Physician’s Global Assessment of RA Disease Activity (generally assessed using a visual 
analog scale [VAS])
4. Acute Phase Reactant – erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
5. Physical function (as assessed using the HAQ-DI or other validated instrument)
6. Pain (as assessed using the Patient’s Assessment of Arthritis Pain VAS)
7. Patient’s Global Assessment of RA Disease Activity
The definition of an ACR20 response, and many other assessments in RA (eg, ACR50, ACR70, 
CDAI, SDAI, DAS28, EULAR Responder Index), are calculated from evaluation of the ACR Core 
Set. Criteria for remission and LDA are also assessed using items from the ACR Core Set or indices 
derived thereof (eg, ACR/EULAR remission criteria, CDAI ≤3.3, DAS28 ≤3.2, SDAI ≤3.3).
ACR20 – An ACR20 response, the most extensively used criterion for response in RA, is defined 
as an improvement of at least 20% in the number of tender joints and swollen joints, and at least 
20% improvement in 3 out of the remaining 5 ACR core-set measures (patient pain, patient and 
physician’s global assessment, physical function, acute phase reactants). ACR20 is the 
FDA-recommended efficacy endpoint for dose-ranging studies in RA in the FDA guidance, and is 
in line with EMA guidance for dose-ranging studies in RA. In this trial, the acute phase reactant 
for assessing ACR20 response for the primary endpoint is the high-sensitivity C-reactive protein 
(hsCRP).
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5.2.3.2
Secondary Endpoints
5.2.3.2.1
Key Secondary Endpoints
5.2.3.2.1.1
Efficacy
DAS28-hsCRP low disease activity (DAS28 < 3.2) rate, DAS28-hsCRP remission (DAS28 < 2.6) 
rate, and ACR50 and ACR70 responses at Week 12 are the key secondary efficacy endpoints.
DAS28 – The DAS28 is a composite score derived from 4 measures (Aletaha 2008, 
Vander Cruyssen 2005). The components of DAS28 are:
∀The number of swollen joints (out of the 28)
∀The number of tender joints (out of the 28)
∀Erythrocyte sedimentation rate or hsCRP
∀Patient’s Global Assessment of Disease Activity (0-10 scale).
In this study, DAS28-hsCRP will be used for determination of any endpoint that includes the 
DAS28 (eg, DAS28 remission, DAS28 LDA). DAS28-hsCRP is computed as follows, with hsCRP 
expressed in units of mg/L:
DAS28-hsCRP = 0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.36 × ln(hsCRP +1) + 0.014 × GH + 0.96
Thresholds for disease severity grading, including remission, have been established for the DAS28 
and other composite disease activity measures used in the assessment of RA (Anderson 2012), and 
are presented in Table 5 for the DAS28, CDAI, and SDAI.
Table 5
Disease Activity Cutoffs for Select American College of Rheumatology -
Recommended Disease Activity Measures
Disease Activity 
Measure
Scale
Remission
Low/Minimal
Moderate
High/Severe
CDAI
0 – 76
≤2.8
> 2.8 to ≤10.0
> 10.0 to 
≤22.0
> 22.0
DAS28 (
 or CRP)
0 – 9.4
< 2.6
≥2.6 to < 3.2
≥3.2 to ≤5.1
> 5.1
SDAI
0 – 86
≤3.3
> 3.3 to ≤11.0
> 11 to ≤26
> 26
Source: Anderson 2012.
CDAI = Clinical Disease Activity Index, CRP = C-reactive protein, DAS28 = Disease Activity Score with 28-Joint 
Counts, ESR = erythrocyte sedimentation rate, SDAI = Simplified Disease Activity Index.
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A change of 1.2 (twice the measurement error) is defined as a significant change of the disease 
activity state (Prevoo 1995). Yet, a change of 0.6 may be already considered as a clinically 
meaningful variation in the context of defining response to therapy: indeed DAS28 is the core 
element of the EULAR response criteria. It is validated for use in clinical research and it is 
extensively used in clinical practice as well (den Broeder 2002). DAS28 remission and 
DAS28 LDA are also being assessed as secondary endpoints.
ACR50, ACR70 – These are defined as an improvement of at least 50% and 70%, respectively, 
in the number of tender joints and swollen joints, and at least 50% and 70% improvement in 3 out 
of the remaining 5 ACR core-set measures (patient pain, patient and physician’s global assessment, 
physical function, and acute phase reactants). In this trial, the acute phase reactant for assessing 
ACR50 and ACR70 responses is the hsCRP.
5.2.3.2.1.2
Safety
The nature, severity, and occurrence of AEs and SAEs
Absolute values and change from Baseline in:
∀Vital signs
∀ECG parameters including RR interval, PR interval, QRS duration, QT interval, and QTcF 
interval
∀Serum Ig levels (IgG, IgA, IgM)
∀Total B cell counts
∀Clinical laboratory parameters.
5.2.3.2.2
Other Secondary Endpoints
5.2.3.2.2.1
Efficacy Endpoints
ACR Hybrid - The ACR hybrid score was developed to provide a quasi-continuous score that can 
detect smaller changes between treatments than the categorical ACR20/50/70 scores by combining 
the continuous score of the mean improvement in the core set measures combining the ACR20, 
ACR50, and ACR70 scores with the mean percent change from Baseline in all 7 ACR response 
core set components (Felson 2007, American College of Rheumatology Clinical Trial Priorities 
and Design Conference 2010, van Vollenhoven 2011). ACR hybrid, along with the DAS28, is 
recommended by the FDA regulatory guidance as a way to support dose-response assessment. It 
is calculated according to Table 6 (Felson 2007).
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Table 6
Scoring Method for the Hybrid American College of Rheumatology 
Response Measure
ACR Status
Mean % Change in Core Set Measures
< 20
≥20, < 50
≥50, < 70
≥70
Not ACR20
Mean % change
19.99
19.99
19.99
ACR20 but not ACR50
20
Mean % change
49.99
49.99
ACR50 but not ACR70
50
50
Mean % change
69.99
ACR70
70
70
70
Mean % change
Source: Felson 2007.
ACR = American College of Rheumatology, ACR20 = American College of Rheumatology 20% Response Criteria, 
ACR50 = American College of Rheumatology 50% Response Criteria, ACR70 = American College of Rheumatology 
70% Response Criteria.
Note: 1) Calculate the average percentage change in core set measures. For each core set measure, subtract score 
after treatment from Baseline score and determine percentage improvement in each measure. Next, if a core set 
measure worsened by > 100%, limit that percentage change to 100% (a - 100% bound). Then average the 
percentage changes for all core set measures. 2) Determine whether the subject has achieved ACR20, ACR50, or 
ACR70. 3) Using the table above, obtain the Hybrid ACR response measure. To use the table, take the ACR20, 
ACR50, or ACR70 status of the subject (left column) and the mean percentage improvement in core set items; the 
Hybrid ACR score is where they intersect in the table.
DAS28 – as described above.
EULAR Responses – Assessments of subjects with RA by EULAR response criteria will be used 
to categorize subjects as having had no response, moderate response, good response, or any 
response (moderate + good responders) according to Table 7 (van Gestel 1998).
Table 7
Categorization of Subject Responses as No Response, Moderate 
Response, or Good Response Based on EULAR Response Criteria
Post-baseline Level of 
DAS28
Improvement Since Baseline in DAS28
> 1.2
≤1.2 and > 0.6
≤0.6
DAS28 ≤3.2
Good response
3.2 < DAS28 ≤5.1
Moderate response
DAS28 > 5.1
No response
Source: van Gestel 1996 and van Gestel 1998.
DAS28 = Disease Activity Score modified to include the 28 diarthrodial joint count.
SDAI – The SDAI is the numerical sum of 5 outcome parameters: tender and swollen joint count 
(based on a 28-joint assessment), the Patient’s and the Physician’s Global Assessments of disease 
activity (0–10 cm VAS), and level of CRP (expressed in units of mg/dL). The SDAI is a valid and 
sensitive assessment of disease activity (Aletaha 2005, Smolen 2014) and treatment response that 
is comparable with the DAS28 and ACR response criteria; it is easy to calculate and therefore a 
viable tool for day-to-day clinical assessment of RA treatment (Fransen 2005, Smolen 2014). The 
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ACR/EULAR 2011 Index-based definition of remission is based on SDAI (SDAI ≤3.3), and is 
being assessed as a secondary endpoint (Felson 2011, Smolen 2014).
CDAI – The CDAI is a composite index (without acute-phase reactant) for assessing disease 
activity. CDAI is based on the simple summation of the count of swollen and tender joint counts 
of 28 joints along with the Patient’s and Physician’s Global Assessments (0–10 cm VAS) for 
estimating disease activity. The greater advantage associated with CDAI is its potential to be 
employed in evaluation of subjects with RA consistently with close frequency and independently 
of any calculating device; therefore, it can essentially be used everywhere and anytime for disease 
activity assessment in subjects with RA (Aletaha 2005, Smolen 2014). Thresholds for disease 
severity grading are included in Anderson (Anderson 2012). Remission based on CDAI is also 
being assessed as a secondary endpoint.
EULAR/ACR Boolean Remission – Following the Boolean-based definition of remission of 
ACR/EULAR, at any time point, a subject must satisfy all of the following: tender joint count 
(TJC) ≤1, swollen joint count (SJC) ≤1, CRP ≤1 mg/dL and Patient’s Global Assessment ≤1 (on 
a 0–10 scale). The Patient’s Global Assessment must be elicited as follows: “Considering all of 
the ways your arthritis has affected you, how do you feel your arthritis is today? (0–10, where 
0 = very well and 10 = very poorly)”. The Boolean criteria appear more stringent than the DAS28 
remission and have been specifically created for use in clinical trials (Bykerk 2012, Felson 2011).
5.2.3.2.2.2
Physical Function
HAQ-DI – The HAQ-DI is a validated tool for the evaluation of physical function. There are 
8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are 2 or 
3 questions for each section. Scoring within each section is from 0 (without any difficulty) to 3 
(unable to do). For each section, the score given to that section is the worst score within the section, 
ie, if 1 question is scored 1 and another 2, then the score for the section is 2. In addition, if an aid 
or device is used or if help is required from another individual, then the minimum score for that 
section is 2. If the section score is already 2 or more then no modification is made. The 8 scores of 
the 8 sections are summed and divided by 8. The result is the DI or FDI, the disability index or 
functional disability index (Emery 2011). The HAQ-DI has been validated for use in RA over 
3 decades (Bruce 2003).
5.2.3.2.2.3
Quality of Life
Medical Outcomes Study 36-item Short-Form Health Survey – The SF-36 is a validated 
36-item, subject-reported indication of overall health status not specific to any age, disease, or 
treatment group (Ware 1992). The SF-36 has been extensively studied in RA, and a significant 
association has been shown between the physical functioning score of the SF-36 and the HAQ-DI 
score, as well as with other measures of disease activity and severity, and comorbidities 
(Fries 1980). 
The SF-36 includes multi-item scales
measuring each of the following 8 health 
concepts: (1) physical functioning; (2) role limitations because of physical health problems; 
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(3) bodily pain; (4) social functioning; (5) general mental health (psychological distress and 
psychological wellbeing); (6) role limitations because of emotional problems; (7) vitality 
(energy/fatigue); and (8) general health perceptions. These are summarized in two summary 
measures of physical and mental health: the Physical Component Summary and Mental 
Component Summary.
Questions in the standard version of the SF-36 refer to a 4-week time period. Scales are scored 
according to the Likert method. Lower scores equate to higher disability and higher scores equate 
to lower disability.
Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue – FACIT-Fatigue is a 
13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and 
function (Wolfe 1996). It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 
2 = somewhat; 3 = quite a bit; 4 = very much). As each of the 13 items of the FACIT-Fatigue scale 
ranges from 0–4, the range of possible scores is 0–52, with 0 being the worst possible score and 
52 the best. To obtain the 0–52 score, each negatively worded item response is recoded so that 0 is 
a bad response and 4 is good response. All responses are added with equal weight to obtain the 
total score.
5.2.3.2.2.4
Prevention of Joint Structural Damage Progression
Rheumatoid Arthritis MRI Scoring System Scores – Images of the MRI-designated hand and 
wrist (the hand being used in the MRI assessments) will be acquired using an MRI scanner as 
specified in the imaging guidelines. OMERACT RAMRIS scores for synovitis, tenosynovitis, 
bone marrow edema (osteitis), and erosions (Ostergaard 2004, Ostergaard 2017) will be read 
centrally by 2 independent readers, who are blinded to treatment and dose assignment and to 
chronology of each time point. Discrepancies in RAMRIS scores between the 2 readers will be 
reviewed at a consensus adjudication session with both readers to reach a consensus score for the 
designated cases. At a minimum, the images with the top 10% discrepancies in scores between the 
2 readers will be reviewed (refer to Imaging Guidelines for details of Adjudication and Selection 
of Cases for Adjudication). Unlike conventional radiography scored using the mTSS, which is 
generally sensitive to changes in joint structure over 52 weeks or more, the OMERACT RAMRIS 
scores have been shown to be sensitive to changes as early as 12 weeks, and these changes predict 
radiographic progression as measured by the mTSS (Baker 2014, Baker 2016, Conaghan 2016, 
Genovese 2016b).
Cartilage Loss Scale (CARLOS) – The images used for RAMRIS scoring above will also be 
evaluated using the validated 9-point cartilage loss scale (Peterfy 2012), to provide another 
assessment of the impact of study interventions on joint structural damage progression.
 
 
 
 
 
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5.2.4
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments not part of the subject’s routine medical care, 
the Investigator will ensure that the subject has provided written informed consent following the 
procedure described in Section 9.2.
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5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Ability to understand the purposes and risks of the trial
2. Has signed the appropriate written Informed Consent Form (ICF), approved by the 
Investigator’s Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to 
the performance of any trial activities. In Japan, if a subject is < 20 years of age, the written 
informed consent from the subject’s parent or guardian will be required in addition to the 
subject’s written consent.
3. Male or female subjects, 18 to 75 years of age
4. Subjects should be able to complete (read and write) the PRO questionnaires
5. Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at 
least 6 months duration prior to Screening
6. Persistently active moderate to severe RA at both Screening and Randomization (if significant 
surgical treatment of a joint has been performed, that joint cannot be counted for entry or 
enrollment purposes), as defined by (see Appendix II):
a.
≥6 swollen joints (of 66 assessed) and
b. ≥6 tender joints (of 68 assessed).
7. An hsCRP ≥5.0 mg/L (≥0.50 mg/dL) from 2 samples collected during Screening. The second 
hsCRP must be collected: 
a.
At least 7 days after the initial screening hsCRP, and
b. At least 7 days prior to randomization or baseline MRI (for subjects in the MRI 
substudy), and
c.
No more than 14 days prior to randomization (21 days for MRI sites that are not able 
to transfer X-rays electronically) or baseline MRI (for subjects in the MRI substudy).
8. Positive rheumatoid factor (RF) and/or anti-cyclic citrullinated protein (anti-CCP)
9. Treatment for ≥16 weeks with 7.5 to 25 mg/week MTX. MTX at a stable dose and route of 
administration (oral or parenteral) for at least 8 weeks prior to dosing with the IMP and 
maintained throughout the trial
10. For subjects entering the trial on MTX doses < 15 mg/week (< 10 mg/week in Japan), there 
must be clear documentation in the medical record that higher doses of MTX were not tolerated 
or that the dose of MTX is the highest acceptable dose based on local clinical practice 
guidelines
11. Subjects should be on an adequate and stable dose of folic acid (not less than 5 mg total dose 
weekly [800 μg to 1 mg per day], unless this would violate the local label) for at least 2 weeks 
prior to the first dose of the IMP
12. No evidence of active TB as defined by all of the following:
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a.
A negative QuantiFERON®-TB test at Screening
b. No signs or symptoms consistent with the diagnosis of active TB upon medical history 
and/or physical examination
c.
Normal CXR at Screening or within the 3 months prior to Screening
d. No household contacts with active TB.
NOTE: Individuals that have completed appropriate LTBI treatment, and provide 
documentation thereof, are eligible and are not required to be tested for TB. Individuals with 
indeterminate or positive QuantiFERON-TB test results during Screening that are felt to 
represent a false positive result by the Investigator, with no clinical features consistent with 
active TB, will be subsequently 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. Sites that are not able to process T.SPOT.TB should contact the Medical 
Monitor for additional guidance. 
13. No evidence of latent TB infection (LTBI) that is undergoing treatment, is inadequately treated, 
or is untreated as defined by all of the following:
a.
A negative QuantiFERON-TB test at Screening
b. No clinical symptoms consistent with active TB
c.
Normal CXR at Screening or within the 3 months prior to Screening.
NOTE: Individuals that have completed appropriate LTBI treatment, and provide 
documentation thereof, are eligible and are not required to be tested for TB. Individuals with 
indeterminate or positive QuantiFERON-TB GOLD test results during Screening that are felt 
to represent a false positive result by the Investigator will be subsequently 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. Sites that are not able to 
process T.SPOT.TB should contact the Medical Monitor for additional guidance. 
14. Female participants: 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least 1 of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix I of this 
protocol OR
b. A WOCBP who agrees to use 2 methods of birth control: a barrier method together 
with a highly effective method (ie, methods with a failure rate of less than 1% per year) 
as detailed in Appendix I of this protocol, at least 28 days before start of first dose of 
the IMP (as appropriate), during the Treatment Period, and for 90 days after the last 
dose of the IMP.
15. History of vaccinations, as required per local guidelines:
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a.
Vaccination against Streptococcus pneumoniae with PPSV23 and/or PCV13 or local 
equivalent with repeat administration as necessary to be up to date. If vaccinated during 
screening, there must be at least 2 weeks between vaccination and randomization.
b. Vaccination against influenza virus (as seasonally required, as per local guidelines); or 
vaccination against these pathogens during Screening (as seasonally required for 
influenza virus, as per local guidelines). If vaccinated during screening, there must be 
at least 2 weeks between vaccination and randomization. If the subject is screened after 
the most recent influenza season and/or the influenza vaccine is no longer available, 
the influenza vaccine should be given during the study once available, as required per 
local guidelines.
MRI Substudy Subjects:
16. In addition to meeting inclusion criteria 1–15 above and the criteria for inclusion into the study, 
subjects must have palpable synovitis of the wrist and/or ≥1 of metacarpophalangeal (MCP)
joints #1 to #5, defined as loss of bony contours with palpable joint effusion and/or swelling, 
in the MRI-designated hand (ie, the hand being used in MRI assessments).
5.3.2
Exclusion Criteria
Subjects who fulfill any of the following should not be enrolled into this trial: 
1. ACR functional class IV as defined by the ACR classification of functional status or 
wheelchair/bedbound
2. Use of oral corticosteroids > 10 mg daily prednisone equivalent, or change in dose of 
corticosteroids within 2 weeks prior to Screening or during Screening
3. Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular 
hyaluronic acid within 4 weeks prior to Screening or during Screening
4. Initiation or change in dose for NSAIDs (including low-dose aspirin and COX-2 inhibitors) 
within 2 weeks prior to dosing with the IMP
5. High potency opioid analgesics (eg, methadone, hydromorphone, oxycodone, fentanyl, or 
morphine) are prohibited within 2 weeks prior to Screening and during the trial; other 
analgesics are allowed (eg, acetaminophen, codeine, hydrocodone*, propoxyphene*, or 
tramadol), although not within 24 hours of study visits with clinical assessments (*not 
approved in Japan).
6. Current or prior treatment with any of the following:
a.
Biologic DMARDs (approved or investigational), including but not limited to:
i. TNF antagonists (eg, adalimumab, infliximab, certolizumab pegol, golimumab, 
etanercept, or any biosimilars of these agents [approved or investigational], or 
any investigational TNF antagonist)
ii. Interleukin-6 
antagonists 
(eg,
tocilizumab, 
sarilumab, 
sirukumab, 
vobarilizumab*) (*not approved in Japan)
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iii. Abatacept (CTLA4-Fc)
iv. Anakinra* (IL-1 receptor antagonist) (*not approved in Japan)
v. B cell-depleting antibodies (eg, rituximab, ocrelizumab*, ofatumumab, 
obinutuzumab*, ocaratuzumab*, veltuzumab*, or any biosimilars of these 
agents [approved or investigational]) (*not approved in Japan)
vi. Anti-BLyS (B lymphocyte stimulator) agents (eg, belimumab, tabalumab*)
(*not approved in Japan)
vii. Dual BLyS/ A proliferation-inducing ligand (APRIL) neutralizing agents (eg,
atacicept*, RCT-18*) (*not approved in Japan).
b. Targeted synthetic DMARDs (approved or investigational), specifically:
i. JAK inhibitors (eg, tofacitinib, baricitinib, ruxolitinib, filgotinib*, ABT-494*, 
etc.) (*not approved in Japan)
ii. Other BTK inhibitors (eg, CC-292, GDC-0853, BMS-986142, etc.).
c.
Alkylating agents (eg, chlorambucil*, cyclophosphamide) (*not approved in Japan).
7. The following restrictions on nonbiologic DMARD must be followed, otherwise the subject is 
excluded:
a.
Auranofin (Ridaura®), minocycline, penicillamine, sulfasalazine, cyclosporine, 
mycophenolate
(mycophenolate sodium not approved in Japan), tacrolimus, 
azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP
b. Leflunomide (Arava®) must have been discontinued 12 weeks prior to dosing with the 
IMP if no elimination procedure is followed. Alternately, it should have been 
discontinued with the following elimination procedure at least 4 weeks prior to dosing 
with the IMP: Cholestyramine at a dosage of 8 g 3 times a day for at least 24 hours, or
activated charcoal at a dosage of 50 g 4 times a day for at least 24 hours
c.
Injectable Gold (aurothioglucose* or aurothiomalate): must have been discontinued for 
8 weeks prior to dosing with the IMP (*not approved in Japan)
d. Anti-malarials (hydroxychloroquine, chloroquine*) will be allowed in this trial. 
Subjects may be taking oral hydroxychloroquine (≤400 mg/day) or chloroquine*
(≤250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with 
the IMP, and will need to be continued at that stable dose for the duration of the trial. 
If discontinued prior to this trial, they must have been discontinued for 4 weeks prior 
to dosing with the IMP (*not approved in Japan).
8. MRI Substudy Subjects:
a.
Inability to comply with MRI scanning, including contraindications to MRI such as 
known allergy to gadolinium contrast media, claustrophobia (if the site does not have 
ability to scan extremities only), presence of a pacemaker, cochlear implants, 
ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, and nerve 
stimulators.
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b. More than 25% of applicable joints of the target hand and wrist having had prior 
surgery or showing maximum Genant-modified Sharp erosion (3.0) or joint-space 
narrowing (4.0) scores, based on single posteroanterior radiographs of target hand and 
wrist read centrally.
9. Immunologic disorder other than RA, with the exception of secondary Sjogren’s syndrome 
associated with RA, and well-controlled diabetes or thyroid disorder
a.
Thyroid Disorder: See exclusion criterion #29
b. Diabetes: For purposes of this study, subjects with diabetes with Hemoglobin A1C 
≥10% at Screening are excluded.
10. Any condition other than RA or Sjogren’s syndrome associated with RA that requires oral, 
intravenous, intramuscular, or intra-articular corticosteroid therapy
11. Diagnosis of Felty’s syndrome
12. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening or 
during Screening
13. Vaccination with Bacille Calmette-Guérin (BCG) within 12 months of Screening
14. Known hypersensitivity to any trial treatment, diluents, excipients, latex, including placebo 
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16. 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 during Screening, or completion of oral anti-infectives within 2 weeks before 
or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of 
infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or 
oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not 
be exclusionary. 
17. Any of the following:
a.
History of or positive testing for Human Immunodeficiency Virus (HIV) at Screening
b. History of or positive testing for hepatitis C antibody and/or hepatitis C ribonucleic 
acid (RNA) by polymerase chain reaction (PCR) at Screening
c.
Positive for hepatitis B surface antigen (HBsAg) at Screening
d. For subjects who are negative for HBsAg at Screening, but are anti-hepatitis B surface
antibody positive and/or anti-hepatitis B core antibody positive at Screening, reflex 
testing for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR will be 
performed:
i. Hepatitis B antibody-positive subjects who have detectable HBV DNA 
≥20 IU/mL are excluded
ii. Hepatitis B antibody-positive subjects who are HBV DNA-negative OR have 
detectable HBV DNA < 20 IU/mL are not excluded from the study. However, 
these subjects will need HBV DNA measured by PCR and liver function tests 
at Weeks 4, 8, 12/End of Treatment/Early Withdrawal, and 16/Safety 
Follow-up/End of Trial Visit.
e.
Testing for HIV, hepatitis C Virus (HCV), and HBV is required for participation in the 
study. Individuals unwilling to have this testing done are excluded.
18. History of:
a.
Latent or active granulomatous infection other than TB (eg, nontuberculous 
mycobacteria) within 6 months prior to randomization
b. Any opportunistic infection (eg, histoplasmosis, coccidioidomycosis, blastomycosis, 
pneumocystis, listeriosis, legionellosis, or parasitic infections) within 6 months prior to 
randomization
c.
Symptomatic herpes zoster within 3 months prior to randomization
d. Disseminated/complicated herpes zoster (eg,
multidermatomal involvement, 
ophthalmic zoster, central nervous system involvement, or postherpetic neuralgia).
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19. Presence of uncontrolled or New York Heart Association (NYHA) Class 3 or 4 congestive 
heart failure. 
a.
NYHA Class 3: Cardiac disease resulting in marked limitation of physical activity. 
Subjects are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain
b. NYHA Class 4: Cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased.
20. History of splenectomy at any time and/or history of infected joint prosthesis if that joint 
prosthesis is still in place
21. History of any major surgery or joint surgery within 2 months prior to Screening, or will 
require major surgery or any planned joint surgery during trial
22. History of myocardial infarction or cerebrovascular event within 6 months prior to Screening, 
or current active angina pectoris, symptomatic heart failure, seizures, untreated hypertension, 
gastrointestinal bleeding, or any other significant medical condition in the Investigator’s 
opinion
23. On anti-coagulation or anti-platelet therapy other than low dose daily aspirin for 
cardioprotection
24. On fish oil (unless discontinued prior to first dose)
25. History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin 
(no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical 
intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years
26. Breastfeeding/lactating
or pregnant, or discontinued lactation within 3 months of 
randomization. Lactating women are excluded regardless of whether or not they are nursing 
infant(s).
27. Clinically significant abnormality on ECG, or an active infective process or any other clinically 
significant abnormality on Screening CXR. If a CXR has been taken within the previous 
3 months prior to Screening and results are available and normal, the CXR does not need to be 
carried out.
28. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 as calculated by the 
4 component Modification of Diet in Renal Disease (MDRD) equation by the central 
laboratory:
a.
The 4-component Modification of Diet in Renal Disease equation (Levey 2006):
eGFR = 175 × (serum creatinine in mg/dL) – 1.154 × (age in years) – 0.203 × 0.742 (if 
female) × 1.212 (if race is black).
29. TSH < 0.01 or ≥7.1 mIU/L. Subjects receiving thyroxine as replacement therapy may 
participate in the study provided that thyroxine has been at a stable dose for ≥12 weeks, and 
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TSH is within the reference range. TSH may be repeated once within approximately 2 weeks 
of the initial testing, if the first result is exclusionary, and the value from repeat testing may be 
accepted for eligibility to participate in the study if it is within the reference range.
30. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), amylase, or lipase 
> 2 × above upper limit of normal (ULN) of laboratory reference range, total bilirubin 
> 1.5 × ULN, any other clinically significant laboratory abnormality
31. B cell (CD19) count < 50% of the lower limit of normal (LLN) 
32. Significant cytopenia, including absolute neutrophil count < 1,500/mm3, platelet count 
< 100,000/mm3, or absolute lymphocyte count < 1,000/mm3
33. Has taken an investigational drug within 1 month or 5 half-lives of the investigational drug, 
whichever is longer, prior to Screening (exclusion criteria 6 to 8 and 10 take priority)
34. Subjects currently receiving (or unable to stop using prior to receiving the first dose of IMP) 
medications or herbal supplements known to be potent (strong or moderate) inhibitors of 
cytochrome P450 isozyme 3A (CYP3A) (must stop at least 1 week prior to dosing), potent 
(strong or moderate) inducers of CYP3A (must stop at least 3 weeks prior to dosing), or drugs 
mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least 1 day prior
to dosing), see Table 9.
35. History of/or current alcohol, substance, or drug abuse:
a.
Excessive alcohol use is defined as alcohol and/or substance abuse or dependence (as 
defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text 
revision) in the past year OR
b. A history of alcohol or substance abuse, as determined by the Investigator.
36. Legal incapacity or limited legal capacity.
37. Positive serum β-D-glucan test (Japan only).
5.4
Criteria for Randomization and Initiation of Trial Treatment
Randomization should occur on Day 1 after all Screening procedures have been completed; subject 
eligibility must be reviewed again and confirmed at the site on Day 1 prior to randomization. If a 
subject does not meet eligibility criteria, the subject can be retested and rescreened once at the 
Investigator’s discretion as described in Section 7.1.1.
Eligible subjects will be randomized to treatment through a central randomization process by an 
IWRS. This will be a double-blind trial. Subjects will be stratified by whether or not they are in 
the MRI substudy and by region. There are no systematic differences between MRI and non-MRI 
sites beyond the availability and suitability of MRI for study purposes, to avoid potential selection 
bias. Participation in the MRI substudy will be mandatory for subjects participating at designated 
MRI sites.
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5.5
Criteria for Subject Withdrawal
Subjects will be informed they have the right to withdraw from the trial at any time, without 
prejudice to their medical care, and they are not obliged to state a reason for withdrawing. Any 
withdrawal must be fully documented in the eCRF and source documents, and should be followed 
up by the Investigator.
The Investigator may withdraw a subject at any time if this is considered to be in the subject’s best 
interest.
5.5.1
Withdrawal from Trial Therapy
Subjects who withdraw from therapy must return for an End of Treatment/Early Withdrawal Visit 
followed by a Safety Follow-up Visit. At the time of early withdrawal from trial therapy, all 
information/assessments noted at the End of Treatment Visit in the Schedule of Assessments are 
to be completed. For any subject that withdraws from the MRI substudy prior to Week 12, contact 
the Study Sponsor. If the IMP is prematurely discontinued, the primary reason for discontinuation 
must be recorded in the appropriate section of the eCRF, and all efforts will be made to complete 
and report the observations as thoroughly as possible. A complete final evaluation at the time of 
the subject's withdrawal should be made and any AEs followed up until resolution or a period of 
30 days after the last Safety Visit (or withdrawal from the trial).
A subject must be withdrawn from IMP if any of the following occur:
∀Adverse events, if permanent discontinuation of the IMP is desired or considered necessary by 
the Investigator and/or subject
∀Use of prohibited medications, as defined in Section 6.5.2. However, any medications may be 
administered to address adverse reactions, or emergency situations. Should a prohibited 
medication be needed during the study, the subject would be withdrawn from the trial. All 
medications other than study therapy given during the course of the trial must be recorded (see 
Section 6.5.1).
∀Interruption of MTX more than twice in a period of 4 weeks
∀Pregnancy (for further details in case of pregnancy, see Section 7.4.2)
∀Protocol noncompliance judged as significant by the Investigator and/or the Sponsor. If a 
subject has failed to attend scheduled trial assessments or had failed to comply with the trial 
protocol otherwise, the Investigator must determine the reasons and the circumstances as 
completely and accurately as possible.
∀Subject withdrawal of consent
∀Loss to follow-up; at least 3 attempts (2 telephone calls, 1 Acknowledgement of Receipt letter) 
should be made to contact the subject to ensure the reason for not returning is not an AE
∀Death
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∀Participation in another clinical trial, with the exception of noninterventional studies
∀Any event(s) that endanger the safety of the subject, with the exception of AEs that will be 
handled as above
∀If during the study, in the opinion of the Investigator, the subject's RA disease level is 
unacceptably high requiring therapy not permitted per the protocol, the subject may withdraw 
from the study treatment and initiate therapy recommended per the treating physician. In this 
case, the subject will be considered a nonresponder.
5.5.1.1
Stopping Rules
The severity of AEs will be graded using the NCI-Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03 grading scale (Hahn 2012).
The IMP should be temporarily withheld or permanently withdrawn if the following abnormalities 
occur or re-occur, as relevant, and re-initiation following temporarily withholding of IMP should 
be discussed with the Medical Monitor. If a subject’s predose baseline value falls within any of 
the below criteria, consult with the Medical Monitor regarding potential withdrawal, continued 
participation in study, and additional monitoring if needed:
∀For a neutrophil count < 500/mm3 or platelet count < 25,000/mm3 or lymphocyte count 
<200/mm3 (Grade 4) or neutrophil count 500 to 999/mm3 (Grade 3) with fever or platelet count 
25,000 to 49,999/mm3 (Grade 3) with bleeding, the IMP should be permanently withdrawn. 
o For a Grade 3 decrease in neutrophil count without fever or Grade 3 decrease in platelet 
count without bleeding, temporarily hold the IMP and recheck the value. If the value is still 
Grade 3, permanently discontinue the IMP. 
o For a decrease to Grade 2, temporarily hold the IMP and recheck the value. Discontinue the 
IMP if the neutrophil or platelet count continues to decrease, and re-initiate the IMP if no 
downward trend is observed.
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∀For an increase in serum creatinine to > 3 × Baseline (Grade 3 or higher), the IMP should be 
permanently withdrawn. 
o For any other increase in serum creatinine > 1.5 × Baseline, temporarily hold the IMP and 
recheck the value. Discontinue the IMP if the value does not decrease, or re-initiate the IMP 
if a downward trend is observed.
∀For any serum IgG level < 3 g/L, confirmed by repeat testing, the IMP should be permanently 
withdrawn.
∀For any increase in HBV DNA by PCR from negative/undetectable to detectable, AND/OR 
increase in HBV DNA by PCR from < 20 IU/mL to ≥20 IU/mL, the IMP should be 
permanently withdrawn. The subject should be followed with additional testing and hepatitis B 
treatment, as indicated per local guidelines, including consultations with a specialist, such as a 
Hepatologist, at the Investigator’s discretion and in conjunction with the Medical Monitor.
∀For any other laboratory abnormality of Grade 4 severity, the IMP should be temporarily 
withdrawn, and the subject discussed with the Medical Monitor and Sponsor prior to 
re-initiation. 
∀For any other laboratory increase/decrease of Grade 3 from Baseline, discuss with the Medical 
Monitor and consider temporarily holding the IMP. 
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Unscheduled duplicate blood samples will be collected for selected safety laboratories to be 
processed by both the central laboratory and local laboratories to permit rapid confirmation of a 
central laboratory test result that requires an action such as drug interruption. A detailed list of 
these tests is provided in the laboratory manual. The Investigator should review local laboratory 
results within 24 hours and should base decisions regarding retesting or IMP dose interruption or 
discontinuation on local laboratory results if local laboratory results are obtained prior to the 
central laboratory results and show an abnormality requiring action. The local laboratory reference 
range should be used to determine grade in this case. Only the central laboratory results will be 
automatically reported and used for analyses. If an action is taken to retest or adjust the IMP dose 
based on local laboratory results, the results should be entered in the eCRF (with date, time and 
result, and local reference range) on an unscheduled visit page to document why the decision was 
made.
The reason for IMP withdrawal and the nature, duration, and results of any planned follow-up 
observations should be recorded in the appropriate section of the eCRF.
5.5.2
Withdrawal from the Trial
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. In addition to voluntary withdrawal from the trial, a 
subject must be withdrawn if the subject is permanently withdrawn from trial therapy (see 
Section 5.5.1). Subjects withdrawn from the trial while still on the IMP should return immediately 
for an End of Treatment/Early Withdrawal Visit upon discontinuation of the IMP and a Safety 
Follow-up Visit (see Section 5.5.1). Subjects who are withdrawn from the trial and are no longer 
on the IMP must complete the Safety Follow-up Visit assessments described in Section 7.1.4.
If a subject fails to return for the post-treatment Safety Visit, at least 3 attempts (2 telephone calls, 
1 Acknowledgement of Receipt letter) should be made to contact the subject to ensure the reason 
for not returning is not an AE. Likewise, if a subject wishes to discontinue from the trial (eg, for 
personal reasons), an attempt should be made to establish the true reason is not an AE (bearing in 
mind the subject is not obliged to state the reasons). A complete final evaluation at the time of the 
subject's withdrawal should be made and any AEs followed up until resolution or a period of 
30 days after the last Safety Visit (or withdrawal from the trial).
Subjects who are withdrawn after randomization (eg, due to AEs or lack of efficacy) will not be 
replaced. Subjects who are withdrawn from the trial will not be allowed to re-enroll in the trial.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP.
The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, 
for poor enrollment, or because of discontinuation of clinical development of an IMP or 
withdrawal of an IMP from the market for safety reasons.
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Health Authorities and IECs/IRBs will be informed about the discontinuation of the trial in 
accordance with applicable regulations.
5.7
Definition of End of Trial
The end of the trial is defined as the last subject’s end of trial visit.
A clinical trial protocol may not be considered closed as long as:
∀Any subject is still receiving any IMP as part of this protocol
∀Visits specified by the protocol are still taking place
∀Procedures or interventions according to the protocol are still being undertaken in any subject
∀The post-treatment follow-up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Product
Investigational Medicinal Product:
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical trial, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized form.
The IMPs to be administered in this trial are evobrutinib (also known as M2951) and evobrutinib
placebo.
Evobrutinib will be administered as film-coated tablets for oral administration and containing 
25 mg of drug substance (chemical name 1-(4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-
ylamino]-methyl}-piperidin-1-yl)-propenone) formulated with excipients. The evobrutinib
placebo will be administered as tablets ready for oral administration matching the active tablets in 
color, size, and shape. 
The Sponsor will provide IMP to the trial sites.
Specific Rules for Treatment Modifications: 
Not applicable.
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6.2
Dosage and Administration
Details describing evobrutinib dosing and administration are provided in Table 8. Subjects will 
receive oral evobrutinib or placebo tablets daily as detailed in Table 8. Treatment regimens and 
sequences are detailed in Table 3.
Table 8
Dosage and Administration of Evobrutinib
Product 
Description
Dosage 
Form
Evobrutinib
Dose
Number of Tablets
(Morning Dose)
Number of Tablets
(Evening Dose)
25 mg
25 mg
Evobrutinib
Placebo
Evobrutinib
Placebo
Evobrutinib
Oral
25 mg QD
1
2
0
2
Evobrutinib
Oral
75 mg QD
3
0
0
2
Evobrutinib
Oral
50 mg BID
2
1
2
0
Placebo
Oral
0 mg
0
3
0
2
Note: To maintain the blind, all subjects will receive BID treatment. Subjects will self-administer 3 tablets in the 
morning and 2 tablets in the evening (every 12 hours ± 2 hours).
At the visits indicated in the Schedule of Assessments (Table 1), IMP should be administered 
during the trial visit. 
Subjects should take each dose more than 1 hour prior to a meal or snack and more than 2 hours 
after a meal or snack. Clear fluids are allowed at any time.
6.3
Assignment to Treatment Groups
Eligible subjects will be randomized through a central stratified randomization process by the 
IWRS prior to dosing on Day 1.
The trial is fully controlled by the IWRS, which assigns treatment individual (unique) kit numbers 
for each subject. The kit number is linked via the Good Manufacturing Practice qualified system 
to the corresponding treatment as well as to the subject.
Subject identifiers will be comprised of 3 sets of numbers representing the trial number, the site 
number, and the subject number, which is allocated sequentially at each site starting with 
.
Treatment kits will contain enough medication for administration for 1 week (+ 2 days). In 
addition to the subject and Investigator/site, all Sponsor and CRO trial staff will be blinded to the 
treatment group assignment.
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6.4
Noninvestigational Medicinal Products to be Used
Throughout the trial, subjects will remain on their chronic stable doses of MTX at the time of 
Screening (see Section 5.3.1), along with other permitted medications (see Section 6.5.1) as part 
of their standard of care and adjusted only for safety reasons.
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration (ie, start and end dates), dosing regimen (eg, once daily, twice daily, etc.), and indication 
of each drug. Nondrug interventions and any changes to a concomitant medication or other 
intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
Permitted medications are any medications required per the medical history and not specifically 
prohibited by the protocol during the trial. These standard of care medications are part of the 
subject’s previous RA treatment and will therefore not be provided by the Sponsor. Any such 
medications prescribed or used should be recorded in the eCRF.
Methotrexate: All subjects should maintain a stable MTX dose (up to 25 mg/week, via oral, 
intramuscular, or subcutaneous administration) during the trial period. Any modification of the 
route of administration is not allowed. However, if modification to the route of administration is 
determined by the Investigator to be in the best interest of the subject at any time, please contact 
the Medical Monitor to discuss. However, a dose reduction of MTX will be allowed in case of AEs
attributed to MTX. Temporary interruptions of administration are allowed for up to 14 days (can 
be interrupted up to twice because MTX is administered once weekly). 
Folic Acid: It is possible that AEs commonly associated with MTX treatment will occur. In order 
to minimize MTX toxicity, all subjects treated with MTX should receive folic acid or equivalent 
at a dose of at least 5 mg/week according to local guidelines. This either can be given as a single 
dose weekly or be divided into daily doses to achieve at least 5 mg folic acid per week. It is the 
Investigator’s decision as to which dosing regimen is used.
Anti-malarials (hydroxychloroquine or chloroquine*):
Subjects may be taking oral 
hydroxychloroquine (≤400 mg/day) or chloroquine* (≤250 mg/day). The dose must have been 
stable for at least 12 weeks prior to dosing with the IMP, and will need to be continued at that 
stable dose for the duration of the trial. If discontinued prior to this trial, they must have been 
discontinued for 4 weeks prior to dosing with the IMP. Dose adjustment of anti-malarials is not 
allowed. Subjects who were not previously on anti-malarials should not initiate anti-malarial 
therapy during the trial (*not approved in Japan).
Oral corticosteroids: Oral corticosteroids are permitted at a dose of ≤10 mg/day prednisone or 
equivalent. The dose of oral corticosteroids must remain stable. Subjects who were not previously 
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on oral corticosteroids should not initiate corticosteroid therapy during the trial. Any changes must 
be discussed with a Medical Monitor to determine if the changes are compatible with continued 
participation in the trial.
NSAID: Subjects may be treated with NSAIDs (including low-dose aspirin and COX-2 inhibitors) 
for symptomatic treatment of arthritis up to the maximum recommended dose per local labeling 
during the trial (including COX-2 inhibitors). Drug(s) must be at a stable dose, route, and regimen
for at least 2 weeks prior to Baseline. Increases in the NSAID dose during the trial are not allowed. 
Discontinuation or reduction is allowed in case of NSAID-related toxicity/to protect the subject’s 
safety. In subjects who receive NSAIDs, prophylactic treatment with proton pump inhibitors or 
H2 receptor blockers is recommended (per local guidelines). NSAIDs are also allowed for the 
management of AEs not related to RA such as colds or sprains throughout the trial (including 
COX-2 inhibitors); however, the daily dosage of NSAIDs must not be modified within 24 hours 
prior to any study visit, except if an adjustment is needed to protect a patient’s safety.
Non-NSAID Analgesics: High potency opioids (eg, methadone, hydromorphone, oxycodone, 
fentanyl, or morphine) are prohibited during the trial. Other analgesics (eg, acetaminophen, 
codeine, hydrocodone*, propoxyphene*, or tramadol), up to the maximum recommended doses, 
may be used for pain control as required. Subjects should not take non-NSAID analgesics within 
24 hours prior to a visit where clinical efficacy assessments are performed with the exception of 
those subjects who entered the trial on a stable dose, route, and regimen of non-NSAID analgesics 
(at least 28 days prior to Screening). (*not approved in Japan)
Any concomitant medications (including over-the-counter medications, herbal medications, 
preventive vaccines, vitamins, proton pump inhibitors [prescription or over-the-counter], and food 
supplements) and procedures must be recorded. A description of the type of drug or procedure, 
name of the active substance, dosage, frequency, duration, reason for administration of drug, and 
outcome of any procedure must be documented. AEs related to the administration of a concomitant 
medication or the performance of a procedure must also be recorded.
Any medications (other than those excluded as per exclusion criteria in Section 5.3.2 or prohibited 
as per Section 6.5.2) that are considered necessary for the subjects’ welfare and will not interfere 
with the trial medication may be given at the Investigator’s discretion. Any medications may be 
administered to address adverse reactions, or emergency situations. Should a prohibited 
medication be needed during the study, the subject would be withdrawn from the trial.
6.5.2
Prohibited Medicines
The following medications and therapies are not permitted during the trial and would require 
discontinuation of trial treatment:
∀Oral corticosteroid dose > 10 mg/day
∀Intramuscular or intravenous corticosteroids
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∀Intra-articular corticosteroids. Intra-articular hyaluronic acid, although this option may be 
discussed with the Medical Monitor if required to prevent early discontinuation. Any injected 
joints will be censored from joint counts for the duration of the study.
∀Biologic therapies for treatment of RA (bDMARDs) are strictly prohibited. Biologic therapies 
for other indications must be discussed with the medical monitor on a case-by-case basis, with 
the exception of insulin and antibodies used for bone density (eg, denosumab), which are
permitted
∀tsDMARD (eg, JAK inhibitors, other BTK inhibitors)
∀Intravenous Ig therapy and/or plasmapheresis
∀Live and live-attenuated vaccines
∀Anticoagulants and anti-platelet therapy other than low dose daily aspirin for cardioprotection
∀Fish oil
∀Herbal supplements including, but not limited to, St. John’s wort, grapefruit, Seville oranges, 
cranberries, or juices of these fruits
∀Moderate or strong inhibitors of CYP3A (see Table 9). The additive effects of weak inhibitors 
taken in combination must also be taken into account
∀Moderate or strong inducers of CYP3A (see Table 9)
∀Drugs mainly metabolized by CYP3A with a narrow therapeutic index (see Table 9).
New therapies for RA should not be initiated during the trial. Initiation of any new 
immunosuppressant or immunomodulatory therapy would be considered a treatment failure and 
should result in withdrawal of the subject from the IMP (see Section 5.5.1).
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Table 9
Examples of Inhibitors or Inducers of CYP3A Enzymes or Substrates 
with Narrow Therapeutic Range
Inhibitors
Strong
Moderate
Weak
Boceprevir, clarithromycin, conivaptan,
grapefruit juice,a indinavir, 
itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole
Amprenavir, aprepitant, atazanavir, 
ciprofloxacin, darunavir/ritonavir, 
diltiazem, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice,a
imatinib, verapamil
Alprazolam, amiodarone, amlodipine, 
atorvastatin, bicalutamide, cilostazol, 
cimetidine, cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, goldenseal, 
isoniazid, nilotinib, oral contraceptives, 
ranitidine, ranolazine, 
tipranavir/ritonavir, zileuton
Inducers
Strong
Moderate
Weak
Avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin
Amprenavir, aprepitant, armodafinil, 
echinacea, pioglitazone, prednisone, 
rufinamide
Substrates With a Narrow Therapeutic Range
Alfentanil, astemizole,b cisapride,b cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadineb
AUC = area under the curve, CYP = cytochrome P450, CYP3A = cytochrome P450 isozyme 3A.
a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation is used (eg,
high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation is used (eg, low dose, 
single strength).
b Withdrawn from the US and certain other markets because of safety reasons.
Notes:
∀
This is not an exhaustive list. For an updated list, see Tables 5, 6, and 7 in the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
80499.htm
∀
A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate sensitive for that CYP ≥5-fold 
or decreases clearance by > 80%, and a strong inducer decreases AUC of a substrate by ≥80%.
∀
A moderate inhibitor is defined as an inhibitor that increases the AUC of a substrate sensitive for that CYP 
≥2-fold but < 5-fold or decreases clearance by 50% to 80%, and a strong inducer decreases AUC by 50% to 
80%.
∀
A weak inhibitor is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP < 2-fold or 
decreases clearance 20% to 50%, and a weak inducer decreases AUC by 20% to 50%.
∀
CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de pointes).
6.5.3
Other Interventions
6.5.3.1
Other Trial Considerations
Women of childbearing potential must be willing to follow very specific requirements for birth 
control as indicated in Section 5.3.1. While there is no requirement for contraception in male 
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participants based on the nonclinical data, it is recommended that conception be avoided during 
exposure to evobrutinib as there is limited experience in humans.
6.5.3.2
Other Interventions/Therapies
Use of potentially excluded procedures such as acupuncture or joint replacement therapy is to be 
discussed with the Sponsor or designee on a case-by-case basis. Use of acupuncture is allowed to 
continue if it is started before Screening. Major elective surgeries such as abdominal, thoracic, or 
joint replacement surgeries should not be planned to occur during the Trial Period. Unplanned 
joint replacement surgery should be discussed at the earliest opportunity prior to the surgery with 
the Medical Monitor regarding continuation of the subject in the trial. Surgical procedures 
involving the hands, wrists, or feet are prohibited during the trial due to their likely effects on 
imaging endpoints. Unplanned procedures involving the hands, wrists, or feet should be discussed 
at the earliest opportunity prior to the surgery with the Medical Monitor regarding continuation of 
the subject in the trial.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
Evobrutinib and matching placebo are supplied by the Sponsor. A description of the 
pharmaceutical properties and composition of the formulation of evobrutinib is provided in the 
Investigator’s Brochure. Additional details of packaging and labeling of the IMP will be defined 
in a separate Operations Manual.
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6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The IMP must be carefully stored at the trial site in a location with restricted access and separately 
from other drugs. Storage conditions for evobrutinib will be specified in the Manual of Procedures 
(MOP). Any deviations from the recommended storage conditions should be immediately reported 
to the Sponsor, and the medication should not be used until authorization has been received from 
the Sponsor.
The IMPs must not be used for any purpose other than the trial. The administration of the IMPs to 
subjects who have not been enrolled into the trial is not covered by the trial insurance.
Disposal of the IMPs should be according to local regulations and institutional guidelines.
6.8
Investigational Medicinal Product Accountability
The Investigator or designee (or head of the trial site, in Japan only) is responsible for ensuring 
IMP accountability, including reconciliation of drugs and maintenance of records. (In Japan only,
the head of the trial site can delegate the control of and accountability for the study drug to an 
investigational product storage manager.) Upon receipt of IMP, the responsible person (in Japan 
only: the head of the trial site or the investigational product storage manager) will check for 
accurate delivery and acknowledge receipt by signing or initialing and dating the appropriate
documentation and returning it to the location specified. A copy will be archived for the 
Investigator Site File.
IMP dispensing will be recorded on the appropriate drug accountability forms so that accurate 
records will be available for verification at each monitoring visit. Trial site IMP accountability 
records will include the following:
∀Confirmation of IMP receipt, in good condition and in the defined temperature range
∀The inventory of IMP provided for the clinical trial and prepared at the site
∀The use of each dose by each subject
∀The disposition (including return, if applicable) of any unused IMP
∀Dates, quantities, batch numbers, vial numbers, expiry dates, and the individual subject trial 
numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms.
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6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered at the site on trial visit days as defined in Table 1. All other dosing 
will be done by the subject at home throughout the rest of the trial. Compliance may be assessed 
via the subject diary for dosing and food intake around dosing. Diaries will be collected and 
reviewed at the trial visits specified in Table 1.
Subjects will be instructed to bring all IMP, including the used packaging, to each trial visit to 
allow for the assessment of compliance with trial treatment. Prior to discharge from each scheduled 
visit, subjects will be given sufficient IMP for at-home dosing until the next scheduled visit during 
the Treatment Period.
Insufficient compliance with the protocol-specified dosing regimen is defined as receiving < 80% 
of the required number of scheduled doses of study medication. If a subject has insufficient 
compliance, the Investigator or designee is to counsel the subject and ensure steps are taken to 
improve compliance. 
6.10
Blinding
This will be a double-blind trial. After Day 1, the trial site staff, the Sponsor, and the CRO trial
team will be blinded to results that can reveal the 
 effects of evobrutinib in an individual subject 
(ie, hsCRP, ESR).
Blinding to treatment codes or laboratory results capable of revealing treatment will be maintained 
throughout the trial duration, except for the unblinded IDMC, or in the event that emergency 
unblinding is necessary for subject safety or the reporting of SUSARs.
In order to maintain the blinded nature of the trial, only the randomization statistician, an 
independent person at the trial site responsible for receiving local laboratory ESR results and 
conveying those results to the central laboratory, and an independent statistical team (independent 
of the 
trial team) responsible for production of the IDMC analyses, will be fully 
unblinded during trial conduct.
 
 
The procedures of database lock and unblinding for the statistical analysis will be documented in 
the Data Management Plan and Unblinding Plan.
The IDMC will also be unblinded to treatment, and as such, will have unblinded access to all 
laboratory data for the duration of the trial, as described in the IDMC Charter.
All breaks of the trial blind must be adequately documented in the Unblinding Plan.
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6.11
Emergency Unblinding
The Investigator will have the ability to break the blind with regard to IMP for any subject at any 
time through the IWRS. However, the Investigator should make every effort to contact the 
responsible Medical Monitor or their designee to discuss the subject’s emergency situation and the 
need to unblind prior to unblinding any subject and must contact the Sponsor or designee within 
1 working day after the event occurs without revealing to the Sponsor personnel the result of the 
code break. The Investigator will be able to access the subject’s treatment assignment 24 hours a 
day through the IWRS using a unique access code and user number (different from those used to 
assign subjects to treatment through the IWRS). Should the IWRS be unavailable for any reason, 
the Investigator will be able to break the blind via a telephone call to the IWRS help desk, which 
is available 24 hours a day. The help desk can access the database manually to perform the 
unblinding via telephone in the event that the IWRS is not operational. The Investigator must 
record the date of unblinding and the reason in the eCRF and source documents. Contact 
information for breaking the blind in an emergency is given on the subject emergency card 
provided to each subject (see Section 9.4).
Under certain circumstances, Drug Safety may be required to unblind the treatment assignment for 
an individual subject following an SAE or other serious event; for example, if an expedited 
regulatory report is required. See Section 7.4.1.4 for further details on expedited reporting and 
SAEs.
If emergency unblinding is required, discontinuation of the affected subject from the IMP and/or 
trial is not mandatory unless there are other circumstances that require subject discontinuation. If 
the affected subject is discontinued from the IMP, the subject must immediately complete the End 
of Treatment/Early Withdrawal Visit, followed by the Safety Follow-up Visit 28 days (+ 5-day 
window) later.
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the study. Any overdose must be recorded 
in the study medication section of the eCRF.
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious or 
nonserious) – must be reported to the Sponsor’s Global Drug Safety department or designee in an 
expedited manner using the appropriate reporting form (see Section 7.4).
The effects of an overdose of evobrutinib are unknown, and there is no known specific treatment 
in case of overdose. In the event of overdose, subjects should be considered for hospitalization for 
observation if clinically indicated, and the Investigator or treating physician should use appropriate 
clinical judgment for the management of any clinical or investigational findings.
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6.13
Medical Care of Subjects after End of Trial
After a subject has completed the trial or has withdrawn early, the subject is free to access further 
treatment as deemed appropriate by the Treating Investigator. 
7
Trial Procedures and Assessments
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
Throughout the trial, subjects will undergo the assessments detailed in Table 1 including blood 
sampling. Details of the blood volumes to be collected for each sample/visit will be detailed in the 
laboratory manual. Instructions on how samples will be collected, labeled, processed, stored, and 
shipped as well as specification on bioanalytical methods will be detailed in the laboratory manual.
All blood and urine tests will be analyzed by a central laboratory, with the following exceptions:
∀Blood samples will be sent for duplicate analysis of selected safety tests by both central and 
local laboratories. These duplicate safety samples are listed in the laboratory manual.
∀Erythrocyte sedimentation rate will be analyzed by local laboratories.
∀T.SPOT.TB test, if applicable at Screening, will be analyzed at local laboratories. 
Every effort should be made to perform assessments as close as possible to the scheduled time 
points, within the range of days noted for each day on trial as noted in Table 1. The details of 
efficacy assessments and safety assessments are described in Sections 7.3 and 7.4, respectively.
The Schedule of Assessments for the trial is presented in Table 1 and details of the trial procedures 
are provided in Section 7.1.1 for the Screening Period, Section 7.1.2 for the Treatment Period, 
Section 7.1.2.1 for the End of Treatment Visit, and Section 7.1.4 for the Safety Follow-up Visit.
The Sponsor and CRO should be notified immediately of any major violations of the trial 
procedures. Major and minor protocol violations will be defined in the MOP and in the SAP
(relevant only). Procedures for documenting protocol violations will be provided in the MOP.
7.1
Schedule of Assessments
Assessments during the trial will be performed according to Table 1. It is strongly recommended 
that patient-reported outcome measures be performed prior to any other assessments and should 
only be conducted after ICF has been signed. For volumes of blood collected, see laboratory
manual.
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7.1.1
Screening Period
At Screening, the prospective subject will be informed of the trial objectives and overall 
requirements, and informed consent will be obtained prior to initiating any Screening procedures 
or collecting any data. Screening procedures will be performed according to assessments in 
Table 1, within 28 days prior to the first administration of the IMP (or within 8 weeks if a screening 
test needs to be repeated, as applicable; see Section 5.1).
After signing of informed consent, Screening assessments will include, but are not limited to, 
recording of demographic information and other Baseline characteristics, detailed RA history, 
medical history, and medications history and reviewing of inclusion/exclusion criteria. If a subject 
does not meet eligibility criteria, the subject can be retested and rescreened once within the 
Screening Period at the Investigator’s discretion and on discussion with the Medical Monitor.
If a subject is rescreened, the subject will be assigned a new subject number and reconsented.
Subjects who have completed the Screening assessments and have fulfilled all of the eligibility 
criteria will be entered into the trial.
7.1.2
Treatment Period
At all applicable visits, patient-reported outcome questionnaires must be performed prior to any 
other assessments. At the Day 1 visit, assessments should be performed prior to randomization and 
the administration of the IMP. Scheduled assessments will be performed according to Table 1
before administration of the IMP, with the exception of relevant postdose blood draws (eg,
).
The first dose of the IMP will be given while the subject is still on site for the Day 1 visit.
At subsequent visits (Weeks 2 through 12), all scheduled visits during the Treatment Period may 
take place within the visit windows specified in Table 1. Subjects who discontinue early must 
return for the End of Treatment/Early Withdrawal Visit and Safety Follow-up Visit.
7.1.2.1
End of Treatment Visit
The End of Treatment Visit will be performed at Week 12 or within 5 days of early discontinuation 
of treatment with the IMP. Subjects will undergo assessments as described in Table 1. In case of 
premature discontinuation, the PRO assessments have to be completed at the End of Treatment 
visit.
7.1.3
Open-label Extension Period (Only Applicable Prior to 
Protocol Version 3.0)
In Protocol version 2.0, subjects completing the Treatment Period could have entered an optional 
Open-label Extension (OLE) Period, but the Sponsor made the decision to not initiate the OLE 
Period. As of the effective date of Protocol version 3.0 at study sites, all subjects completing the 
Treatment Period will enter the Safety Follow-up Period, and any subjects already participating in 
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the OLE Period at that time will be immediately withdrawn from the study following the protocol-
specified withdrawal procedures outlined in Section 5.5.2: subjects would return for an End of 
Treatment Visit and return 4 weeks later for an End of Study/Safety Follow-up Visit.
7.1.4
Safety Follow-up Visit
The Safety Follow-up Visit will be performed 28 days (+ 5-day window) after the End of 
Treatment/Early Withdrawal Visit.
Subjects who discontinue the IMP or withdraw from the trial early will attend the Safety 
Follow-up Visit according to procedures described in Sections 5.5.1 or 5.5.2, respectively.
Any ongoing SAEs must be followed up until the SAE/AE has resolved, is considered stable, or 
is considered no longer clinically relevant by the Investigator.
7.2
Demographic and Other Baseline Characteristics
7.2.1
Demography
At Screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity, smoking history and current smoking status (if former smoker, capture date of 
discontinuation).
7.2.2
Medical History
To determine the subject’s eligibility for the trial, a complete medical history of each subject will 
be collected and documented during Screening, which will include, but may not be limited to, the 
following:
∀Past and concomitant diseases
∀Full Physical examination
∀Laboratory assessments
∀All medications (including herbal medications) taken and procedures carried out within 28 days 
prior to Screening. RA-related medications and procedures from within 1 year prior to 
Screening should be documented. Additional medications and procedures (with particular 
attention to RA-related medications and procedures), should be included as deemed relevant by 
the Investigator.
For the trial entry, all of the subjects must fulfill all inclusion criteria described in Section 5.3.1, 
and none of the subjects should have any exclusion criterion from the list described in 
Section 5.3.2.
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7.3
Efficacy Assessments
The following tests and procedures have been selected to evaluate the efficacy of evobrutinib and 
describe clinical improvement in subjects with RA and will be performed according to the 
Schedule of Assessments (Table 1).
7.3.1
Disease Activity Assessments
Assessments for RA disease activity will include ACR response criteria, hsCRP analyses, 
DAS28-hsCRP, DAS28-ESR, and subject and physician VAS, which are described below.
7.3.1.1
American College of Rheumatology Response Rates
The primary efficacy endpoint is ACR20 at Week 12 in subjects with RA. The individual 
components that make up the ACR Core Set of measures for RA are described below. Relief of 
signs and symptoms will be assessed using the ACR Responder Index, a composite of clinical, 
laboratory, and functional measures in RA. The ACR responses are presented as the minimal 
numerical improvement from Baseline in multiple disease assessment criteria. The response 
criteria is based on the 68-joint tender/painful joint count, the 66-joint swollen joint count, and the 
hsCRP level (see Appendix II).
a.
Tender Joint Count
For ACR measures, the number of tender and painful joints will be determined by examination of 
68 joints (34 joints on each side of the subject’s body; see Appendix II). The 68 joints to be 
assessed and classified as tender or not tender include: 2 temporomandibular joints, 
2 sternoclavicular joints, 2 acromioclavicular joints, 2 shoulder joints, 2 elbow joints, 2 wrist 
joints, 10 MCP joints, 2 interphalangeal joints of the thumb, 8 proximal interphalangeal joints of 
the hands, 8 distal interphalangeal joints of the hands, 2 hip joints, 2 knee joints, 2 ankle joints, 
2 tarsus, 10 metatarsophalangeal joints of the feet, 2 great toes (first proximal interphalangeal joint 
of the feet), and 8 proximal interphalangeal joints of the feet. 
Joints will be assessed for tenderness by pressure and joint manipulation on physical examination. 
The subject will be asked for pain sensations on these manipulations and watched for spontaneous 
pain reactions. Any positive response on pressure, movement, or both will then be translated into 
a single tender-versus-nontender dichotomy. Joint assessments of 1 particular subject should be 
performed (if at all possible) by the same assessor throughout the trial to minimize inter-observer 
variation.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at 
Screening and will be excluded from evaluation during the trial. The locations (or a listing) of 
surgical procedures should be documented in the subject’s source documents/eCRF pages.
b.
Swollen Joint Count
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For ACR measures, the number of swollen joints will be determined by examination of 66 joints 
(33 joints on each side of the subject’s body). The 66 joints to be assessed and classified as swollen 
or not swollen include: 2 temporomandibular joints, 2 sternoclavicular joints, 2 acromioclavicular 
joints, 2 shoulder joints, 2 elbow joints, 2 wrist joints, 10 MCP joints, 2 interphalangeal joints of 
the thumb, 8 proximal interphalangeal joints of the hands, 8 distal interphalangeal joints of the 
hands, 2 knee joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal joints of the feet, 2 great toes 
(first proximal interphalangeal joint of the feet), and 8 proximal interphalangeal joints of the feet.
Joints will be classified as either swollen or not swollen. Swelling is defined as palpable fluctuating 
synovitis of the joint. Swelling secondary to osteoarthrosis will be assessed as not swollen, unless 
there is unmistakable fluctuation. Joint assessments of 1 particular subject should be performed by 
the same assessor (if at all possible) throughout the trial to minimize inter-observer variation.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at 
Screening and will be excluded from evaluation during the trial. The locations (or a listing) of 
surgical procedures should be documented in the subject’s source documents/eCRF pages.
c.
High sensitivity C-Reactive Protein
High-sensitivity C-reactive protein will be the ACR Core Set measure of acute phase reactant. It 
will be measured at the central laboratory to help assess the effect of evobrutinib on the subject’s 
RA.
ACR20
The ACR20 is a primary efficacy measure for which, at Week 12, a subject must have at least 20% 
improvement in the following ACR Core Set values.
TJC (68 joint count) and
SJC (66 joint count) and
An improvement of at least 20% in at least 3 of the following 5 assessments (see Section 7.3.1.7):
∀Patient’s Global Assessment of Disease Activity 
∀Patient’s Assessment of Pain
∀Patient’s Assessment of Physical Function as measured by the HAQ-DI
∀Physician’s Global Assessment of Disease Activity
∀Acute phase reactant as measured by hsCRP.
In this trial, ACR20 response calculations will use the HAQ-DI for the subject’s assessment of 
physical function and hsCRP as the measure of acute phase reactant.
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ACR50 and ACR70
The ACR50 and ACR70 are defined in the same way as the ACR20 using at least 50% and 
70% improvement, respectively.
ACR Hybrid
The ACR hybrid score provides a quasi-continuous score that can detect smaller changes between 
treatments than the categorical ACR20/50/70 scores by combining the ACR20, ACR50, and 
ACR70 scores with the mean percent change from Baseline in all 7 ACR core set components. It 
is calculated according to Table 6.
7.3.1.2
European League Against Rheumatism Responder Index
Assessments of subjects with RA by EULAR response criteria will be used to categorize subjects 
as nonresponders, moderate responders, good responders, or responders (moderate + good 
responders) according to Table 7 (van Gestel 1998). In this study, DAS28-hsCRP will be used to 
determine EULAR response.
7.3.1.3
American College of Rheumatology/European League 
Against Rheumatism Boolean Remission
Following the Boolean-based definition of remission of ACR/EULAR, at any time point, a subject
must satisfy all of the following: TJC ≤1, SJC ≤1, CRP ≤1 mg/dL and Patient’s Global 
Assessment of Disease Activity ≤1 (on a 0–10 scale). The Boolean criteria appear more stringent 
than the DAS28 remission and have been specifically created for use in clinical trials (Felson 2011, 
Bykerk 2012).
7.3.1.4
Disease Activity Score - high-sensitivity-C-Reactive Protein
The DAS28-hsCRP is a measure of disease activity in 28 joints that consists of a composite 
numerical score of the following variables: TJC, SJC, hsCRP, and Patient’s Global Assessment of 
Disease Activity (Vander Cruyssen 2005).
For DAS28-hsCRP, the 28 joints to be examined and assessed as tender or not tender for TJC and 
to be examined and assessed as swollen or not swollen for SJC include 14 joints on each side of 
the subject’s body: 2 shoulders, 2 elbows, 2 wrists, 10 MCP joints, 2 interphalangeal joints of the 
thumb, 8 proximal interphalangeal joints, and 2 knees (Smolen 1995).
In this trial, the acute phase reactant for computing DAS28 is the hsCRP. DAS28-hsCRP will be 
derived using the following formula from the DAS28 website (DAS 2016):
DAS28-hsCRP =  0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.014 × GH + 0.36 × ln(hsCRP + 1) +
0.96
Where:
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∀TJC28 = 28 joint count for tenderness
∀SJC28 = 28 joint count for swelling
∀ln(hsCRP) = natural logarithm of hsCRP
∀GH = the general health component of the Disease Activity Score (DAS) (ie, Patient’s Global 
Assessment of Disease Activity).
7.3.1.5
Clinical Disease Activity Index
The CDAI is calculated based on the following formula (Smolen 2014):
CDAI =  SJC28 + TJC28 + GH + PhGA
Where:
∀TJC28 = 28 joint count for tenderness
∀SJC28 = 28 joint count for swelling
∀GH = the general health component of the DAS (ie, Patient’s Global Assessment of Disease 
Activity on a 100-mm horizontal VAS, where the left end represents “very well”, and the right 
end represents “very poor”, converted to a cm scale [0 to 10 cm]).
∀PhGA = Physician’s Global Assessment of Disease Activity on a 100-mm horizontal VAS, 
where the left end represents “very well”, and the right end represents “very poor”, converted 
to a cm scale (0 to 10 cm).
7.3.1.6
Simplified Disease Activity Index
The SDAI is calculated based on the following formula (Smolen 2014):
SDAI =  SJC28 + TJC28 + GH + PhGA +hsCRP
Where:
∀TJC28 = 28 joint count for tenderness
∀SJC28 = 28 joint count for swelling
∀GH = the general health component of the DAS (ie, Patient’s Global Assessment of Disease 
Activity on a 100-mm horizontal VAS, where the left end represents “very well”, and the right 
end represents “very poor”, converted to a cm scale [0 to 10 cm])
∀PhGA = Physician’s Global Assessment of Disease Activity on a 100-mm horizontal VAS, 
where the left end represents “very well”, and the right end represents “very poor”, converted 
to a cm scale (0 to 10 cm)
∀hsCRP = high sensitivity C-reactive protein in mg/dL.
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7.3.1.7
Visual Analog Scales
Visual analog scales will include the patient’s assessment of pain, the patient’s assessment of 
disease activity, and the physician’s assessment of disease activity. Patient-reported outcome 
questionnaires must be performed prior to any other assessments at all visits.
Patient’s Assessment of Arthritis Pain: The subject’s assessment of his or her current level of 
pain related to arthritis over the previous 7 days will be recorded using the 100-mm horizontal 
VAS where the left end represents “no pain” and the right end represents “severe pain.” The scale 
should be administered prior to the tender and swollen joint count examination.
Patient’s Global Assessment of Disease Activity: The subject’s overall assessment of his or her 
disease activity during the last 24 hours will be recorded using a 100-mm horizontal VAS, where 
the left end represents “very well”, and the right end represents “very poor.” The subject will be 
asked “considering all the ways that your arthritis affects you, draw a single vertical line (|) through 
the line below to indicate how your arthritis is today.”
Physician’s Global Assessment of Disease Activity: The Investigator’s assessment of the 
subject’s current arthritis disease activity will be recorded using a 100-mm horizontal VAS, where 
the left end represents “no arthritis activity”, and the right end represents “extremely active 
arthritis.”
7.3.2
Physical Function Assessments
7.3.2.1
Health Assessment Questionnaire – Disability Index
The HAQ-DI is a subject-reported questionnaire that is commonly used in RA to measure disease 
associated disability (assessment of physical function). It consists of 24 questions referring to 
8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities 
(Fries 1980, Fries 1982, Ramey 1996).
The disability section of the questionnaire scores the subject’s self-perception on the degree of 
difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 
3 = unable to do) covering the following domains: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and performing other daily activities. The reported use of special aids or 
devices and/or the need for assistance of another person to perform these activities is also assessed. 
The scores for each of the functional domains will be averaged to calculate the functional disability 
index. 
Validated translated versions of the HAQ-DI will be used for each country participating in this 
trial.
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7.3.3
Prevention of Joint Structural Damage Progression
Joint structural damage will be assessed using MRI at Baseline and Weeks 4 and 12 in subjects 
participating in the MRI substudy.
7.3.3.1
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring 
System (RAMRIS)
Images of the MRI-designated hand and wrist (the hand being used in the MRI assessments will 
be assigned at Baseline and used consistently for the duration of the study) will be acquired using 
an MRI scanner as specified in the imaging guidelines. OMERACT RAMRIS scores for synovitis, 
bone marrow edema (osteitis), and erosions (Ostergaard 2004) will be read centrally by 
2 independent readers, who are blinded to dose assignment and to chronology of each time point. 
Discrepancies in RAMRIS scores between the 2 readers will be reviewed at a consensus 
adjudication session with both readers to reach a consensus score for the designated cases. At a 
minimum, the images with the top 10% discrepancies in scores between the 2 readers will be 
reviewed (refer to Imaging Guidelines for details of Adjudication and Selection of Cases for 
Adjudication).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs, ECGs, and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The Investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). 
The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Events
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not 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 CTCAE, version 4.03 (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.
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Only if a particular AE’s severity is not specifically graded by the guidance document, the 
Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following
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.
According to Sponsor convention, 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 1 of the serious criteria described 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 will 
not be recorded as separate event. Only, if no cause of death can be reported (eg, 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 the IMP/trial
treatment (including any other non-IMPs, radiation therapy, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP include, but may 
not be limited to, temporal relationship between the AE and the IMP, known side effects of IMP, 
medical history, de-challenge or re-challenge, concomitant medication, course of the underlying 
disease, concomitant disease and relevant history, and trial procedures.
Unrelated:
Not reasonably related to the IMP/trial treatment. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP under trial in this clinical trial 
protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
IMP/trial
treatment. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP under trial in this clinical trial 
protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the Investigator. If 
a laboratory abnormality fulfills these criteria, the identified medical condition (eg, anemia, 
increased ALT) must be reported as the AE rather than the abnormal value itself.
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Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
∀Results in death.
∀Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject 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. (Note: 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 subject or may 
require medical or surgical intervention to prevent 1 of the outcomes listed above. Examples of 
such events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood 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 an IMP is also 
considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (eg, an
overnight stay to facilitate the administration of intravenous fluids) are not considered SAEs. 
However, all events leading to unplanned hospitalizations or unplanned prolongation of an elective 
hospitalization (eg, 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 trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are not to be considered AEs.
Predefined Adverse Events of Special Interest
No adverse events of special interest have been designated for evobrutinib.
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7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject 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 eCRF. 
All SAEs must be additionally documented and reported using the appropriate Report Form as 
described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the IMP, and its outcome. In addition, serious cases should 
be identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues until the Safety Follow-up Visit
(see Section 7.1.4). SAEs occurring after a subject has taken the last dose of IMP will be collected 
throughout the subject’s participation until the Safety Follow-up Visit, regardless of the 
Investigator’s opinion of causation. Thereafter, SAEs are not required to be reported unless the 
Investigator determines the SAE was related to IMP, or protocol procedure. 
Any SAE assessed as related to evobrutinib must be reported whenever it occurs, irrespective of 
the time elapsed since the last administration of evobrutinib.
7.4.1.4
Procedure for Reporting Serious Adverse Events
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 SAE Report Form, following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be provided immediately thereafter.
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Relevant pages from the eCRF may be provided in parallel (eg, medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (eg, laboratory 
results, hospital report, autopsy report). In all cases, the information provided on the SAE Report 
Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (eg, additional 
information, outcome, final evaluation, or 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 responsible Medical Monitor, although in 
exceptional circumstances, the Global Drug Safety department may contact the Investigator 
directly to obtain further information or to discuss the event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards, and Investigators
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 trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial, or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are 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 with regard to Safety Report notifications 
to Investigators will be taken into account.
For Japan only: In accordance with ICH GCP and the Japanese ministerial ordinance on GCP, the 
Sponsor/designee will inform the Investigator and the head of the trial site of “findings that could 
adversely affect the safety of subjects, impact the conduct of the trial, or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial”. In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator and the head of the trial sites of AEs 
that are both serious and unexpected and are 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 with regard to Safety 
Report notifications to Investigators will be taken into account. The head of the trial site should 
also maintain copies of safety reports appropriately.
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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 trials 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.
7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final 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 subject 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. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (eg, resulting from 
a drug interaction with a contraceptive medication) are considered to be AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 7.4.1.3 must 
be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
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 subject sustains 
an event and the Parent-Child/Fetus AE Report Form if the child/fetus sustains an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from the IMP immediately. The Sponsor/designee must be notified without delay 
and the subject must be followed as mentioned above.
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7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in Table 10, 
following the timing noted in the Schedule of Assessments (Table 1). For the lipid panel, fasting 
for a minimum of 8 hours is required. All samples should be clearly identified. Sample collection, 
preparation, and handling/shipment procedures are described in the laboratory manual. For
WOCBP, including those who are postmenopausal for less than 12 months, serum pregnancy tests 
will be performed at initial screening, and high sensitivity urine pregnancy tests will be performed 
at the visits specified in Table 1. Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active Treatment Period (or when potential pregnancy is otherwise suspected), 
and at the end of the study to confirm the subject has not become pregnant during the study. 
Pregnancy tests may also be repeated as per request of institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.
Additional laboratory tests may be performed after abnormal findings.
Table 10
Clinical Safety Laboratory Evaluations
Screening 
virologya

Human immunodeficiency virus I and II antigen and antibodies

Hepatitis C antibody

Hepatitis C virus polymerase chain reaction (reflex test if hepatitis C antibody positive)

Hepatitis B core total and IgM antibody

Hepatitis B surface antigen

Hepatitis B surface antibody
Biochemistry

Albumin

Aspartate 
aminotransferase

Alanine aminotransferase

Alkaline phosphatase

γ-Glutamyl-transferase

Lactate dehydrogenase

Bilirubin (total) 

Protein (total)

Creatinineb

Amylasec

Lipasec

Total carbon dioxide 

Blood urea nitrogen

Glucose

Sodium

Potassium

Chloride

Calcium

Magnesium

Phosphate

Uric Acid
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Hematology

Hematocrit

Hemoglobin

Hemoglobin A1Cd

Red blood cell count

Mean corpuscular 
volume

Mean corpuscular 
hemoglobin

Mean corpuscular 
hemoglobin 
concentration

Reticulocyte count

Platelet count

White blood cell count

White blood cell 
differentials and absolute 
counts:
o
Basophils
o
Eosinophils
o
Lymphocytes
o
Monocytes
o
Neutrophils
Coagulationa

International normalized ratio

Partial thromboplastin time
Lipid panele

HDL-C

LDL-C

Total cholesterol

Triglycerides
Urinalysis/
microscopy

pH

Nitrite

Protein

Blood

Glucose

Ketone bodies

Urobilinogen

Bilirubin

Specific gravity

Microscopy (white blood 
cells, red blood cells, 
casts)f
Other screening 
testsa

QuantiFERON®
tuberculosis test

Serum β-D-glucan 
(Japan only)

Thyroid-stimulating 
hormone

Serum β-hCG (women 
only)

FSH (women who are 
postmenopausal only)
Reflex Testing 
for HBV DNA

HBV DNA PCR
Urine 

Highly sensitive urine
β-hCG (WOCBP only)
β-hCG = beta-human chorionic gonadotropin, DNA = deoxyribonucleic acid, FSH = follicle-stimulating hormone; 
HBsAg = hepatitis B surface antigen, HBV = hepatitis B Virus, HCV = hepatitis C Virus, HDL-C = high-density 
lipoprotein cholesterol, hsCRP = high sensitivity C-reactive protein, Ig = immunoglobulin, LDL-C = low-density 
lipoprotein cholesterol, PCR = polymerase chain reaction, WOCBP = women of childbearing potential.
a Performed only at Screening.
b Estimated glomerular filtration rate will be derived from serum creatinine.
c Reflex test for iso-enzymes if results are > 2 × upper limit of normal.
d Only for subjects with a diagnosis of diabetes; only at Screening.
e Subjects required to fast for a minimum of 8 hours prior to lipid panel.
f Microscopy will be performed if urinalysis results are abnormal for blood, protein, or nitrite.
7.4.3.1
Immunological Assessments
Blood samples for Ig levels (IgA, IgG, and IgM) and for B cell number will be collected as safety 
evaluations according to the Schedule of Assessments in Table 1. The actual date and time of each 
sample will be recorded.
Samples will be analyzed by the central analytical laboratory selected under the responsibility of 
the Sponsor using an appropriately validated bioanalytical method.
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For blood sample volumes, see laboratory manual.
 
7.4.3.2
High-Sensitivity 
C-Reactive 
Protein 
and 
Erythrocyte 
Sedimentation Rate
Samples for hsCRP and ESR will be collected at visits indicated in Table 1.
Samples for hsCRP will be analyzed by the central laboratory; ESR will be analyzed by local 
laboratories. Samples will be collected, labeled, processed, stored, and shipped according to the 
instructions in the laboratory manual.
7.4.3.3
B Cell Counts
Blood samples will be collected for counts of total B cells (as outlined in the laboratory manual) 
as indicated in Table 1. This population will be counted using flow cytometry.
The actual date and time of each sample will be recorded. Samples will be analyzed by the 
laboratory selected by the Sponsor using an appropriately validated method. Samples will be 
collected, labeled, processed, stored, and shipped according to the instructions in the laboratory 
manual.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs, including seated blood pressure, pulse rate, respiratory rate, weight, height, and oral 
temperature will be assessed predose at all trial visits (except height, only at Screening) (see
Table 1).
A semiautomated pulse rate and blood pressure recording device with an appropriate cuff size will 
be utilized. Pulse rate and blood pressure will be measured after 10 minutes rest with the subject’s 
arm unconstrained by clothing or other material. The blood pressure should be assessed in a seated 
position on the same arm for each subject throughout the trial.
7.4.4.2
Physical Examinations
Physical examinations will be assessed as indicated in Table 1.
Physical examination includes assessment of the following: general appearance, skin, head and 
neck, mouth, lymph nodes, thyroid, abdomen, and musculoskeletal, cardiovascular, and respiratory 
systems. Physical examination findings during Screening will be recorded as medical history 
events and new findings during the trial as AEs.
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An abbreviated physical examination should always include assessment of head, ears, eyes, nose, 
throat, lungs, heart, abdomen, and extremities and other systems as required by symptoms.
7.4.4.3
12-lead ECG and Chest X-ray
A single 12-lead ECG will be performed as indicated in Table 1. The 12-lead ECG recordings will 
be obtained after 10 minutes of rest in a semisupine position.
 blood sampling should 
be collected immediately following ECG assessment.
The following ECG parameters will be obtained from the computerized 12-lead ECG recordings: 
rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. The 
corrected QT interval (QTcF) will be calculated using Fridericia’s formula. 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 printout of the ECG is to be signed, dated, and filed in the Investigator’s Site File along with 
a signed and dated copy (if the printouts are not on archive-quality paper). In addition, ECGs will 
also be stored digitally by the Sponsor.
Posterioanterior CXRs will be performed during Screening according to local standard practice. 
Subjects who had a CXR performed for clinical reasons within the last 3 months of Screening 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 12-lead ECG and CXR will be performed and read locally.
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Every effort should be made to collect
 according to the Schedule of Assessments 
at the exact nominal time relative to dosing. Samples will not be considered protocol deviations as 
long as the actual collection date and time is recorded and is within the window referenced in the 
Schedule of Assessments. 
For subjects randomized to placebo treatment, 
 samples will be collected but not analyzed 
unless determined necessary by the Investigator and/or Sponsor.
 
 
Samples will be collected, labeled, processed, stored, and shipped as detailed in the laboratory 
manual.
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7.7
Assessment of Symptoms and Health Related Quality of Life 
(HRQoL)
7.7.1
Medical Outcomes Study 36-item Short-Form Health Survey
The SF-36v2 is a 36-item scale constructed to survey HRQoL on eight domains: limitations in 
physical activities due to health problems; limitations in social activities due to physical or 
emotional problems; limitations in usual role activities due to physical health problems; bodily 
pain; general mental health (psychological distress and well-being); limitations in usual role 
activities due to emotional problems; vitality (energy and fatigue); and general health perceptions 
(Ware 1992).
The SF-36v2 has a 4 weeks recall period and yields scale scores for each of the eight health 
domains, and 2 summary measures of physical and mental health: the Physical Component 
Summary and Mental Component Summary.
7.7.2
Functional Assessment of Chronic Illness Therapy-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue is a 13-item 
questionnaire that assesses self-reported fatigue and its impact upon daily activities and function 
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(Wolfe 1996). It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 
3 = quite a bit; 4 = very much). As each of the 13 items of the FACIT-Fatigue scale ranges from 
0–4, the range of possible scores is 0–52, with 0 being the worst possible score and 52 the best. To 
obtain the 0–52 score, each negatively worded item response is recoded so that 0 is a bad response 
and 4 is good response. All responses are added with equal weight to obtain the total score.
 
 
 
 
 
 
 
 
 
 
 
 
 
7.8
Other Assessments
 
 
8
Statistics
8.1
Sample Size
The primary endpoint of the trial is the ACR20 response at Week 12.
A sample size of 80 evaluable subjects per group will provide approximately 90% power at an 
α of 0.05, 2-sided significance level to detect a difference in Week 12 ACR20 response proportion 
between evobrutinib- and placebo-treated subjects, assuming a placebo response proportion of 
30% to 45% and an expected treatment benefit of 30%, after adjusting for multiple comparisons 
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of 3 dose comparisons with placebo. For the same range of placebo response rate, the sample size 
of 80 evaluable subjects per group will also provide adequate power (approximately 80%) for the 
expected difference of 25%. 
To account for reduced information provided by the Modified Intent-to-Treat (mITT) analysis set, 
due to subject dropout and protocol noncompliance, occurring at a rate of approximately 11% over 
a 12-week period, approximately 90 subjects per group will be enrolled. The sample size was 
calculated using a chi-squared test of the odds ratio in nQuery Advisor® 7.0.
The Japanese cohort size was determined to provide an evaluation of consistency in the Week 12 
ACR20 response proportion between the non-Japan and Japan regions. Assuming that:
(i)
the Week 12 ACR20 response proportion in the placebo group is 0.30 for both the 
non-Japan and Japan regions, 
(ii)
the Week 12 ACR20 response proportion due to each of the 3 evobrutinib dose groups 
is 0.60 for both regions, so that the true underlying effect size is 0.30 for both regions, 
(iii)
a total evaluable sample size of 320 (ie, 240:80 randomization for evobrutinib:placebo) 
is involved in analysis of the two regions, 
and applying “Method 2” from the Pharmaceuticals and Medical Devices Agency Guidance, 
32 evaluable subjects in the Japanese cohort are required so that both observed region-specific 
effect sizes exceed 0.10 with probability of approximately 80%. Taking into account a loss of 
information due to 10% dropout at Week 12, the total number of Japanese subjects to be 
randomized is 36, or 10% of the total planned enrollment of 360 subjects. The sample size was 
calculated via simulations with SAS version 9.3. The power is the average of 3 estimated 
probabilities, with each estimate based on 10,000 simulations.
For the evaluation of MRI data, assuming a minimum effect size of 0.7 for the difference in the 
change from Baseline in the OMERACT RAMRIS individual scores for osteitis or synovitis at 
Week 12 between at least one dose and placebo, at a 2-sided α = 0.05, a sample size of 40 evaluable 
subjects per group with MRI data will provide approximately 80% power using the Wilcoxon 
rank-sum test in nQuery Advisor® 7.0. The same sample size will provide approximately 70% 
power for an effect size of 0.6. To account for approximately 11% dropout and nonevaluable MRI 
data, approximately 45 subjects per arm will be enrolled in the MRI study. Since there were no 
high-quality data available to form the basis for accurate sample size calculations for RAMRIS 
scores involving a study population similar to that planned for the present study, the assumed effect 
size of 0.7 is considered comparable to those reported in the published studies (Conaghan 2011, 
Genovese 2016a, Genovese 2016b).
8.2
Randomization
A randomized allocation schedule for IMP assignment will be generated by a third party vendor 
who is not on the study team. Randomization will occur using the IWRS.
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Eligible subjects will be randomized into 1 of 3 evobrutinib arms (25 mg once daily, 75 mg once 
daily, or 50 mg twice daily) or the placebo arm in a ratio of 1:1:1:1 stratified by whether or not 
they are in the MRI substudy (Yes, No) and by region (US, Western Europe, Japan, and the rest of 
world), so that within each treatment arm, there will be approximately 90 subjects, with 
approximately 45 subjects included in the MRI substudy to ensure approximately 80 evaluable 
subjects per arm for the primary analysis, and approximately 40 evaluable subjects per arm for the 
MRI analysis.
To ensure an adequate number of evaluable MRI subjects in the MRI substudy, recruitment of 
non-MRI subjects into the study may be capped. If a subject’s baseline MRI indicates lack of 
osteitis and synovitis, additional subjects may be added to the MRI stratum to account for these 
subjects. Should the MRI substudy recruitment prove more difficult than anticipated, the Sponsor 
reserves the right to terminate the MRI substudy. Should this be done, all sites would be allowed 
to recruit non-MRI subjects into the study.
8.3
Endpoints
8.3.1
Primary Endpoint
The primary efficacy endpoint is ACR20 response assessed using hsCRP (ACR20) at Week 12.
8.3.2
Secondary Endpoints
The key secondary efficacy endpoints are:
∀DAS28-hsCRP low disease activity (DAS28 < 3.2) rate at Week 12
∀DAS28-hsCRP remission (DAS28 < 2.6) rate at Week 12
∀ACR 50% (ACR50) response assessed using hsCRP at Week 12
∀ACR 70% (ACR70) response assessed using hsCRP at Week 12.
The key secondary safety endpoints are: 
∀The nature, severity, and occurrence of AEs and serious AEs (SAEs)
∀Absolute values and change from Baseline in:
o
Vital signs
o
ECG parameters including RR interval, PR interval, QRS duration, QT interval, and QTcF 
interval
o
Serum Ig levels (IgG, IgA, IgM)
o
Total B cell counts
o
Clinical laboratory parameters.
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Other secondary efficacy endpoints are:
At Week 12:
∀Achieving American College of Rheumatology/European League Against Rheumatism 
(EULAR) Boolean remission
∀Achieving Clinical Disease Activity Index (CDAI) score ≤2.8 (CDAI remission)
∀Achieving Simplified Disease Activity Index (SDAI) score ≤3.3 (SDAI remission)
∀EULAR Responder Index (based on DAS-hsCRP)
∀ACR hybrid scores computed using hsCRP
∀Change from Baseline in DAS28-hsCRP
∀Change from Baseline in CDAI and SDAI
∀Changes and percentage changes from Baseline of individual components of the ACR Core Set
∀Imaging:
o
Change from Baseline in Outcome Measures in Rheumatology Clinical Trials 
(OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System 
(RAMRIS) scores (designated hand, minimal assessed joints: wrist, metacarpophalangeal 
(MCP) joints #1 to #5) for subjects in the MRI substudy:

Synovitis score

Bone marrow edema (osteitis) score.
∀Changes from Baseline of Physical Function:
o
Health Assessment Questionnaire – Disability Index (HAQ-DI).
∀Changes from Baseline of HRQoL:
o
Medical Outcomes Study 36-item Short Form Health Survey (SF-36)
o
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue.
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8.4
Analysis Sets
For the purposes of analysis, the following analysis sets are defined in the following table:
Population
Description
Enrolled 
All participants who sign informed consent
Intent-to-treat (ITT)
The ITT analysis set will include all subjects randomly allocated to a treatment, based 
on the intention to treat “as randomized” principle (ie, the planned treatment regimen 
rather than the actual treatment given in case of any difference).
Modified intent-to-treat 
(mITT)
The mITT analysis set will include all randomized subjects who received at least one 
dose of IMP (evobrutinib or placebo). Subjects in the mITT analysis set will be 
included in the treatment group as randomized.
Per-Protocol (PP)
The PP analysis set will include all randomized and treated subjects who do not have 
any clinically important protocol deviations.
MRI 
The MRI analysis set will include all randomized subjects who have at least 1 post 
dose MRI assessment.
Safety (SAF)
The SAF analysis set will include all subjects who receive at least 1 dose of IMP 
(evobrutinib or placebo). Subjects will be analyzed according to the actual treatment 
they receive.
The mITT analysis set will be used for the purpose of efficacy analysis unless otherwise stated; 
the SAF analysis set will be used for the purpose of safety analysis; and the PP analysis set will be 
used for the purpose of sensitivity analysis of the primary efficacy endpoint.
8.4.1
Subgroups
The following subgroups may be considered for primary/key secondary efficacy analyses:
∀Region: US, Western Europe, Japan, the rest of world
∀MRI substudy participation: Yes/No
∀Ethnicity: Japanese/Non-Japanese
∀Gender: Male/Female.
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Other subgroups may be defined in the SAP.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
A general description of the statistical methods to be used to analyze the efficacy and safety data 
is outlined below. Prior to locking of the database for the study, a detailed SAP will be finalized. 
Any changes to the data analysis methods described in the protocol will require an amendment 
only if a principal feature of the protocol is affected. Any other changes to the planned data analysis 
that does not require a protocol amendment will be described in the SAP and the CTR. Additional 
exploratory analyses will be conducted as deemed appropriate.
A 2-sided α level of 0.05 will be applied for tests of treatment effect within the study. 
For the purpose of statistical analyses, baseline is defined as the last assessment prior to first dose. 
In general, continuous variables will be summarized descriptively using the number of 
observations (N), mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), 
minimum, and maximum. Categorical variables will be summarized using frequency counts and 
percentages.
Statistical analysis will be performed using the computer program package SAS® System for 
Windows (version 9.4 or higher; SAS Institute, Cary North Carolina, USA).
Missing Data Handling:
For the primary and key secondary endpoints of ACR response, the Last Observation Carried 
Forward will be used as the primary method for the imputation of missing values of the ACR 
components. For the ACR20 response at Week 12, a subject will be considered as a nonresponder 
if the subject discontinues prior to Week 12. Other imputation methods will be provided in the 
SAP as additional sensitivity analyses of the primary endpoint.
Missing data for all other secondary efficacy endpoints of binary data will be handled using a 
similar manner to ACR20. Further details for each endpoint will be provided in the SAP.
For the MRI analysis, a Missing At Random (MAR) pattern will be assumed for missing data in 
the Mixed Model for Repeated Measures. 
Details of handling missing data for all other secondary efficacy endpoints of continuous data will 
be provided in the SAP.
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Multiplicity Adjustment:
A family-wise Type I error rate (FWER) at the primary analysis will be controlled at the 2-sided 
0.05 significance level for the 3 pairwise comparisons of evobrutinib dose versus placebo, using 
the Hochberg procedure. Further details will be provided in the SAP.
8.5.2
Analysis of Primary Endpoint
8.5.2.1
Efficacy Endpoints
The primary analysis of ACR20 at Week 12 will be based on the mITT analysis set using Last 
Observation Carried Forward for imputation of missing values of each ACR component. A subject 
will be considered as a nonresponder if the subject discontinues prior to Week 12.
The estimate of the odds ratio (OR), together with the associated 2-sided 95% CI and p-value, 
comparing each evobrutinib dose group to placebo, will be provided based on a logistic regression 
model for the odds of ACR20 response, with evobrutinib dose group or placebo as a factor and 
adjustment for covariates based on randomization strata (region, MRI-substudy participation). In 
order to further characterize the dose-response, the proportion of ACR20 response at Week 12 will 
also be presented for each treatment group, along with the difference in ACR20 response 
proportion between evobrutinib and placebo, and the 95% CI for the difference. Details will be 
provided in the SAP.
The dose response will also be assessed via a modeling approach as additional supportive analyses. 
Details will be provided in the SAP.
Additional sensitivity analyses will be performed to assess the robustness of the primary missing 
data imputation method and will be described in detail in the SAP.
8.5.3
Analysis of Secondary Endpoints
8.5.3.1
Key Secondary Efficacy Endpoints
Analyses of all key secondary efficacy endpoints will be performed using the same approach as 
the ACR20, based on the mITT analysis set.
8.5.3.2
Key Secondary Safety Endpoints
Analysis of safety secondary endpoints is described in Section 8.5.4.1.
8.5.3.3
Imaging Data and Other Efficacy Endpoints
Analysis of the change from Baseline scores of the MRI data will be performed on the appropriate 
analysis sets (MRI analysis set for the RAMRIS and CARLOS scores) using a Mixed Model for 
Repeated Measures, with treatment arm as factors, and randomization strata, and Baseline as 
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covariates. Missing data will be handled as MAR. Other imputation methods will be provided in 
the SAP as additional sensitivity analyses.
Analyses of all other efficacy endpoints will be exploratory in nature and details will be further 
provided in the SAP.
8.5.3.4
Patient-reported Health Related Quality of Life (HRQoL)
Change in SF-36 Physical Component Summary and Mental Component Summary scores (and 
their components) over time and change in FACIT-Fatigue score over time will be summarized 
using descriptive statistics.
Further details will be presented in the SAP that will be finalized before database lock.
8.5.4
Analysis of Safety and Other Endpoints
8.5.4.1
Safety
Analyses of safety will be carried out as follows.
Adverse events will be summarized by treatment group, severity, and relationship to IMP. Serious 
AEs, AEs leading to treatment discontinuation (permanent, temporary), and AEs leading to study 
withdrawal will be summarized by treatment group.
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects experiencing 1 or more treatment-emergent 
AEs (TEAEs) will be summarized according to the MedDRA system organ classes and preferred 
terms by treatment group, relationship to IMP, and severity. The severity of AEs will be graded 
using NCI-CTCAE v4.03 toxicity grades (US Department of Health and Human Services 2010).
Summary and analysis of AEs will be performed based on the 3-tier approach (Crowe 2009) as 
further detailed in the trial SAP.
Summary statistics will be used to present observed values and changes from Baseline in 
continuous laboratory parameters and vital signs. Shift tables will be used to present changes in 
categorical laboratory parameters. Figures may be generated to assist safety evaluation.
The 12-lead ECG data (RR [ms], PR [ms], QRS [ms], QT [ms], and QTcF [ms]) will be
summarized for observed values and change from baseline values by treatment using descriptive 
statistics. Electrocardiogram outlier values will be summarized by treatment in frequency tables 
using number and percentage of subjects. Investigator reported overall interpretation results will 
be listed and tabulated by treatment using the number and percentage of subjects for each 
interpretation category (Normal, Abnormal Not Clinically Significant, Abnormal Clinically 
Significant, and Abnormal Overall). A concentration-QT analysis may be conducted.
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Additional details of safety data analyses will be provided in the SAP.
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8.5.4.7
Subgroup Analyses
All subgroup analyses are descriptive in nature and primarily aim at assessing the consistency of 
the results.
Analysis of the MRI change from Baseline scores will be performed on the MRI analysis set.
In addition, the following subgroup analyses will be performed for the primary and key secondary 
efficacy endpoints:
∀Region: US, Western Europe, Japan, the rest of world
∀MRI substudy participation: Yes/No
∀Ethnicity: Japanese/Non-Japanese
∀Gender: Male/Female.
Other subgroup analyses may also be performed. Details will be provided in the SAP.
8.6
Planned Analysis
There is 1 planned analysis from this study. The final analysis will be triggered when 100% of 
subjects randomized complete the safety follow-up or discontinue prematurely from the study, the 
protocol violations are determined, and the database is locked. All data collected up to and 
including the Safety Follow-up Visit will be included in this analysis. A consistency analysis is 
also planned to be performed as part of the final analysis to evaluate the consistency of efficacy at 
Week 12 between the Japan and non-Japan subjects. If the Japanese cohort enrollment is too slow 
to have n = 32 to 36 evaluable subjects included in the consistency analysis, then the consistency 
analysis will not occur.
All data collected will be included for statistical analyses. Further details will be provided in the 
SAP.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that only 
subjects who have given informed consent are included in the trial. For Japan only: The 
Investigator is also responsible for the standards stipulated in Article 14, Paragraph 3, and Article 
80-2 of the Pharmaceutical Affairs Act in Japan, and the “Ministerial Ordinance on Good Clinical 
Practice for Drugs” (GCP) in Japan. 
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According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration for marketing approval and could contribute significantly to the demonstration of 
efficacy and safety of an IMP (which are considered “covered clinical trials” by the FDA), the 
Investigator and all Subinvestigators are obliged to disclose any financial interest which they, their 
spouses or their dependent children may have in the Sponsor or the Sponsor’s product under study. 
This information is required during the trial and for 12 months following completion of the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. In Japan when a 
subject is < 20 years of age, the written informed consent must be obtained from the subject’s 
parent or guardian in addition to the subject’s voluntary written consent. Adequate information 
must therefore be given to the subject by the Investigator or an appropriate designee (if local 
regulations permit) before informed consent is obtained. 
A Subject Information Sheet must be prepared in the local language in accordance with Note for 
Guidance on GCP (ICH Topic E6, 1996) and will be provided by the Sponsor for the purpose of 
obtaining informed consent. In Japan, a subject information sheet in the local language and 
prepared in accordance with Japan’s GCP and the Note for Guidance on GCP (ICH Topic E6, 
1996) will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the trial and sign the ICF, as above.
Where the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. In Japan, where the information is provided by the Investigator, the 
ICF must be signed and personally dated by the subject and/or the subject’s legal representative as 
applicable, and the Investigator.
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing and 
inspection purposes. A copy of the signed and dated information sheet and ICF should be provided 
to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the Subject Information Sheet and any other written information to be
provided to the subjects and submit them to the IRB for review and opinion. Using the approved 
revised Subject Information Sheet and other written information, the Investigator will explain the 
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changes to the previous version to each trial subject and obtain new written consent for continued 
participation in the trial. In Japan, the Investigator will explain the changes to the previous version 
to each study subject and/or the subject’s legal representative as applicable and obtain new written 
consent for continued participation in the study. The subject will be given sufficient time to read 
the information and the opportunity to ask questions and to request additional information and 
clarification about the changes.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. For each subject, original medical data will be accessible for the purposes of source 
data verification by the Monitor, audits and regulatory inspections, but subject confidentiality will 
be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor for use
during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the 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 trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he or she will answer 
any questions. Any subsequent action (eg, unblinding) will follow the standard process established 
for Investigators.
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In cases where the Investigator is not available, the Sponsor provides the appropriate means to 
contact a Sponsor physician. This includes the provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor physician 
to assist with the medical emergency and to provide support for the potential unblinding of the 
subject concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the trial. Insurance conditions 
shall meet good local standards, as applicable.
In Japan, the Sponsor is entirely responsible for AEs that are associated with this trial and impair 
the health of the subjects, except for AEs caused by an intentional and/or significant deviation on 
the part of the Investigator, the trial site, and/or the subject. The Sponsor will provide insurance to 
fulfill this responsibility.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents to the responsible IEC or IRB for its favorable opinion or 
approval, which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial 
Master File.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members were present. Written evidence of 
favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version and 
the Subject Information and ICF version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements.
In Japan, the person installing an IEC/IRB must retain all records, including documents that relate 
to the clinical trial for the required period in accordance with Japan’s GCP.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (eg, IMP Dossier, Subject 
Information Sheet, and ICF) will be submitted or notified to the Health Authorities in accordance 
with all local and national regulations for each site.
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10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely. The data in the eCRF should be consistent with the relevant source 
documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names.
For subject-reported outcome data such as HRQoL, physical functioning and pain assessments, an 
electronic patient-reported outcome system (ePRO) will be used.
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures have been completed. Portable 
document files of the eCRFs will be provided to the Investigators at the completion of the trial.
10.2
Source Data and Subject Files
The Investigator (or in Japan the head of trial site) must keep a file (medical file, original medical 
records) on paper or electronically for every subject in the trial. It must be possible to identify each 
subject by using this subject file. This file will contain the demographic and medical information 
for the subject listed below and should be as complete as possible. 
∀Subject’s full name, date of birth, sex, height, and weight
∀Medical history and concomitant diseases
∀Prior and concomitant therapies (including changes during the trial)
∀Trial identification, ie, the Sponsor trial number for this clinical trial, and subject number
∀Dates for entry into the trial (informed consent) and visits to the site
∀Any medical examinations and clinical findings predefined in this clinical trial protocol
∀All AEs
∀Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
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All documents containing source data must be filed, including, but not limited to CT or MRI scan 
images, ECG recordings, and laboratory results. Such documents must bear the subject number 
and the date of the procedure. If possible, this information should be printed by the instrument 
used to perform the assessment or measurement. As necessary, medical evaluation of such records 
should be performed; all evaluations should be documented, signed, and dated by the Investigator.
For data that may be recorded directly in the eCRF such as a questionnaire or diary, there will be 
no record in the original subject file and therefore the data entered in the eCRF will be considered 
source data. The clinical trial protocol or the Manual of Operations should clearly and completely 
specify all subject data in the eCRF to be considered source data. 
Electronic subject files will be printed whenever the Medical Monitor performs source data 
verification. Printouts must be signed and dated by the Investigator, countersigned by the Medical 
Monitor, and kept in a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Medical Monitor, during Sponsor audits,
and for inspection by Health Authorities during and after the trial, and must be safely archived for 
at least 15 years (or longer, per local requirements or as otherwise notified by the Sponsor) after 
the end of the trial. The documents to be archived include the Subject Identification List and the 
signed subject ICFs. If archiving of the Investigator Site File is no longer possible at the site, the 
Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
In Japan, a record retainer designated by the head of the trial site must retain all records, including 
documents and data, which relate to the clinical trial in accordance with GCP. The head of the trial
site must retain the records at the site (hospital, research institute, or practice) for the longest 
possible time permitted by Japan’s GCP, and/or as per ICH GCP guidelines, whichever is longer. 
In any case, the head of the trial site should ensure that no destruction of medical records is 
performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP, the Japanese ministerial ordinance 
on GCP (for Japan only), and any other applicable regulations. The site Medical Monitor will 
perform visits to the trial site at regular intervals.
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The clinical trial protocol, each step of the data capture procedure, and the handling of the data,
including the final CTR, will be subject to independent Quality Assurance activities. Audits may 
be conducted at any time during or after the trial to ensure the validity and integrity of the trial 
data. Representatives of the Quality Assurance unit from the Sponsor or a designated organization, 
as well as Health Authorities, must be permitted to access all trial documents and other materials 
at the site, including the Investigator Site File, the completed eCRFs, all IMP and IMP 
accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to the Health Authorities and to the relevant IEC/IRB (or through the 
head of the trial site, in Japan only) for approval or favorable opinion. In such cases, the 
amendment will be implemented only after approval or favorable opinion has been obtained (or 
only after written approval from the head of the trial site has been obtained, in Japan only).
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a CTR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 within the legally required 
period of the participating countries.
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoint and will include 
data from all trial sites. The Investigator will inform the Sponsor in advance about any plans to 
publish or present data from the trial. Any publications and presentations of the results (abstracts 
in journals or newspapers, oral presentations, etc.), either in whole or in part, by Investigators or 
their representatives will require review by the Sponsor before submission. The Sponsor will not 
suppress publication, but maintains the right to delay publication in order to protect intellectual 
property rights.
Posting of data on clinicaltrials.gov and eudract.ema.europa.eu is planned and will occur 
12 months after the last clinic visit of the final trial subject or another appropriate date to meet 
applicable requirements.
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11
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Kivitz A, Gupta R, Valenzuela G, et al. A Phase 2a, 4-Week Double-Blind, Proof-of-Concept 
Efficacy and Safety Study of CC-292 Versus Placebo As Co-Therapy with Methotrexate in Active 
Rheumatoid Arthritis. Poster session presented at: Rheumatoid Arthritis – Small Molecules, 
Biologics and Gene Therapy, Annual Meeting of the American College of Rheumatology; 
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Levey A, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification 
of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 
2006;145:247–54.
Louder AM, Singh A, Saverno K, et al. Patient Preferences Regarding Rheumatoid Arthritis 
Therapies: A Conjoint Analysis. Am Health Drug Benefits. April 2016;9(2):84-93.
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Nakayamada S, Kubo S, Iwata S, et al. Review Erratum: Recent Progress in JAK Inhibitors for the 
Treatment of Rheumatoid Arthritis. BioDrugs. 30 October 2016;30(5):407-19. Review Erratum 
in: BioDrugs. October 2016;30(5):483.
Norman P. Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid 
arthritis. Expert Opin Investig Drugs. 2016;25(8):891-9.
Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic 
Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, and the 
OMERACT RA-MRI scoring system. J Rheumatol. 2003;30(6):1385-6. Erratum in: J Rheumatol. 
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Ostergaard M, Peterfy CG, Bird P, et al. The OMERACT Rheumatoid Arthritis Magnetic 
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Patel A, Moreland L. Interleukin-6 inhibition for treatment of rheumatoid arthritis: A review of 
tocilizumab therapy. Drug Des Devel Ther. 2010;4:263-78.
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van Gestel A, Haagsma C, van Riel P. Validation of rheumatoid arthritis improvement criteria that 
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of certolizumab pegol plus methotrexate in patients with active rheumatoid arthritis: Data from a 
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Vander Cruyssen B, Van Looy S, Wyns B, et al. DAS28 best reflects the physician’s clinical 
judgment of response to infliximab therapy in rheumatoid arthritis patients: validation of the 
DAS28 score in patients under infliximab treatment. Arthritis Res Ther. 2005;7(5):R1063-71.
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J Rheumatol. 1996;23:1407-17.
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12
Appendices
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Appendix I:
Contraceptive Guidance and Woman of Childbearing Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
∀Documented hysterectomy
∀Documented bilateral salpingectomy
∀Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal
3. Postmenopausal female
∀Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening.
∀Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use 1 of the nonhormonal highly effective contraception methods if they 
wish to continue their HRT during the trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrollment.
Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctlya. 
∀
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of 
ovulationb
∀
oral 
∀
intravaginalc
∀
transdermalc
∀
Progestogen-only hormonal contraception associated with inhibition of ovulationb
∀
oral 
∀
injectablec
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Highly Effective Methods That Are User Independent 
∀
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb,c
∀
Intrauterine device (IUD)
∀
Intrauterine hormone-releasing system (IUS)
∀
bilateral tubal occlusion
∀
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of
contraception should be used).
∀
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the trial treatment. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the participant.) 
Barrier Methods
∀
Male or female condom with or without spermicidec
∀
Capc, diaphragm or sponge with spermicidec
Notes: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the trial treatment, which may reduce the efficacy of 
the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during the 
Treatment Period and for at least 90 days after the last dose of trial treatment.
c) Not approved in Japan apart from male condom.
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Appendix II: Joint Count Assessment Forms (66/68 Joint Evaluation)
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Patient Right
Patient Left
Pain/Tenderness
Swelling
Pain/Tenderness
Swelling
JOINTa
(Circle Correct Answer)
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
0 = Absent
1 = Present
9 = Not applicablea
1.  Temporomandibular
0
1
9
0
1
9
0
1
9
0
1
9
2.  Sternoclavicular
0
1
9
0
1
9
0
1
9
0
1
9
3.  Acromio-clavicular
0
1
9
0
1
9
0
1
9
0
1
9
4.  Shoulder
0
1
9
0
1
9
0
1
9
0
1
9
5.  Elbow
0
1
9
0
1
9
0
1
9
0
1
9
6.  Wrist
0
1
9
0
1
9
0
1
9
0
1
9
7.  Metacarpophalangeal I
0
1
9
0
1
9
0
1
9
0
1
9
8.  Metacarpophalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
9.  Metacarpophalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
10. Metacarpophalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
11. Metacarpophalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
12. Thumb Interphalangeal
0
1
9
0
1
9
0
1
9
0
1
9
13.  Proximal Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
14.  Proximal Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
15.  Proximal Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
16.  Proximal Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
17.  Distal Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
18.  Distal Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
19.  Distal Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
20.  Distal Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
21.  Hip
0
1
9
N/A
0
1
9
N/A
22.  Knee
0
1
9
0
1
9
0
1
9
0
1
9
23.  Ankle
0
1
9
0
1
9
0
1
9
0
1
9
24.  Tarsus
0
1
9
0
1
9
0
1
9
0
1
9
25.  Metatarsophalangeal I
0
1
9
0
1
9
0
1
9
0
1
9
26.  Metatarsophalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
27.  Metatarsophalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
28.  Metatarsophalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
29.  Metatarsophalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
30.  Great Toe
0
1
9
0
1
9
0
1
9
0
1
9
31.  Interphalangeal II
0
1
9
0
1
9
0
1
9
0
1
9
32.  Interphalangeal III
0
1
9
0
1
9
0
1
9
0
1
9
33.  Interphalangeal IV
0
1
9
0
1
9
0
1
9
0
1
9
34.  Interphalangeal V
0
1
9
0
1
9
0
1
9
0
1
9
a For replaced, ankylosed, or arthrodesed joints, please record as 9 (not applicable) and record details of replaced, 
ankylosed, arthrodesed joints in sections of the eCRF that relate to medical history and physical examination.
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Appendix III:Signature Pages and Responsible Persons for the Trial
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Signature Page – Protocol Lead
Trial Title:
A Phase IIb, Randomized, Double-blind Study in 
Subjects with Rheumatoid Arthritis Evaluating the 
Safety and Efficacy of Evobrutinib Compared with 
Placebo in Subjects with an Inadequate Response to 
Methotrexate
IND Number:
EudraCT Number:
2017-000384-32
Clinical Trial Protocol 
Date/Version:
12 July 2018/Version 3.0
Protocol Lead:
I approve the design of the clinical trial:
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
EMD Serono Research & Development Institute
Address:
45A Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number:
E-mail address:
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Signature Page – Coordinating Investigator
Trial Title
A Phase IIb, Randomized, Double-blind Study in 
Subjects with Rheumatoid Arthritis Evaluating the 
Safety and Efficacy of Evobrutinib Compared with 
Placebo in Subjects with an Inadequate Response to 
Methotrexate
IND Number
EudraCT Number
2017-000384-32
Clinical Trial Protocol Date/Version
12 July 2018/Version 3.0
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
 
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Signature Page – Principal Investigator
Trial Title
A Phase IIb, Randomized, Double-blind Study in 
Subjects with Rheumatoid Arthritis Evaluating the 
Safety and Efficacy of Evobrutinib Compared with 
Placebo in Subjects with an Inadequate Response to 
Methotrexate
IND Number
EudraCT Number
2017-000384-32
Clinical Trial Protocol 
Date/Version
12 July 2018/Version 3.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials 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 the purpose of complying with the regulatory requirements. I therefore 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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Sponsor Responsible Persons not Named on the Cover Page
Name, academic degree:
Function/Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike, Billerica MA 01821, USA
Telephone number:
E-mail address:
Name, academic degree:
Function/Title:
Project Biostatistician
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number:
E-mail address:
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Appendix IV: Protocol Amendment History
The information for the current amendment is on the title page.
The original Protocol version 1.0 was issued on 11 May 2017.
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or 
Country
Included 
in the 
current 
document
(Y/N)
Version
Amendment 1
N
03 July 2017
United States
N
1.1
Amendment 2
Y
13 December 2017
Global
Y
2.0
Amendment 3
Y
16 November 2017
United States
N
2.1
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Amendment 2
Protocol Version 1.0 (11 May 2017) was the original global protocol. A global amendment was 
issued on 13 December 2017.
Rationale and Major Scientific Changes
Major scientific changes to the protocol were made to add a Japanese cohort, to align the protocol 
with Japan GCP and local regulatory requirements in Japan, to add fasting requirements, to reduce 
the Treatment Period from 24 weeks to 12 weeks and remove rescue therapy, to increase safety 
monitoring by adding visits at Week 6 and Week 10 during the Treatment Period, and to reduce 
the length of the OLE Period from 24 months to 12 months.
Administrative and Editorial Changes
Minor editorial changes were made to correct typos, formatting, and stylistic consistency.
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Evobrutinib
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Integrated Analysis Plan
Clinical Trial Protocol 
Identification No.
MS200527-0060
Title:
A Phase IIb, Randomized, Double-blind Study in Subjects with
Rheumatoid Arthritis Evaluating the Safety and Efficacy of 
Evobrutinib Compared with Placebo in Subjects with an 
Inadequate Response to Methotrexate
Trial Phase
IIb
Investigational Medicinal 
Product(s)
Evobrutinib
Clinical Trial Protocol 
Version
12 July 2018/Version 3.0
16 November 2017/Version 2.1 (for US only)
Integrated Analysis Plan 
Authors
Coordinating Author
, Merck KGaA / EMD Serono Research & Development 
Institute, Inc.
Function
Author(s) / Data Analyst(s)
, EMD Serono 
Research & Development Institute, Inc.
Integrated Analysis Plan
Date and Version
14 October 2019 / Version 2.0
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Integrated Analysis Plan 
Reviewers
Merck KGaA / EMD Serono Research & Development Institute, 
Inc. Reviewers:
Function
Name
 
 
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 © 2019 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Signature Page
Integrated Analysis Plan: MS200527-0060
A Phase IIb, Randomized, Double-blind Study in Subjects with Rheumatoid Arthritis Evaluating
the Safety and Efficacy of Evobrutinib Compared with Placebo in Subjects with an Inadequate 
Response to Methotrexate
Approval of the IAP by Merck KGaA / EMD Serono Research & Development Institute, Inc.
Responsible is documented within CARA. Wet ink signature outside CARA – for 
 use only.
Merck KGaA / EMD Serono Research & 
Development Institute, Inc. responsible
Date
Signature
responsible
Date
Signature
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1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
..............................................................................................................3
1
Table of Contents..................................................................................4
2
List of Abbreviations and Definition of Terms ....................................9
3
Modification History ..........................................................................13
4
Purpose of the Integrated Analysis Plan.............................................14
5
Objectives and Endpoints ...................................................................15
6
Overview of Planned Analyses...........................................................19
6.1
Independent Data Monitoring Committee review..............................19
6.2
Final Analysis .....................................................................................19
7
Changes to the Planned Analyses in the Clinical Trial Protocol........20
8
Protocol Deviations and Analysis Sets...............................................21
8.1
Definition of Protocol Deviations and Analysis Sets .........................21
8.2
Definition of Analysis Sets and Subgroups........................................21
8.2.1
Sample Size ........................................................................................21
8.2.2
Analysis Sets.......................................................................................21
8.2.3
Subgroup Analysis..............................................................................23
9
General Specifications for Data Analyses ..........................................24
9.1
Actual Treatment Assignment ............................................................24
9.2
Presentation of Tables/Listings/Figures (TLFs).................................24
9.3
Data handling for the planned analyses..............................................24
9.4
Presentation of continuous and qualitative variables..........................25
9.5
Definition of baseline .........................................................................26
9.6
Other Specifications............................................................................26
10
Trial Subjects......................................................................................29
10.1
Disposition of Subjects and Discontinuations....................................29
10.2
Protocol Deviations ............................................................................30
10.2.1
Important Protocol Deviations............................................................31
10.2.2
Clinically Important Protocol Deviations...........................................31
11
Demographics and Other Baseline Characteristics.............................32
11.1
Demographics.....................................................................................32
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11.2
Medical History ..................................................................................33
11.3
Other Baseline Characteristics............................................................33
11.3.1
Disease History...................................................................................33
11.3.2
Other ...................................................................................................35
12
Previous or Concomitant Medications/Procedures.............................36
13
Treatment Compliance and Exposure.................................................39
13.1
Exposure .............................................................................................39
13.2
Compliance.........................................................................................42
14
Endpoint Evaluation ...........................................................................44
14.1
Primary Endpoint: ACR20 Response Rate at Week 12......................44
14.2
Secondary Endpoints ..........................................................................53
14.2.1
Key Secondary Endpoints at Week 12 ...............................................53
14.2.2
Other Secondary Endpoints at Week 12.............................................54
14.2.3
Imaging Endpoints at Week 4 and Week 12 ......................................56
14.2.4
HRQoL Endpoints at Week 12...........................................................60
14.2.5
Exploratory Efficacy Endpoints at Week 12 ......................................62
14.3
Subgroup Analysis..............................................................................63
14.4
Open-label Extension..........................................................................65
15
Safety Evaluation................................................................................66
15.1
Adverse Events ...................................................................................66
15.1.1
All Adverse Events.............................................................................67
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................70
15.2.1
Deaths .................................................................................................70
15.2.2
Serious Adverse Events......................................................................70
15.3
Clinical Laboratory Evaluation...........................................................71
15.4
Vital Signs ..........................................................................................73
15.5
12-Lead Electrocardiogram (ECG).....................................................74
15.6
Physical Examination .........................................................................75
15.7
Pregnancy Test....................................................................................75
15.8
Serum IgG, IgA, IgM Levels..............................................................75
15.9
B (CD19+) Cell Count........................................................................76
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15.10
Urinalysis Microscopic Evaluation.....................................................76
15.11
HBV DNA ..........................................................................................76
16
Analyses of Other Endpoints..............................................................77
17
References...........................................................................................81
18
Appendices .........................................................................................84
18.1
Definitions of Efficacy Endpoints ......................................................84
18.2
HAQ-DI Scoring.................................................................................88
18.3
36-Item Short Form Survey (SF-36) Scoring Instructions .................90
18.4
FACIT-Fatigue Scoring Instructions..................................................97
18.5
SAS/R Sample Code...........................................................................99
18.8
Laboratory Parameters to be summarized in the TLFs.....................124
18.9
Justification for the MCPMOD parameters......................................127
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Table of In-Text Tables
Table 1: Objectives and Endpoints ....................................................................................15
Table 2: Analysis Sets........................................................................................................22
Table 3: Subgroups ............................................................................................................23
Table 4: Treatment Groups and Regimens ........................................................................24
Table 5: Definition of Baseline..........................................................................................26
Table 6: Protocol Deviations .............................................................................................31
Table 7: Demographic Characteristics...............................................................................32
Table 8: Disease History....................................................................................................33
Table 9: Definition of Previous/Concomitant Medications...............................................37
Table 10: Exposure Time...................................................................................................39
Table 11 : Dosage and Administration ..............................................................................40
Table 12 : Data Handling for Efficacy Analysis................................................................44
Table 13 : Analysis of the Primary Endpoint – ACR20 Response Rate at Week 12 ........44
Table 14 : MCP-MOD Approach: Selected Candidates Models.......................................52
Table 15 : Analysis of the Key Secondary Endpoints at Week 12....................................53
Table 16 : Analysis of the Other Secondary Endpoints at Week 12..................................55
Table 17 : Analysis of Imaging Endpoints ........................................................................58
Table 18 : Analysis of HRQoL Endpoints at Week 12......................................................60
Table 19 : Analysis of Exploratory Efficacy Endpoints at Week 12.................................62
Table 20 : Logistic regression models for subgroup analysis............................................64
Table 21 : Subgroup Analysis – Endpoints........................................................................65
Table 22 : Data Handling for Safety Analysis...................................................................66
Table 23: Definition of TEAE ...........................................................................................66
Table 24: Summary Tables of TEAEs...............................................................................68
Table 25: TEAE Tables to be produced.............................................................................69
Table 26: Laboratory Parameters.......................................................................................72
Table 27: Vital Signs Categories .......................................................................................74
Table 28: Scoring Method for the Hybrid American College of Rheumatology 
Response Measure ..............................................................................86
Table 29: Categorization of Subject Responses as No Response, Moderate Response, 
or Good Response Based on EULAR Response Criteria...................87
Table 30: List of Questions from HAQ-DI Questionnaire ................................................88
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Table 31: HAQ-DI: Relationship between Aids, Devices Help from Another Person 
and the Disability Domain..................................................................89
Table 32: SF-36 – Abbreviated Item Content for the SF-36v2 Health Domain Scales.....91
Table 33: SF-36 – Recoding ..............................................................................................92
Table 34: SF-36 – Values used in transforming SF-36v2 Health Survey Health 
Domain Scale Total Raw Scores on the 0-100 Scale .........................93
Table 35: SF-36 – 1998 General US Population Means and Standard Deviations used 
to Calculate Normalized Health Domain Scores................................94
Table 36: SF-36 – Factor Score Coefficients used to Calculate PCS and MCS Scores 
for the SF-36v2...................................................................................95
Table 37: SF-36 – Numerical Example – Raw Data..........................................................95
Table 38: SF-36 – Numerical Example – Domain Scores.................................................96
Table 39: FACIT-Fatigue: Description of 13-item Questionnaire ....................................97
Table 40: FACIT-Fatigue: Guideline to Compute Total Score .........................................98
Table 41: FACIT-Fatigue : Example.................................................................................98
Table 42: Time Windows for supplementary LFTs.........................................................109
Table 43: Time Windows for Urinalysis .........................................................................110
Table 44: Time Windows for Vital Signs, Serum IgA, IgG, IgM, Total B cell counts, 
Plasma/serum collection for 
, Hematology and 
Biochemistry.....................................................................................111
Table 45: Time Windows for B cell subsets....................................................................112
Table 46: Time Windows for ECG..................................................................................113
Table 47: Time Windows for ACR components .............................................................114
Table 48: Time Windows for SF-36, FACIT-Fatigue and 
........115
Table 49: Time Windows for ESR, Anti-CPP, 14-3-3!, RF, Whole blood/T cells, NK 
cells, monocytes, and T cell subsets, Whole blood RNA.................116
Table 51: Time Windows for MRI assessments..............................................................118
Table 52: Time Windows for HBV DNA assessments ...................................................119
Table 53: Laboratory Parameters to be Summarized in the TLFs...................................124
Table 54: Results from Jonckheere-Terpstra trend test ...................................................127
Table 55: Results from negative binomial and Poisson models ......................................128
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2
List of Abbreviations and Definition of Terms
Δ
Difference
ACR
American College of Rheumatology
ADaM
Analysis Data Model
AE
adverse event
AESI
adverse event of special interest
ANCOVA
analysis of covariance
ANOVA
analysis of variance
anti-CCP
anti-cyclic citrullinated peptide
ATC
anatomical therapeutic class
BID
twice daily
BMI
body mass index
BOA
biostatistics outputs assembly
BTK
Bruton’s tyrosine kinase
CARLOS
cartilage loss scale
CDAI
clinical disease activity index
CFB
change from baseline
CI
confidence interval
CTP
Clinical Trial Protocol
CV
coefficient of variation
DAS28-hsCRP
disease activity score based on 28 joints and high-sensitivity C-reactive 
protein
DMARD
disease-modifying anti-rheumatic drug
DNA
deoxyribonucleic acid
DR 
distal radius
DRM
data review meeting
DTS
data transfer specifications
EAIR
exposure adjusted incidence rates
eCRF
Case Report Form, electronic
ECG
electrocardiogram
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ESR
erythrocyte sedimentation rate
EULAR
The European League Against Rheumatism
FACIT
functional assessment of chronic illness therapy
HAQ-DI
Health Assessment Questionnaire - Disability Index
HBV
Hepatitis B Virus
HL
Hodges-Lehmann
hrQoL
health-related quality of life
hsCRP
high-sensitivity C-reactive protein
IAP
Integrated Analysis Plan
IDMC
Independent Data Monitoring Committee
Ig
immunoglobulin
IMP
investigational medicinal product
ITT
intent-to-treat
IWRS
Interactive Web Response System
JSW
Joint Space Width
LFT
Liver Function Test
LOCF
last observation carried forward
MAR
missing at random
MCID
minimal clinically important difference
MCMC
Markov chain Monte Carlo
MCP
metacarpophalangeal
MCP-MOD
multiple comparison procedures - modeling
MCS
mental component summary
MedDRA
medical dictionary for regulatory activities
mITT
modified intent-to-treat 
MMRM
Mixed model with repeated measures
MN
Miettinen-Nurminen
MNAR
missing not at random
MRI
magnetic resonance imaging
MTX
methotrexate
N
number of subjects
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NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
NK
natural killer
NSAID
nonsteroidal anti-inflammatory drug
OLE
open-label extension
OMERACT
outcome measures in rheumatology clinical trials
OR
odds ratio
PCR
polymerase chain reaction
PCS
physical component summary
PP
per protocol
 
PT
preferred term
Q1
25th percentile
Q3
75th percentile
QD
once daily
QoL
quality of life
RA
rheumatoid arthritis
RAMRIQ
rheumatoid arthritis MRI quantitative
RAMRIS
rheumatoid arthritis magnetic resonance imaging scoring system
RF
rheumatoid factor
ROW
rest of the world
SAE
serious adverse event
SAF
safety analysis set
SCR
screening analysis set
SD
standard deviation
SDAI
simplified disease activity index
SDTM
Study Data Tabulation Model
SF-36
36-item short form health survey
SJC
swollen joint count
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SOC
system organ class
TEAE
treatment-emergent adverse event
TJC
tender joint count
TLF
table/listing/figure
ULN
upper limit of normal
VAS
visual analog scale
WHO-DD
World Health Organization drug dictionary
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3
Modification History
Unique
Identifier for
IAP Version
Date of
IAP Version
Authors
Changes from the Previous Version
Version 1.0
18 April 2019
NA – first version
Version 2.0
14 October 
2019
∀
Magnetic Resonance Imaging (MRI) substudy participation 
removed from the list of covariates in statistical models
∀
Wording for subgroup analyses clarified (See Section 14.3)
∀
Correction of Hochberg procedure terminology in Appendix 
18.5
∀
Correction of SAS Sample code for: 
∀
Stratified Miettinen-Nurminen (MN) 95% Confidence 
Interval (CI),
∀
Mixed model with repeated measures (MMRM),
∀
Logistic regression with repeated measures.
∀
Correction of Table 43
∀
Correction of Table 53
∀
Addition of MRI Per-Protocol (PP) Analysis Set
∀
Update of PP Analysis Set
∀
Clarification of the wording in Section 15.11
∀
The cumulative proportion of subjects achieving the 
primary endpoint will be presented as a bar chart instead of 
a curve (See Section 14.1)
∀
The term “point estimate” has been removed throughout 
the document and replaced by difference of response rate
compared to placebo
∀
The term “Hyperuricemia” has been removed from Table 
53, since the parameter will not be analyzed based on 
Grade values, only normal ranges.
∀
Addition of hsCRP at baseline as a covariate in multiple 
imputations models as well as joint counts
∀
Addition of a paragraph for actual treatment assignment 
(See Section 9.1)
∀
Update time window tables for MRI endpoints and ePRO 
questionnaires
∀
Remove adjusted p-values for supportive analyses (except 
tipping point analysis)
∀
Add a specific imputation rule for number of missing 
returned tablets in Section 13
∀
Clarification of the multiple imputation process
∀
Update of total inflammation score for RAMRIQ (See 
Section 14.2.3).
∀
Addition of imputation rule in case of discrepancies 
between the two independent readers of MRI scan with 
regards to RAMRIS data (See Section 14.2.3). 
∀
Removal of compliance during the OLE (See Section 13.2)
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4
Purpose of the Integrated Analysis Plan
The purpose of this Integrated Analysis Plan (IAP) is to document technical and detailed 
specifications for analyses of data collected for protocol MS200527-0060 version 3.0 dated 12 
July 2018 and version 2.1 dated 16 November 2017 (US only). The IAP is based upon Section 8 
(Statistics) of the trial protocols and is prepared in compliance with International Council for 
Harmonisation E9. 
This version (version 2.0) of the IAP includes details for the final analysis planned at the end of 
study.
Results of the analyses described in this IAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analysis identified in this IAP will be included in regulatory submissions 
or future manuscripts. Any post-hoc, or unplanned analyses performed to provide results for 
inclusion in the CSR but not identified in this prospective IAP will be clearly identified in the CSR. 
The final clinical database cannot be locked until the final IAP has been approved and signed.
Another document (ms200527-0060-idmc-sap-version1-0-06aug2018) detailed specifications for
the Independent Data Monitoring Committee (IDMC) analysis.
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5
Objectives and Endpoints
Objectives and Endpoints are summarized in Table 1:
Table 1: Objectives and Endpoints
Objective
Endpoint
IAP 
section
Primary
Objective
To evaluate the efficacy and dose 
response of 12 weeks of treatment with 
evobrutinib compared with placebo in 
subjects with rheumatoid arthritis (RA) 
with inadequate response to
methotrexate (MTX-IR) on stable MTX 
therapy by assessment of the signs 
and symptoms of RA, as measured by 
American College of Rheumatology 
(ACR) 20% (ACR20) response 
assessed using high-sensitivity C-
reactive protein (hsCRP) at Week 12.
Primary Endpoint:
∀
ACR20 at Week 12.
Section 
14.1
Key Secondary 
Objectives
To further evaluate the efficacy and 
dose response of 12 weeks of 
treatment with evobrutinib in MTX-IR 
subjects with RA on stable MTX 
therapy by assessment of the signs 
and symptoms of RA, as measured by 
Disease activity score based on 28 
joints and high-sensitivity C-reactive 
protein (DAS28-hsCRP) low disease 
activity (DAS28 < 3.2) rate at Week 12
Secondary Endpoint:
∀
DAS28-hsCRP < 3.2 at Week 12.
Section 
14.2
To further evaluate the efficacy of 
12 weeks of treatment with evobrutinib 
compared to placebo in MTX-IR 
subjects with RA on stable MTX 
therapy by assessment of the signs 
and symptoms of RA, as measured by 
DAS28-hsCRP remission (DAS28 
< 2.6) rate at Week 12
Secondary Endpoint:
∀
DAS28-hsCRP < 2.6 at Week 12.
Section 
14.2
To further evaluate the efficacy and 
dose response of 12 weeks of 
treatment with evobrutinib in MTX-IR 
subjects with RA on stable MTX 
therapy by assessment of the signs 
and symptoms of RA, as measured by 
ACR50 and ACR70 at Week 12
Secondary Endpoints:
∀
ACR50 at Week 12
∀
ACR70 at Week 12.
Section 
14.2
To evaluate the safety of evobrutinib in 
MTX-IR subjects with RA on stable 
MTX therapy
Safety Endpoints:
∀
The nature, severity, and occurrence 
of Adverse Events (AEs) and serious 
AEs (SAEs)
∀
Absolute values and change from 
Baseline (CFB) in:
∀
Vital signs
∀
Electrocardiogram (ECG)
parameters including RR interval, 
Section 
15
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PR interval, QRS duration, QT 
interval, and QTcF interval
∀
Serum Immunoglobulin (Ig) levels 
(IgG, IgA, IgM)
∀
Total B cell counts
∀
Clinical laboratory parameters.
Other 
secondary
Objectives
To further evaluate the efficacy of 
evobrutinib on the signs and symptoms 
of RA with inadequate response to 
MTX
Secondary Endpoints:
∀
Clinical Disease Activity Index 
(CDAI)
∀
Simplified Disease Activity Index 
(SDAI)
∀
European League Against 
Rheumatism (EULAR) Responder 
Index
∀
EULAR Boolean Remission
∀
ACR hybrid score
∀
Changes and percentage changes 
from Baseline of individual 
components of the ACR Core Set
Exploratory Endpoints:
Section 
14.2
To evaluate the effect of evobrutinib on 
joint structures and inflammation, at 
Week 4 and Week 12 in the MRI 
substudy, as assessed by MRI
Secondary Endpoints:
∀
Change from Baseline in Outcome 
Measures in Rheumatology Clinical 
Trials (OMERACT) Rheumatoid 
Arthritis Magnetic Resonance 
Imaging Scoring System (RAMRIS) 
scores at Week 12 for subjects in the 
MRI substudy
∀
Synovitis score
∀
Bone marrow edema (osteitis) 
score 
Exploratory Endpoints:
Section 
14.2
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To evaluate the effect of evobrutinib on 
physical function in RA subjects
Secondary Endpoint:
∀
Health Assessment 
Questionnaire – Disability Index 
(HAQ-DI).
Section 
14.2
To evaluate the effect of evobrutinib on 
subject-reported health-related quality 
of life (HRQoL)
Secondary Endpoint:
∀
Medical Outcomes Study 36-Item 
Short Form Health Survey (SF-36).
Section 
14.2
To evaluate the effect of evobrutinib on 
subject-reported fatigue (using 
Functional Assessment of Chronic 
Illness Therapy [FACIT]-Fatigue)
Secondary Endpoint:
∀
FACIT-Fatigue.
Section 
14.2
Exploratory
Objectives
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6
Overview of Planned Analyses
6.1
Independent Data Monitoring Committee review
An IDMC will be set up to continually review available efficacy, safety and tolerability data and 
will be mandated to make immediate decisions regarding the conduct of the trial; no additional 
risk minimization measures are proposed. Further details are described in the IDMC charter. 
Details of the statistical analyses and data presentations for the IDMC meetings are provided in 
the IDMC Statistical Analysis Plan.
6.2
Final Analysis
The final analysis will be triggered when 100% of subjects randomized either complete the Week 
12 visit or discontinue prematurely prior to Week 12, the protocol violations are determined, and 
the database is locked. All data collected from the Safety follow-up visit during the double-blind 
12-week treatment period will be included. 
Data collected during the OLE period from earlier versions of the protocol will not be part of the 
Final analysis for the 12 Weeks treatment period but be summarized separately (See Section 7).
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7
Changes to the Planned Analyses in the Clinical Trial Protocol
∀The CTP states a consistency analysis is also planned to be performed as part of the final 
analysis to evaluate the consistency of efficacy at Week 12 between the Japan and non-Japan 
subjects. 
However, the decision has been taken by the Sponsor not to recruit in Japan. As a result, this 
consistency analysis will not be performed. Subgroup analysis on Ethnicity Japanese/Non-
Japanese will not be performed either.
∀In CTP version 2.0, subjects completing the Treatment Period could have entered an optional 
Open-Label Extension (OLE) period, but the Sponsor made the decision to not initiate the OLE
(CTP version 3.0). As a result, some data have been recorded during the OLE for a subset of 
subjects. Safety and efficacy data from the OLE will then be summarized at the time of final 
analysis, as detailed in Section 12, 13, 14 and 15.
∀The MRI Analysis Set has been redefined to include a pre-dose assessment.
∀The CTP states that the primary endpoint will be evaluated based on a logistic regression model 
for the odds of ACR20 response, with evobrutinib dose group or placebo as a factor and 
adjustment for covariates based on randomization strata (region, MRI-substudy participation). 
This assumed a study design in which subjects could choose whether or not they would 
participate in the MRI substudy on an individual basis. However, as participation in the MRI 
substudy was shifted from a per-subject decision to a per-site decision (sites are either MRI or 
non-MRI), the selection bias is reduced and no clinically significant differences between MRI 
and non-MRI subjects is expected. Therefore, the adjustment for the covariate of participation 
in the MRI substudy has been removed. The same change in planned analysis applies for all 
efficacy endpoints.
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8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations and Analysis Sets
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 
subject's rights, safety, or well-being. Important protocol deviations are defined in the latest 
version of document named MS200527-0060_List_of_IPDs_Version 2.0_24JUL2019.docx.
All deviations will be identified and confirmed prior to or at the Data Review Meeting (DRM), 
which will occur before the database lock, including clinically important deviations if leading to 
the exclusion of a subject from PP analysis set (see Section 8.2).
The outcome of the DRM will document the important protocol deviations as well as the 
finalization of the analysis populations in a memo. Important protocol deviations will be 
documented in Clinical Data Interchange Standards Consortium Study Data Tabulation Model 
(SDTM) whether identified through sites monitoring, medical review and/or programming.
8.2
Definition of Analysis Sets and Subgroups
8.2.1
Sample Size
The primary endpoint of the trial is the ACR20 response at Week 12. A sample size of 80 evaluable 
subjects per group will provide approximately 90% power at an α of 0.05, 2-sided significance 
level to detect a difference in Week 12 ACR20 response proportion between evobrutinib- and 
placebo-treated subjects, assuming a placebo response proportion of 30% to 45% and an expected 
treatment benefit of 30%, after adjusting for multiple comparisons of 3 dose comparisons with 
placebo. For the same range of placebo response rate, the sample size of 80 evaluable subjects per 
group will also provide adequate power (approximately 80%) for the expected difference of 25%.
To account for reduced information provided by the Modified Intent-to-Treat (mITT) analysis set, 
due to subject dropout and protocol noncompliance, occurring at a rate of approximately 11% over 
a 12-week period, approximately 90 subjects per group will be enrolled. 
8.2.2
Analysis Sets
Table 2 provides the definitions of the Analysis Sets and their purposes.
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Table 2: Analysis Sets
Analysis Set
Definition
Purpose
Screening 
Analysis Set 
(SCR)
The SCR includes all subjects who signed the informed 
consent.
The purpose of this analysis set 
is to count how many subjects 
signed the informed consent
Intent-To-Treat 
(ITT) Analysis 
Set
The ITT analysis set will include all subjects randomly 
allocated to a treatment, based on the intention to treat 
“as randomized” principle (i.e., the planned treatment 
regimen rather than the actual treatment given in case of 
any difference).
The ITT Analysis Set will be 
used for TLFs based on 
randomized subjects, such as 
randomization listing and TLFs 
on protocol deviations.
mITT Analysis 
Set
The mITT analysis set will include all randomized 
subjects who received at least one dose of IMP 
(evobrutinib or placebo). Subjects in the mITT analysis 
set will be included in the treatment group as 
randomized. 
The mITT Analysis Set will be 
used for demographic/baseline 
characteristics and efficacy 
endpoints. 
Quality of Life 
(QoL) Analysis 
Set
The QoL Analysis Set will include all randomized 
subjects who have received at least one dose of IMP 
(evobrutinib or placebo) and have at least one Baseline 
and one post-Baseline QoL assessment (among the 
following: HAQ-DI, SF-36, FACIT, 
). 
Subjects will be analyzed according to randomized 
treatment.
The QoL Analysis Set will be 
used for QoL endpoints. 
Safety Analysis 
Set (SAF)
The SAF analysis set will include all subjects who 
receive at least 1 dose of IMP (evobrutinib or placebo). 
Subjects will be analyzed according to the actual 
treatment they receive. The SAF will be used for safety 
analyses. 
The SAF will be used for 
medications, 
exposure/compliance and safety 
endpoints. 
PP Analysis Set
The PP analysis set will include all mITT subjects who 
do not have any clinically important protocol deviations
before or at the time of Week 12 visit. Subjects in the PP 
analysis set will be included in the treatment group as 
randomized. Clinically important protocol deviations 
related to MRI assessments (protocol deviation PDEV63 
from the List of Important Protocol Deviations) will not 
be considered.
The PP analysis set will be used 
for the primary and key 
secondary efficacy endpoints.
MRI Analysis Set
The MRI analysis set will include the mITT subjects 
who have at least 1 pre-dose and 1 post-dose MRI 
assessment. Subjects in the MRI analysis set will be 
included in the treatment group as randomized.
The MRI Analysis Set will be 
used for all the analyses of the 
MRI endpoints.
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MRI PP Analysis 
Set
The MRI PP analysis set will include all MRI subjects 
who do not have any clinically important protocol 
deviations before or at the time of Week 12 visit. 
Subjects in the MRI PP analysis set will be included in 
the treatment group as randomized. All clinically 
important protocol deviations (including protocol 
deviation PDEV63 from the List of Important Protocol 
Deviations) will be considered.
The MRI PP analysis set will be 
used for the MRI endpoints.
8.2.3
Subgroup Analysis
Table 3 below defines the subgroups to be used for subgroup analysis as described in Section 14
and Section 15.
Table 3: Subgroups
Subgroup
Content
Definition
A
MRI sub-study participation
Yes; No (from IWRS – Is the subject participating in the MRI 
substudy?)
B
Gender
Male; Female (from DEMO form of electronic case report form 
[eCRF])
C
Region
US; Western Europe; ROW (from IWRS)
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9
General Specifications for Data Analyses
All statistical analyses will be performed by 
, except the modeling and simulation analysis,
which will be performed by Merck KGaA / EMD Serono Research & Development Institute, Inc.
9.1
Actual Treatment Assignment
A subject who received 2 different types of treatment regimen over the course of treatment should 
be tabulated according to the treatment regimen received most frequently. If there is a “tie”, the 
highest dose will be chosen.
9.2
Presentation of Tables/Listings/Figures (TLFs)
Tables and figures will be sorted by treatment group (in the order stated in Table 4) and 
chronological time point (where applicable). 
Table 4: Treatment Groups and Regimens
Treatment 
Group
Regimen
Presentation for the 
12-week treatment period
Presentation for the OLE (*)
1
Placebo
Placebo
Placebo/Evobrutinib 50 mg BID
2
Evobrutinib 25 mg QD 
(once daily)
Evobrutinib 25 mg QD
Evobrutinib 25 mg QD/Evobrutinib 
50 mg BID
3
Evobrutinib 75 mg QD
Evobrutinib 75 mg QD
Evobrutinib 75 mg QD/Evobrutinib 
50 mg BID
4
Evobrutinib 50 mg BID 
(twice daily)
Evobrutinib 50 mg BID
Evobrutinib 50 mg 
BID/Evobrutinib 50 mg BID
(*): As detailed in Section 7, some subjects have entered in the OLE, even if the Sponsor decided not to initiate the 
OLE in CTP V3.0. Subjects who agreed to participate in the OLE were administered evobrutinib 50 mg BID.
All data recorded during the trial will be presented in individual data listings (in the order stated 
in Table 4). All listings are sorted by treatment group, subject, and time point (where applicable), 
if not otherwise stated.
9.3
Data handling for the planned analyses
As the database lock will be based on data up to and including the last patient’s last visit, all data 
from screening up to and including the Safety Follow-up visit for all subjects will be locked and 
available in the database for the final analysis.
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9.4
Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics, ie,
∀number of subjects (N)
∀number and percentage of non-missing values
∀number and percentage of missing values 
∀mean, standard deviation (SD)
∀median, 25th Percentile - 75th Percentile (Q1-Q3)
∀minimum and maximum
Unless otherwise specified, the number of digits for non-derived and derived data, presented in 
outputs or available in ADaM datasets, is specified in the Biostatistics Outputs Assembly (BOA) 
document. For efficacy endpoints from Section 14, median and SD will be presented with 1 more 
digit compared to the original data, whereas mean, min, max, Q1-Q3 will be presented with the 
same number of digits as the original data.
For both continuous and qualitative variables, percentages such as 0% or 100% should be reported 
with the same format used for the column, together with the count of observations. For example, 
if the count of observations is zero, then display ‘0 (0.0)’; if the count of observations represents 
100%, then display ‘xx (100.0)’.
Qualitative variables will be summarized by counts and percentages. Unless otherwise stated, the 
calculation of proportions will be based on the number of subjects in the analysis set of interest. 
Therefore, counts of missing observations will be included in the denominator and presented as a 
separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of subjects 
in the analysis set of interest, unless otherwise specified. Total of missing and non-missing 
observations at each time-point will reflect the population still in the trial at that time. For example, 
if a subject is still in the trial at the time-point but with missing data, it should be counted in the 
number of missing observations.
 
 
 
 
 
 
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Mean, Min, Median, Max: 
3 significant digits
SD:
4 significant digits
CV%:
1 decimal place 
9.5
Definition of baseline
For the purpose of statistical analysis, baseline is defined as the last non-missing measurement 
prior to the first dose of study drug as described in Table 5: 
Table 5: Definition of Baseline
Randomized
Time Period
Baseline
∀
Placebo
∀
Evobrutinib 25 mg QD 
∀
Evobrutinib 75 mg QD
∀
Evobrutinib 50 mg BID
12-week treatment period
Last non-missing measurement 
prior to first dose of study drug of 
the 12-week treatment period
OLE Period
Last non-missing measurement 
prior to the first dose of evobrutinib 
of the OLE period
9.6
Other Specifications
Difference between the randomization strata (MRI site) and MRI substudy participation
In case of difference between the two variables “Was the subject enrolled in an MRI site?” and 
“Did the subject participate in the MRI substudy?”, the MRI substudy participation will be used 
for the statistical analysis.
Definition of Change from Baseline (CFB): 
CFB and percent CFB will be computed as follows: 
∀CFB = visit value – baseline value
∀Percent CFB = 100 * (visit value – baseline value) / baseline value
Definition of duration:
Unless otherwise specified, duration will be calculated as the difference between start and stop 
date + 1 (e.g. duration of AE (days) = AE stop date – AE start date + 1). Unless otherwise specified, 
missing dates will not be imputed.
Conversion factors:
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days. For time windows calculation, 1 month is expressed as 30 
days.
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. 
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Handling of missing data:
For efficacy analysis, methods of missing data handling are detailed in Section 14. 
Unless otherwise specified, missing data will not be replaced. 
In all subject data listings, imputed values will be presented. In all listings imputed information 
will be flagged. Non-imputed partial dates will be presented in a format such as “_____YYYY”.
Where imputation is defined, an imputed date with flag (ie, D for day, M for month) will be 
reported.
Missing statistics, eg when they cannot be calculated, should be presented as ‘NE’ (denoting “Not 
Evaluable”). For example, if n=1, the measure of variability (SD) cannot be computed and should 
be presented as ‘NE’.
In case of zero records, an empty output with 0 occurrences, or a sentence mentioning that there 
are no data, will be presented. For tables of AEs and Deaths (outputs required for EudraCT and/or 
clinicaltrial.gov), if there are no observations, the output must contain the first line ‘Subjects
with…’ or ‘Subjects who died’ displayed with 0 occurrence.
If the System Organ Class (SOC) or Anatomical Therapeutic Class (ATC) term is missing/not 
coded yet, then ‘Uncoded SOC’ (or ‘Uncoded ATC’) will be indicated at the TLF level. When a 
Preferred Term (PT) is missing, it will be set to ‘Uncoded PT: verbatim text’.
Treatment day:
Treatment day is defined as relative day to the start date of treatment. Treatment day will be 
calculated accordingly, ie:
∀For the 12 weeks treatment period, treatment day 1 is defined as the date of first administration 
of any IMP.
∀For the OLE period, treatment day 1 is defined as the date of first administration of evobrutinib
50 mg BID during OLE.
The day before is defined as Treatment day –1 (no Treatment day 0 is defined).
Treatment day will only be presented in subject safety data listings. In these listings, the difference 
(in days) between an event (eg, AE or laboratory assessment) and the first administration will be 
calculated as follows: 
∀If the event is posterior to the first IMP administration, the difference is equal to Date of 
event – Date of first IMP administration + 1
∀Otherwise, the difference is equal to Date of first IMP administration – Date of event
Time windows
As a measurement may have been performed out of window, data will be re-allocated according 
to time windows, so that each measurement is allocated to the closest time point.
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Appendix 18.6 provide further details of time window allocations for safety and efficacy 
endpoints.
For efficacy and safety analyses, each measurement will be assigned an analysis visit number first.
The analysis visit will then be used for all missing data imputations, analysis variable derivations, 
statistical calculations and presentations.
For patient data listings by time point, the nominal visit (as collected in the database) as well as 
the analysis visit will be displayed.
For time windows calculation, 1 month is expressed as 30 days.
Unblinding: 
Details 
regarding 
the 
unblinding 
process 
are 
available 
in 
the 
unblinding 
plan 
(MS200527-0060_UnblindingPlan_v2.0_21Feb2019.pdf)
Software:
All statistical analyses will be performed using SAS® (Statistical Analysis System, SAS-Institute, 
Cary North Carolina, USA, Windows Version 9.4 or higher), or R software (R Foundation for 
Statistical Computing, Vienna, Austria, Version 3.4.1 or higher) if certain statistical procedures 
are not available in SAS.
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10
Trial Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
10.1
Disposition of Subjects and Discontinuations
A table on screened subjects describing the number and percent of subjects in each disposition 
category will be produced by treatment group. These categories are summarized below:
∀Total number of screened subjects, ie subjects that gave informed consent (overall summary 
only)
∀Number of subjects who discontinued prior to randomization and reason (overall summary 
only)
∀Number of randomized subjects
∀Number of randomized subjects who did not start treatment
∀Number of randomized subjects who permanently discontinued treatment during 12-week 
treatment period and reason (as reported in the eCRF)
o
Number of randomized subjects who completed safety follow-up period
o
Number of randomized subjects who discontinued from trial during safety follow-up and 
reason
∀Number of randomized subjects who completed 12-week treatment period
o
Number of randomized subjects who completed safety follow-up period
o
Number of randomized subjects who discontinued from trial during safety follow-up and 
reason
∀Number of randomized subjects who signed OLE informed consent under previous versions of 
the protocol
A table based on screened subjects, describing the number and percent of subjects set by treatment 
group, will be produced, with the following categories:
∀Number of screened subjects
∀Number of subjects included in the ITT Analysis Set
∀Number of subjects included in the SAF
∀Number of subjects included in the mITT Analysis Set
∀Number of subjects in MRI Analysis Set
∀Number of subjects included in the PP Analysis Set
∀Number of subjects included in the MRI PP Analysis Set
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∀Number of subjects included in the QoL Analysis Set
∀Number of subjects who received at least 1 dose in the OLE under previous versions of the 
protocol
A table based on screened subjects, describing the number and percent of subjects in each region
(Western Europe, US, ROW), country within region, site within country, by analysis set, will be 
produced.
Another table based on randomized subjects will provide the number and percent of subjects by 
randomization strata and country. The different randomization strata are listed below:
∀MRI substudy participation
o
Yes
o
No
∀Region
o
US
o
Western Europe
o
Rest of the world
Corresponding individual listings will be prepared:
∀Discontinued subjects (from treatment or study) will be listed with their reason for withdrawal
(from treatment or study). 
∀A listing of the subjects screened but not randomized will be produced with the reason for not 
being randomized.
∀A listing of randomized subjects with subject number, randomization date, and randomized 
treatment group, ordered by randomization number within randomization stratum, will be 
produced for the purpose of assessing whether randomization was conducted as planned.
∀The list of re-screened subjects and corresponding subject identifiers will be provided. Only the 
second subject identifier will be used in statistical descriptions and analyses, while the first 
identifier will not be considered from the disposition counts.
10.2
Protocol Deviations
The Table 6 summarizes how protocol deviations will be handled for 12-week treatment period.
Protocol deviations in the OLE period will be listed.
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Table 6: Protocol Deviations
Period covered 
for protocol 
deviations 
reporting
Treatment Group
Observation Period
Analysis Set
12-week treatment 
period
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
First dose of 12-week treatment 
period up to last observed dose 
during the 12-week treatment, 
(safety follow-up posterior to the 
12-week treatment period 
included)
ITT
10.2.1
Important Protocol Deviations
The following summary tables and listings of important protocol deviations will be provided:
∀Tables providing frequency for each type of important protocol deviation/clinically important 
protocol deviation
∀Listing of important protocol deviations
10.2.2
Clinically Important Protocol Deviations
Clinically important protocol deviations, as defined in Section 8.1, will be summarized and listed.
For subjects excluded from the PP, the reasons for exclusion will be summarized and listed:
∀Frequency table per reason of exclusion from the PP population
∀Listing of reasons of exclusion from the PP population
For subjects excluded from the MRI PP, the reasons for exclusion will be summarized and listed:
∀Frequency table per reason of exclusion from the MRI PP population
∀Listing of reasons of exclusion from the MRI PP population
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11
Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized on mITT and presented by 
treatment group and overall. All data will also be listed on mITT.
11.1
Demographics
The demographic characteristics to be summarized are presented in Table 7.
Table 7: Demographic Characteristics
Demographic
Characteristics
Modalities
Gender (from DEMO form of 
eCRF)
∀
Male,
∀
Female.
Race (from DEMO form of 
eCRF)
∀
White, 
∀
Black or African American, 
∀
Asian, 
∀
American Indian or Alaska Native, 
∀
Native Hawaiian or Other Pacific Islander, 
∀
Not collected at this site, 
∀
Other.
Ethnicity (from DEMO form of 
eCRF)
∀
Hispanic or Latino, 
∀
Not Hispanic or Latino.
Age (defined below)
∀
< 65 years, 
∀
≥ 65 years.
Geographic Region (from IWRS)
∀
US, 
∀
Western Europe, 
∀
ROW.
European Economic Area (EEA)
(from DEMO form of eCRF)
∀
Yes, 
∀
No.
Has the subject been enrolled into 
an MRI site?
∀
Yes, 
∀
No.
Is the subject participating in the 
MRI substudy?
∀
Yes, 
∀
No.
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Specifications for computation:
∀Age (years): 
o
(date of given informed consent - date of birth + 1) / 365.25
o
In case of missing day for the date of birth, but month and year available for both dates: 

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 the date of birth, but year available for both dates: 

For the derivation of age, the day and month of birth will be set to 1 and the formula 
above will be used
∀Site codes will be used for the determination of the subject’s geographic region and EEA 
membership.
11.2
Medical History
The medical history will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA), current version, PT as event category and MedDRA SOC body term as Body System 
category. The MedDRA version used will be indicated in footnote. Medical history will be 
tabulated by SOC and PT. SOC and PT will be alphabetically sorted. Medical history will be also 
listed.   
11.3
Other Baseline Characteristics
11.3.1
Disease History
Descriptive statistics will be presented for disease history endpoints as indicated in Table 8. The 
disease history will be repeated for the randomization stratification with marginal total for each 
category of MRI substudy participation and Region by treatment group.
Table 8: Disease History
Disease History
Characteristics
Modalities
Time (months) since confirmed 
diagnosis of RA according to 
2010 ACR/The EULAR RA 
classification criteria.
∀
Summary statistics will be presented.
∀
Time will be computed as (Date of Informed Consent Signature – Date 
of confirmed diagnosis of RA) / 30.4375. If the date of confirmed 
diagnosis of RA is entirely missing, then time since confirmed 
diagnosis of RA will not be computed. In case of partial missing date of 
confirmed diagnosis of RA, this date will be imputed as follows: 
o
If only the day is missing, then it will be replaced by the first 
day of the month
o
If both day and month are missing, then it will be replaced by 
the first of January
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Components from the ACR Core 
Set:
∀
Tender Joint Count ([TJC] 
among the 68-joint count),
∀
Swollen Joint Count ([SJC] 
among the 66-joint count),
∀
Subject’s Global Assessment 
of Disease Activity (100-mm 
VAS),
∀
Subject’s Assessment of Pain
(100-mm VAS),
∀
HAQ-DI total score,
∀
Physician’s Global 
Assessment of Disease 
Activity (100-mm VAS),
∀
hsCRP (mg/L)
∀
Summary statistics
Erythrocyte sedimentation rate 
(ESR) (mm/Hr)
By category (based on local normal ranges collected in electronic case report 
form [eCRF]):
∀
Low
∀
Normal
∀
High
hsCRP (mg/L)
By category:
∀
Normal
∀
High
Acute-phase reactant
At least one test result is needed for the classification:
∀
Normal hsCRP and normal ESR, 
∀
Abnormal hsCRP or abnormal ESR
Abnormal refers to either low or high normal range classification.
Rheumatoid factor (RF) 
(expressed in IU/mL)
By category:
∀
Negative (≤ Upper Limit of Normal [ULN]) 
∀
Positive (> ULN)
Serum Ig levels (IgG, IgA, IgM) 
(mg/dL)
By category:
∀
Negative (≤ ULN) 
∀
Positive (> ULN)
Anti-cyclic citrullinated peptide
(Anti-CCP) (Units)
By category:
∀
Negative (≤ ULN) 
∀
Positive (> ULN)
Serology
By category (At least one test result is needed for the classification):
∀
Negative RF and negative anti-CCP (≤ ULN), 
∀
Low-positive RF or low-positive anti-CCP (> ULN, ≤ 3*ULN), 
∀
High-positive RF or high positive anti-CCP (> 3*ULN)
∀
Missing RF and missing anti-CCP
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14-3-3! (ng/mL)
By category:
∀
Negative (≤ ULN) 
∀
Positive (> ULN)
DAS28-hsCRP (See Appendix 
18.1 for definition)
By category:
∀
< 2.6 [remission], 
∀
≥ 2.6 to < 3.2 [low], 
∀
≥ 3.2 to ≤ 5.1 [moderate],
∀
> 5.1 [high].
CDAI (See Appendix 18.1 for 
definition)
By category:
∀
≤2.8 [remission], 
∀
> 2.8 to ≤10.0 [low], 
∀
> 10.0 to ≤ 22.0 [moderate],
∀
> 22.0 [high].
SDAI (See Appendix 18.1 for 
definition)
By category:
∀
≤3.3 [remission], 
∀
> 3.3 to ≤11.0 [low], 
∀
> 11.0 to ≤ 26.0 [moderate],
∀
> 26.0 [high].
EULAR/ACR Boolean Remission
(See Appendix 18.1 for 
definition)
∀
Yes, 
∀
No.
11.3.2
Other
Chest X-ray evaluations will be listed and tabulated by treatment group using the number and 
percentage of subjects for each interpretation category (Normal, Abnormal Not Clinically 
Significant, Clinically Significant, and Abnormal Overall). 
Other characteristics like viral serology, Quantiferon TB test, thyroid-stimulating hormone and
prior surgeries will be listed only.
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12
Previous or Concomitant Medications/Procedures
Previous or concomitant medications during the 12 weeks treatment period will be summarized 
using the SAF.
As detailed in Section 7, some subjects have entered in the OLE, even if the Sponsor decided not 
to initiate the OLE in protocol V3.0. Therefore, concomitant medications during OLE will also be 
summarized for subjects who received at least 1 dose in the OLE under previous versions of the 
protocol.
The definition of previous or concomitant medications is presented in Table 9:
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Table 9: Definition of Previous/Concomitant Medications
Analysis 
Set
Period 
covered
Treatment groups
Definition
SAF
12-week
treatment 
period
•
Placebo
•
Evobrutinib 25 mg 
QD 
•
Evobrutinib 75 mg 
QD
•
Evobrutinib 50 mg 
BID
Previous medications are medications, other 
than trial medications, which either: 
1.
started 
and 
stopped 
before 
first 
administration of any IMP (placebo or 
evobrutinib) or
2.
started prior to the first administration of 
IMP (placebo or evobrutinib) and are 
taken by subjects on or after the first 
administration of IMP.                   
Concomitant medications
are medications, 
other than IMPs, which either:
1.
started on or after the first administration 
of any IMP (placebo or evobrutinib) or
2.
started prior to the first administration of 
IMP (placebo or evobrutinib) and are 
taken by subjects on or after the first 
administration of IMP.                   
Subjects 
with at 
least 1 
dose 
during 
OLE
OLE
•
Placebo/Evobrutinib 
50 mg BID
•
Evobrutinib 25 mg 
QD/Evobrutinib 50 
mg BID
•
Evobrutinib 75 mg 
QD/Evobrutinib 50 
mg BID
•
Evobrutinib 50 mg 
BID/Evobrutinib 50 
mg BID
Concomitant medications
are medications, 
other than IMPs, which either: 
1.
started on or after the first administration 
of evobrutinib during OLE or
2.
started prior the first administration of 
evobrutinib during OLE and are taken by 
subjects 
on 
or 
after 
the 
first 
administration of evobrutinib during 
OLE.
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.
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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 ATC2nd
level will be used for reporting. 
The number and proportion of subjects with previous or concomitant medications (previous 
medications will not be summarized for final analysis) will be separately summarized by treatment 
group and will be presented by descending frequency of ATC 2nd level term and then by
descending frequency of PT in total column. If multiple ATCs/PTs have the same frequency, they 
will be sorted alphabetically. The WHO-DD version used will be indicated in footnote.
Previous or concomitant medications will be also listed.
All concurrent procedures, which were undertaken any time on trial, will be summarized. Number 
of subjects with concurrent procedures (prior, on or after the first day of IMP) overall and by SOC 
and PT will be summarized by treatment group, using current version of MedDRA dictionary.
Concurrent procedures will be also listed. 
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13
Treatment Compliance and Exposure
13.1
Exposure
As detailed in Section 7, some subjects have entered in the OLE, even if the Sponsor decided not 
to initiate the OLE in CTP V3.0. As a result, exposure during the OLE period will be separately 
summarized for subjects who received at least 1 dose in the OLE period under previous versions 
of the protocol.
The Table 10 summarizes how exposure time will be computed: 
Table 10: Exposure Time
Period 
covered
Treatment groups
Exposure time
Analysis 
sets
12-week
treatment 
period
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
From first dose of 
any IMP during 
12-week treatment 
period to last 
observed dose of 
12-week treatment 
period
SAF
OLE
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg QD/Evobrutinib 50 mg 
BID
•
Evobrutinib 75 mg QD/Evobrutinib 50 mg 
BID
•
Evobrutinib 50 mg BID/Evobrutinib 50 mg 
BID
From first dose of 
evobrutinib during 
OLE to last dose 
of evobrutinib 
during OLE
Subjects 
who receive 
at least 1 
dose in the 
OLE period
12-week treatment period
Exposure for the 12-week treatment period will be presented on SAF. For the 12-week treatment 
period, subjects will receive one of the following IMPs: 
∀Placebo
∀Evobrutinib 25 mg QD 
∀Evobrutinib 75 mg QD
∀Evobrutinib 50 mg BID 
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Dosage and administration are summarized in Table 11: 
Table 11 : Dosage and Administration
Product 
Description
Dosage 
Form
Evobrutinib 
Dose
Number of Tablets
(Morning Dose)
Number of Tablets
(Evening Dose)
25 mg
25 mg
Evobrutinib
Placebo
Evobrutinib
Placebo
Evobrutinib
Oral
25 mg QD
1
2
0
2
Evobrutinib
Oral
75 mg QD
3
0
0
2
Evobrutinib
Oral
50 mg BID
2
1
2
0
Placebo
Oral
0 mg
0
3
0
2
Note: To maintain the blind, all subjects will receive BID treatment. Subjects will self-administer 3 tablets in the 
morning and 2 tablets in the evening (every 12 hours ± 2 hours). Subjects who participate in the optional OLE Period 
will take 50 mg of evobrutinib twice daily, administered as two 25 mg tablets twice daily.
On trial visit days, IMP will be administered during the trial visit after the scheduled trial visit 
procedures are completed.
Exposure time in weeks will be calculated according to the following formula: 
exposure (weeks) = 
(    −    + 1)
7
First dose refers to the first administration of any IMP in 12-week treatment period. Last dose 
refers to the last administration of any IMP in 12-week treatment period. Both dates of first and 
last dose will be retrieved from SDTM EC domain. 
Exposure time will be presented by summary statistics and according to the following categories: 
∀≤ 1 week
∀> 1 to 2 weeks 
∀> 2 to 4 weeks 
∀> 4 to 8 weeks 
∀> 8 weeks
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The calculated total dose (mg) per subject for the 12-week treatment period will also be 
summarized for the active treatment groups, based on the actual treatment the subject receives. 
The calculated total dose is defined according to the following formula: 
The number of ingested tablets will be retrieved from the BATCH (Study Treatment Box Number) 
panel of the CRF, the number of tablets dispensed being equal to 40 for a given kit during the 
treatment period and 32 during the OLE period:
* !+  + ," = * !+  + %, −, !+  +  ,
Cumulative actual dose cannot be calculated for placebo treatment group.
For subjects with missing number of returned tablets (e.g. lost to follow-up), the cumulative actual 
dose will be calculated by imputing the missing returned amount with the number of tablets the 
subjects should have returned if 100% compliance was observed while on treatment for the 
associated dispensed kit. 
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Subject data listings: 
Study drug administrations will also be listed by treatment group, and subject, with start/end dates 
of administration and reason for dose change (if applicable). 
13.2
Compliance
Compliance will be analyzed for the 12-week treatment period on the SAF Analysis set. As the 
Sponsor made the decision to not initiate the OLE, the compliance will not be analyzed during the 
OLE. 
12-week treatment period
For the 12-week treatment period, compliance with treatment is defined as the number of tablets
taken during a period divided by the number of tablets that should have been taken during that 
period, multiplied by 100 to yield a percentage, ie:
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Compliance with  treatment  = 100 × (
*@
5 × *A
)
where 
∀N1 = number of tablets given minus number of tablets returned over N2 days,
∀N2 = number of days between treatment start and treatment termination visit.
, where N1 will be computed using the BATCH form of the eCRF and N2 corresponds to the 
exposure time expressed in days (see Section 13.1 for exposure time and number of tablets ingested 
formulas). 
 
 
 
For subjects with missing number of returned tablets (e.g. lost to follow-up), the compliance will 
be calculated by imputing the missing returned amount with the number of tablets the subjects 
should have returned if 100% compliance was observed while on treatment for the associated 
dispensed kit.
Compliance with treatment will be tabulated by treatment group from first intake to last intake of
12-week treatment period.
Compliance with treatment will also be presented into categories as follows: 
∀< 60%
∀≥ 60% to < 80% 
∀≥ 80% to ≤100% 
∀> 100% to ≤110% 
∀> 110%
Subject data listings: 
The following listings will be provided:
∀listing of kit numbers with date of dispense, and number of tablets returned (from BATCH).
∀listing of start/end dates with number of ingested tablets (from EXPOSUREDT).
∀listing with exposure time, cumulative dose, and compliance.
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14
Endpoint Evaluation
Table 12 details data handling for efficacy analysis.
Table 12 : Data Handling for Efficacy Analysis
Period covered
Treatment groups
Data to be analyzed
12-week treatment period
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
All data collected up to Week 
12 visit
OLE period
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg QD/Evobrutinib 50 mg 
BID 
•
Evobrutinib 75 mg QD/Evobrutinib 50 mg 
BID
•
Evobrutinib 50 mg BID/ Evobrutinib 50 mg 
BID
Data from OLE treatment 
period
14.1
Primary Endpoint: ACR20 Response Rate at Week 12
The primary endpoint, ACR20 response rate at Week 12, is defined in Appendix 18.1. 
The analysis of the primary endpoint and missing data handling are summarized in Table 13.
Table 13 : Analysis of the Primary Endpoint – ACR20 Response Rate at Week 12
Analysis Set
Analysis method
Description
Missing data handling
•
mITT set
•
PP set
Primary analysis: logistic 
regression
Presentation of response rate for 
each treatment group, difference
[Δ] in response rate compared to 
placebo, 2-sided 95% CI of Δ
(non-stratified MN), OR, 
2-sided 95% CI of OR, 2-sided 
nominal p-value, and adjusted 
p-value (using Hochberg 
procedure).  Adjusted p-values 
reported only for primary 
analysis based on mITT set.
LOCF-NR*
•
mITT set
•
PP set
Supportive analysis no. 1:
Stratified difference of 
response rate
Presentation of response rate for 
each treatment group, Δ in
response rate compared to 
placebo, 2-sided 95% CI of Δ
and 2-sided nominal p-value.
LOCF-NR*
•
mITT set
Supportive analysis no. 2: 
Tipping Point
Presentation of p-values and 
response rate for each treatment 
group at the tipping point.
Tipping point analysis
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•
mITT set
Supportive analysis no. 3: 
Stratified difference of 
response rate using 
multiple imputation with 
Missing At Random 
(MAR) pattern
Presentation of response rate for 
each treatment group, Δ in
response rate compared to 
placebo, 2-sided 95% CI of Δ
and 2-sided nominal p-value.
The ACR20 will be 
derived using imputed 
ACR Components. These 
components will be 
imputed using Multiple 
Imputation Procedure with 
MAR pattern for 
discontinuations due to 
reasons other than safety 
or efficacy
•
mITT set
Supportive analysis no. 4: 
Stratified difference of 
response rate using 
multiple imputation with 
Missing Not At Random 
(MNAR) pattern
Presentation of response rate for 
each treatment group, Δ in 
response rate compared to 
placebo, 2-sided 95% CI of Δ
and 2-sided nominal p-value.
The ACR20 will be 
derived using imputed 
ACR Components. These 
components will be 
imputed using Multiple 
Imputation Procedure with 
MNAR pattern, using 
control-based approach, 
regardless of reasons for 
treatment discontinuation.
•
mITT set
Supportive analysis no. 5: 
Non-parametric method: 
Cochran-Armitage test
Presentation of response rate for 
each treatment group, Δ in
response rate compared to 
placebo, 2-sided 95% CI of Δ
(stratified MN), and 2-sided 
p-value from Cochran-Armitage 
test
LOCF-NR*
•
mITT set
Supportive analysis no. 6: 
Multiple Comparison 
Procedures - Modelling 
(MCP-MOD) approach to 
dose response
Presentation of T-statistic and 
p-value from multiple contrast 
test for each model tested, the 
optimal model selected, and the 
estimated dose for the target 
effect using the selected model.
LOCF-NR*
•
mITT set
Descriptive statistics
Number and percentage of 
subjects with response status 
(Yes/No/Missing) over time
As observed
* LOCF-NR: post-baseline last observation carried forward. Patients who discontinued from treatment are considered as 
non-responders.
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Primary analysis: logistic regression
For the primary analysis, the estimate of the odds ratio (OR), together with the associated 2-sided 
95% CI, nominal p-value and adjusted p-value, comparing each evobrutinib dose group to placebo, 
will be provided based on a logistic regression model for the odds of ACR20 response, with 
treatment group as a factor and adjustment based on region. An example of SAS code is available 
in Appendix 18.5.
Missing data will be handled using LOCF-NR as follows: each component will be imputed using 
post-baseline LOCF (ie, baseline value cannot be used for missing data imputation). Then the 
ACR20 will be re-calculated using imputed components. Subjects who prematurely discontinued 
from treatment will be considered as non-responders.
A family-wise Type I error rate (FWER) at the primary analysis will be controlled at the 2-sided 
0.05 significance level for the 3 pairwise comparisons of evobrutinib dose versus placebo, using 
the Hochberg procedure (see Hochberg 1990). 
The statistical test comparing each evobrutinib group to placebo can be written as follows:  
BH0: OR = 1.0
H1: OR ≠1.0
Consider the ordered two-sided p-values (from lowest to highest) that arise from comparing the 3 
comparisons on the basis of the primary endpoint: p(1) ≤ p(2) ≤ p(3). The Hochberg’s step-up method 
proceeds as follows:
1. Step 1: If p(3) < 0.05 reject H(1), H(2) and H(3) (i.e., conclude all evobrutinib dose 
groups are more effective than placebo under the condition the OR are > 1) and 
then stop; otherwise go to Step 2.
2. Step 2: If p(2) < 0.025 reject H(1) and H(2) (i.e., conclude doses associated with H(1)
and H(2) are more effective than placebo under the condition the OR are > 1) and 
then stop; otherwise go to Step 3.
3. Step 3: If p(1) < 0.0167 reject H(1) (i.e., conclude that only one of the dose groups 
associated with H(1) is more effective than placebo under the condition the OR 
is > 1) and stop
Hochberg procedure will be computed with SAS®(see Appendix 18.5). Adjusted p-values will not 
be presented for any analyses based on PP analysis set.
In addition, the number and percentage of ACR20 responders (Yes/No) at Week 12 will be 
summarized by treatment group.
∀For the summary of ACR20 responders (Yes) at Week 12, the number and percentage of 
subjects from each treatment group who have met the responder criterion (at least 20% 
improvement from baseline) for each ACR component will be provided.
∀For the summary of ACR20 non-responders (No) at Week 12, the number and percentage of 
subjects from each treatment group who are imputed as non-responders due to different reasons
(i.e., discontinued due to adverse event, lack of efficacy, etc) will be provided.
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A bar chart will be generated by treatment group to present the cumulative proportion of subjects 
achieving ACRx where x is the cut-off of percentage reduction from baseline for ACR as a 
composite endpoint. The bar chart will start with x=20%, incremented by 10%, and up to the 
maximum observed percentage of improvement. Vertical lines will be drawn at 20%, 50% and 
70%. 
The number of responders/non-responders (Yes, No) at Week 2, Week 4 and Week 8 will also be 
presented in the logistic regression table using the LOCF-NR method.
Supportive analysis no. 1: Stratified difference of response rates 95% CI
In order to further characterize the dose-response, the proportion of ACR20 response at Week 12 
will also be presented for each treatment group, along with the stratified difference in ACR20 
response proportion between each evobrutinib dose and placebo, and the 2-sided 95% CI for the 
difference [Evobrutinib – Placebo]. 
The following will be presented: stratified Δ between response rates for pairwise comparisons
versus placebo, the 2-sided 95% CI, and nominal p-value. As there are 3 regions (Western Europe, 
US, ROW), the number of strata is equal to K=3. 
For each pairwise comparison, the difference of response rate will be computed using the formula 
no. (7), available in Lu 2008. By denoting A the 1st treatment group (evobrutinib 25 mg QD, 
evobrutinib 75 mg QD or evobrutinib 75 mg BID) and B the treatment group of comparison 
(placebo), the difference in response rate is the weighted average of differences within strata. It 
can be written as 
IJ =
∑
LM(
N
MO@
PM −QM)
∑
LM
N
MO@
, where PM represents the response rate of the treatment group A in the strata j, and LM represent 
the CMH weight of the stratum j. This CMH weight must be calculated using the formula no. (9), 
available in Lu 2008, and then standardized to have a sum equal to 1:
LM
RST =
U 1
,PM +
1
,QMV
W@
∑
U 1
,PM +
1
,QMV
W@
N
MO@
X
, where ,PM represents the sample size of the strata j for the treatment group A (,QM for treatment 
B respectively).
Once IY is calculated, the chi-square statistic is given by the formula no. (1), available in Lu 2008. 
Consider the following hypotheses Z(I): [PM −[QM = I for j = 1, …, K, we obtain
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\A(I) =
]∑
LM(
N
MO@
PM −QM −I)^
A
∑
LM
A_`abcW adc
N
MO@
where 
_`abcW adc = ef`PM(1 −f`PM)
,PM
+ f`QM(1 −f`QM)
,QM
g
*M
(*M −1)
denotes the variance of PM −QM under the hypothese Z(I), f`PM and f`QM are the constrained 
maximum likelihood estimates of [PM and [QM so that f`PM −f`QM = I, LM is the CMH weight for 
stratum j, and *M is the total number of subjects in stratum j. The MN weights will not be used to 
compute the chi-square statistic, in order to avoid an additional iterative process.  
For each stratum j, the constrained maximum likelihood estimates are computed as follows, as 
described in Farrington 1990: 
f`PM = 2 cos(h) −+ 3
i
f`QM = f`PM −I
, where 
h = ([ + W@ jk
 l
i
m)/3
k = (+l
3
i
)l −+
6A
i
+  2
i
 = ",(k)p+A
(3)A
i
− 3
i
 = 1 + q
+ = −(1 + q + PM + qQM + I(q + 2))
 = IA + Ir2PM + q + 1s + PM + qQM
 = −PM I(1 + I)
q = ,QM ,PM
i
Finally, the confidence limits based on MN method can be obtained by solving the equation (3), 
available in Lu 2008. Indeed, considering t = 0.05, if we denote u@,w.xy
A
the 95th percentile of the 
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chi-square distribution with one degree of freedom, then we reject Z(I) if \A(I) > u@,w.xy
A
. The 
2-sided 95% confidence limits of  I can be obtained by solving
\ArIY{s = \ArIY|s = u@,@W }
A
To solve this equation, an iterative process must be implemented to reach the lower and upper 
bounds of the 95% CI, ie the I must vary between (−1 ; 1) , bounds excluded, until the equation 
is verified. This will provide the values of the lower bound IY{ and the upper bound IY|.
A sample code to calculate this 2-sided 95% CI is available in Appendix 18.5. It is based on the 
example provided in Garner 2016.
For each pair-wise comparison, the statistical hypothesis test can be written as follows:  
H0: there is no significant difference of response rate between treatment A and B, ie, I = 0
H1: there is significant difference of response rate between treatment A and B, ie,I ≠0
If we denote $ the result the equation (1) in Lu 2008, then the p-value is given by 1(\ > $) where 
X follows a chi-square distribution with one degree of freedom. 
Supportive analysis no. 2: Tipping Point
Subjects with reason of treatment discontinuation related to safety or efficacy will be considered 
as non-responders.
Tipping point analysis will be performed as in Yan 2009, Section 2.3.2. 
Let
,@ = , !+  %,    !,"     )  ,  %+
,A = , !+  %,    !,"     )  ,  )+ ,+ 25 !" 2(
,l = , !+  %,    !,"     )  ,  )+ ,+ 75 !" 2(
, = , !+  %,    !,"     )  ,  )+ ,+ 50 !" 56(
The same analysis method as the primary analysis of the ACR20 at Week 12 will be performed 
using the mITT Analysis Set for each possible combination of ,@, ,A , ,l and ,.
Using the Hochberg procedure, the values of ,@, ,A , ,l and , where the study result will be 
tipped from statistically significant (not statistically significant) to not statistically significant 
(statistically significant) will be assessed for plausibility based on the corresponding response rate 
from each treatment.
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Supportive analysis no. 3: Stratified difference of response rates with imputed ACR 
components using multiple imputations (MAR pattern)
The same method for estimating stratified difference of response rates will be applied, but the ACR 
components will be imputed using multiple imputations process (MI SAS procedure) with MAR 
pattern, as if they follow their original assignment of treatment group. 
Data will be imputed for subjects with reason of discontinuation unrelated to safety or efficacy. 
Subjects with reason of treatment discontinuation related to safety or efficacy will be considered 
as non-responders.
The SAS code is available in Appendix 18.5.
The multiple imputations will be performed as follows: 
1. Monotone missing data structure will be created as follows: intermediate (non-monotone) 
missing data will be multiply imputed using the Markov chain Monte Carlo (MCMC) 
method and assuming MAR and multivariate normality. Transformation of data will only 
be used if there is a clear deviation from normality. The SAS procedure PROC MI with the 
MCMC option will be used with seed number=
. The number of burn-in 
iterations will be set to 200, which is the default value. Nevertheless, if diagnosis plots 
show that the convergence has not yet occurred, this will be adjusted. The ACR 
components must be pre-specified in the following order, the last one being the most 
significant component: 
i.
Physical function (as assessed using the HAQ-DI) from Week 2 to Week 12
ii.
Patient’s Global Assessment of RA Disease Activity from Week 2 to Week 12
iii.
Physician’s Global Assessment of RA Disease Activity from Week 2 to Week 12
iv.
Pain (as assessed using the Patient’s Assessment of Arthritis Pain VAS) from Week 
2 to Week 12
v.
hsCRP from Baseline to Week 12
vi.
Tender Joint Count (of 68 joints assessed) from Baseline to Week 12
vii.
Swollen Joint Count (of 66 joints assessed) from Baseline to Week 12
2. Then, each component will be imputed with treatment group and data at previous visit from 
all ACR20 components as covariates.
3. Imputation will be repeated N=1000 times. The ACR20 will then be calculated for each of 
the data sets from the imputed components. 
4. Single proportion and associated 95% CI of each treatment arm will be computed using 
EXACT BINOMIAL from FREQ procedure with SAS. The 95% CI will be used to 
compute the standard error of each proportion for the N=1000 imputations.
5. The difference of response rate compared to placebo and associated 95% CI based on 
stratified MN method will be computed for each of the N=1000 imputations. The 95% CI 
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will be used to compute the standard error of the difference of response rate compared to 
placebo.
6. Results will be combined using MIANALYZE SAS procedure with the Rubin’s rules.
Supportive analysis no. 4: Stratified difference of response rates with imputed ACR 
components using multiple imputations (MNAR pattern)
The same method as in Supportive analysis no. 3 will be considered, but this time with MNAR 
pattern. Subjects’ missing data due to early discontinuation will be imputed, using data available 
from the placebo arm, regardless of reason for study discontinuation.
Supportive Analysis no. 5: Non-parametric method – Cochran-Armitage test
A monotonic dose-response relationship, between ordered treatment groups and proportion of 
responders will be assessed via the Cochran-Armitage trend test (Dörner 2017). The p-value 
reported tests the null hypothesis that the proportion of ACR20 responders is the same across 
treatment groups, against the alternative that the proportion is ordered (from smallest value to 
largest) according to increasing treatment group. In the Cochran-Armitage test, missing data are 
handled the same as in the main logistic modeling analysis. 
For this Cochran-Armitage trend test, the proportion of ACR20 response rate, the p-value 
(asymptotic) will be presented.
An example of SAS code is available in Appendix 18.5.
Supportive analysis no. 6: MCP-MOD approach to dose response
The MCP-MOD approach to dose response (Bretz 2005) will be implemented using R software, 
in particular the DoseFinding package (see Bornkamp 2007), based on the mITT Analysis Set.
First of all, the following shapes of models will be considered: 
∀Linear model
∀Quadratic model
∀Emax model (with several parameters)
∀Logistic model
For the primary MCP-MOD approach, the highest dose (50 mg BID) is assumed to be equivalent 
to 100 mg QD. Further assumptions of the highest dose in QD regimen may be explored as post 
hoc analyses to assess the robustness of the primary result.
The expected minimal response rate that can be obtained (with the placebo group, given a dose of 
evobrutinib equal to zero) has been estimated at 30%. If we denote w(, q∗) the standardized 
dose-response model function (based on notations from Section 2.1 of Bornkamp 2009), the 
parameters to estimate are as follows: 
∀For the linear model, there are no parameters to estimate.
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∀For the Emax model, the equation is  w(, q∗) = d (EDyw + d)
i
∀For the quadratic model, the equation is w(, q∗) = d + δdA
∀For the logistic model, the equation is w(, q∗) = 1 {1 + exp[(#(yw −) I]}
⁄
i
Table 14 describes the final models to be used for the MCP-MOD Analysis. The estimated 
parameter value(s) for each model are calculated based on efficacy results of the primary endpoint 
from study MS200527-0086 (See appendix 18.9 for rationale and calculations of the estimated 
parameters in Table 14).
Table 14 : MCP-MOD Approach: Selected Candidates Models 
Model
w(, q∗)
Parameters estimated
Linear model

None
Emax model
 (#(yw + )
i
ED50 = 26.35
Quadratic model
 + IA
I = -0.0067
Logistic model
1
{1 + exp[(#(yw −) I]}
⁄
i
#(yw = 73.27 ; I = 1.66
Note: the function w(, q∗), which is the standardized model function driven by the equation
w(, q∗) = qw + q@w(, q), denotes the standardized model parameterized by the vector q∗. 
In this parameterization, qw is a location and q@ a scale parameter such that only the parameter-vector q∗
determines the shape of the model function.
For each of the dose-response models in the candidate set, the null hypothesis that the sum of the 
components of the optimal contrast vector is equal to zero will be tested. To do so, the contrasts 
coefficients of each model are chosen so they maximize the power to detect the absence of dose 
response. The methodology of the MCP-MOD is detailed in Section 2.2 of Bornkamp 2009.
Under the null hypothesis, if the maximum statistic of the optimal contrasts for the candidate 
models exceeds the critical value (corresponding to a unilateral test with alpha = 0.05), then the 
null hypothesis will be rejected and the proof of concept of a non-null dose-response will be 
demonstrated. 
Once the proof of concept has been established, the next step is to estimate the dose-response curve 
and the target doses of interest: 
∀The minimum effective dose (MED), defined as the smallest dose ensuring a clinically relevant 
and statistically significant improvement over placebo, estimated at 20%. 
∀The target dose will be estimated for the difference in ACR20 response over placebo of 25%, 
30% and 35% using the optimal model selected above.
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An example of R code is available in Appendix 18.5.
Descriptive statistics:
Number and percentage of subjects with ACR20 response status (Yes/No/Missing) will be 
presented over time for each treatment group, including the delta from placebo group. Data will 
be analyzed as observed, ie, without any imputation.
14.2
Secondary Endpoints
Statistical analyses of the secondary endpoints are supportive in nature. All p-values and 95% CIs 
from comparisons with placebo are at nominal levels.
14.2.1
Key Secondary Endpoints at Week 12
The following key secondary endpoints will be presented on both mITT and PP analysis sets for 
the primary analysis and mITT analysis set only for supportive analysis: 
∀DAS28-hsCRP low disease activity (DAS28 < 3.2) rate
∀DAS28-hsCRP remission (DAS28 < 2.6) rate 
∀ACR50 response assessed using hsCRP 
∀ACR70 response assessed using hsCRP.
These endpoints are defined in Appendix 18.1 and will be analyzed according to Table 15.
Table 15 : Analysis of the Key Secondary Endpoints at Week 12
Endpoints
Analysis Set
Analysis method
Description
Missing data handling
•
DAS28-hsCRP 
< 3.2
•
DAS28-hsCRP 
< 2.6
•
ACR50
•
ACR70
•
mITT set
Primary analysis: 
Stratified MN for Δ
∀
Presentation of 
response rate for 
each treatment 
group, ∆in
response rate 
compared to 
placebo, 2-sided 
95% CI of ∆,
nominal p-value
∀
Summary Stats 
over time
LOCF-NR*
•
mITT set
Descriptive 
statistics
Number and 
percentage of subjects 
with response status 
(Yes/No/Missing) over 
time
As observed
* LOCF-NR: post-baseline last observation carried forward. Patients who discontinued from treatment are considered as 
non-responders
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14.2.2
Other Secondary Endpoints at Week 12
The following secondary endpoints, defined in Appendix 18.1, will be presented on mITT analysis 
set: 
∀Achieving ACR EULAR Boolean remission
∀Achieving CDAI score ≤2.8 (CDAI remission) 
∀Achieving SDAI score ≤3.3 (SDAI remission)
∀EULAR Responder Index (based on DAS-hsCRP)
∀ACR hybrid scores computed using hsCRP
∀Change from Baseline in DAS28-hsCRP
∀Change from Baseline in CDAI and SDAI
∀Changes and percentage changes from Baseline of individual components of the ACR Core Set
∀ESR (mm/Hr)
These endpoints will be analyzed according to Table 16.
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Table 16 : Analysis of the Other Secondary Endpoints at Week 12
Endpoints
Analysis
Set
Analysis method
Description
Missing data 
handling
•
EULAR 
Boolean 
remission
•
CDAI ≤2.8
•
SDAI ≤ 3.3
•
mITT 
set
Primary analysis: 
Stratified Δ
•
Presentation of response rate for 
each treatment group, Δ in
response rate compared to 
placebo, 2-sided stratified MN 
95% CI of Δ
•
Summary statistics over time
LOCF-NR*
•
EULAR 
Responder 
Index
•
mITT 
set
Primary analysis
for binary data: 
Stratified for Δ
•
Presentation of response rate for 
each treatment group, Δ in
response rate compared to 
placebo, 2-sided stratified MN 
95% CI of Δ
•
Summary statistics over time
LOCF-NR*
•
EULAR 
Responder 
Index
•
mITT 
set
Primary analysis 
for all categories: 
descriptive 
statistics
Summary statistics over time 
LOCF-NR*
•
ACR hybrid 
score
•
DAS28-hsCRP
•
CDAI
•
SDAI
•
mITT 
set
Primary analysis: 
Analysis of 
Covariance 
(ANCOVA) 
model
Presentation of adjusted means, 
adjusted Δ of means, associated 2-
sided 95% CI of Δ.
LOCF 
(components)
Supportive
analysis: 
Hodges-Lehmann 
(HL) estimator
Presentation of difference median 
estimate and 95% CI (Asymptotic 
and exact)
Summary 
statistics
Summary statistics over time 
•
ACR 
components
•
mITT 
set
Summary 
statistics
Summary statistics over time 
LOCF 
(components)
•
ESR
•
mITT 
set
Summary 
statistics
Summary statistics over time 
As observed
* LOCF-NR: post-baseline last observation carried forward. Patients who discontinued from treatment are considered as 
non-responders.
ANCOVA model:
Δ in response rate compared to placebo and corresponding 95% CI will be estimated with SAS®
GLM procedure using LSMEANS statement (see SAS code in Appendix 18.5). The ANCOVA 
will include baseline, region as covariates and treatment group as an independent variable.
Validity of the model will be verified as follows: 
∀The homogeneity of variances between treatment groups will be checked using the Levene’s 
test. A scatter plot of residuals versus fitted values will be also performed.
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∀In order to assess the independence of error terms, a residual lag plot will be performed, ie 
constructed by plotting residual (i) against residual (i-1). 
∀A scatter plot of the response variable against the covariates, using separate symbols for each 
treatment group will be performed to verify the presence of linear relationship between the 
covariates and the response variable, and that all treatment regression lines have the same slope.
∀Homogeneity of regression slopes will be verified by first running the model with the 
interaction between the covariates and the treatment group. This assumption will be validated 
if this interaction is not significant. If this assumption is verified, then the interaction will be 
removed from the model.
∀Normality of residuals will be checked by computing Skewness and Kurtosis, which should fall 
within the interval [-2;2]. Normal QQ-plot of residuals will be performed as well.
HL estimator: 
A sensitivity analysis will be performed using a non-parametric method. The Hodges-Lehmann 
difference median estimate and 2-sided 95% CI will be calculated with SAS® NPAR1WAY 
procedure using HL statement (see SAS code in Appendix 18.5). Asymptotic and exact CIs will 
be computed.
Summary statistics: 
For each continuous endpoint, baseline value will be presented first. Then, for each time point, the 
following will be presented on subjects who have reached this time point: absolute value, CFB and 
percent CFB. 
14.2.3
Imaging Endpoints at Week 4 and Week 12
The following imaging endpoints will be presented on MRI and MRI PP analysis sets: 
∀CFB in OMERACT RAMRIS scores (designated hand, minimal assessed joints: wrist, MCP
joints #1 to #5):
o
Synovitis score,
o
Bone marrow edema (osteitis) score,
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OMERACT RAMRIS scores for synovitis, tenosynovitis, bone marrow edema (osteitis), and 
erosions (Ostergaard 2004, Ostergaard 2017) will be read centrally by 2 independent readers, who 
are blinded to treatment and dose assignment and to chronology of each time point. Discrepancies 
in RAMRIS scores between the 2 readers will be reviewed at a consensus adjudication session 
with both readers to reach a consensus score for the designated cases. At a minimum, the images 
with the top 10% discrepancies in scores between the 2 readers will be reviewed (refer to Imaging 
Guidelines for details of Adjudication and Selection of Cases for Adjudication). In case of further 
discrepancies after the adjudication process, the average between the results from the 2 readers 
will be considered for statistical analysis. In subject data listings, both results from the 2 readers 
will be presented as well as the average result.
In addition, the Total Damage Score and Total Inflammation Scores for both RAMRIS and 
RAMRIQ will be analyzed as well (Total Damage Score will not be computed for RAMRIQ). 
They are defined according to the following formulas (Peterfy 2016, Brett 2018):
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Table 17 : Analysis of Imaging Endpoints
Endpoints
Analysis Set
Analysis method
Description
Missing data 
handling
•
RAMRIS 
scores
•
MRI 
Analysis 
set
•
MRI PP 
Analysis 
Set
Primary analysis: 
MMRM
•
Presentation of adjusted 
means, adjusted Δ 
(Evobrutinib – Placebo) of 
means, associated 2-sided 
95% CI of Δ, nominal 
p-value.
•
Summary statistics over 
time
All available 
data as observed 
(MAR)
Supportive analysis 
#1: ANOVA model 
with repeated 
measures
•
Presentation of adjusted 
means, adjusted Δ 
(Evobrutinib – Placebo) of 
means, associated 2-sided 
95% CI of Δ, nominal 
p-value.
•
Summary statistics over 
time
Missing data 
will be imputed 
using linear 
interpolation or 
linear 
extrapolation
Supportive analysis 
#2: ANOVA model 
with repeated 
measures
•
Presentation of adjusted 
means, adjusted Δ 
(Evobrutinib – Placebo) of 
means, associated 2-sided 
95% CI of Δ, nominal 
p-value.
•
Summary statistics over 
time
As observed
•
Lineplot
•
Lineplots will be presented 
for RAMRIS Synovitis and 
Osteitis only.
As observed
MMRM: 
The MAR are ignorable missingness. When missing data due to dropout are ignorable, the 
parameters of dropout and outcome processes are assumed to be distinct. Hence, likelihood-based 
methods can be used on the marginal distribution of the observed data for statistical inference. 
MMRM is a particular form of a mixed model analysis and is fitted within the ignorable likelihood 
paradigm.
The MRI endpoints (change from baseline) will be analyzed using the MMRM model, with 
treatment group, visit, and treatment by visit interaction as the main effects, baseline MRI 
assessment and region as covariates. The unstructured covariance matrix will be considered.
Denominator degree of freedom will be computed using Kenward and Roger’s method 
(Kenward 1997).
The LSMEANS estimate of MRI mean change from baseline score, difference of the LS Mean 
from placebo, 2-sided 95% CI of the difference and nominal 2-sided p-value of the difference from 
the model contrast will be presented at each visit.
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An example of SAS code is available in Appendix 18.5.
In addition, summary statistics of observed values, change and percent change from baseline will 
be presented at each visit for each treatment group.
Supportive Analysis no. 1:
An ANOVA model for repeated measures will be performed with treatment group and region as 
covariates. Missing data will be imputed using linear interpolation for assessments at Week 4 and 
linear extrapolation for assessments at Week 12. 
The LSMEANS estimate of MRI score, difference of the LS Mean from placebo, 2-sided 95% CI 
of the difference and nominal 2-sided p-value of the difference from the model contrast will be 
presented at each visit. 
Validity of the model will be verified as follows: 
∀Repeated-measures designs have the assumption of Sphericity which means that the variance 
of the population difference scores for any two conditions should be the same as the variance 
of the population difference scores for any other two conditions. This assumption can be tested 
using the Mauchly's sphericity test (available with GLM SAS procedure).
∀Normality of residuals by timepoint will be checked by computing Skewness and Kurtosis, 
which should fall within the interval [-2;2]. Normal QQ-plot of residuals will be performed as 
well.
An example of SAS code is available in Appendix 18.5.
In addition, summary statistics of observed values, change and percent change from baseline will 
be presented at each visit for each treatment group.
Supportive Analysis no. 2:
A similar analysis as the supportive analysis no. 1 will be performed, but this time data will not be 
imputed.
Lineplot: 
Mean score CFB will be presented as a by-visit line plot for each treatment group, with all 
treatment groups included in a single figure, and horizontal axis extending to Week 12 (RAMRIS 
Synovitis and Osteitis only).
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14.2.4
HRQoL Endpoints at Week 12
The following HRQoL endpoints will be presented on QoL analysis set: 
∀HAQ-DI
∀SF-36
∀FACIT-Fatigue
HAQ-DI scoring is detailed in Appendix 18.2. 
A full description of the scoring rules of each health concept of SF-36 as well as Physical 
Component Summary (PCS) and Mental Component Summary (MCS) is available in Appendix 
18.3. 
A full description of the scoring instructions of FACIT-Fatigue scale is available in Appendix 18.4.
Table 18 : Analysis of HRQoL Endpoints at Week 12
Endpoints
Analysis Set
Analysis method
Missing data 
handling
•
HAQ-DI Total Score
•
QoL set
•
MMRM
As observed
•
SF-36 (Change in PCS, 
MCS scores, and their 
components)
•
FACIT-Fatigue (Change in 
Total score over time)
•
QoL set
•
MMRM model
•
Descriptive 
statistics
•
Probability of 
achieving %CFB 
value or higher
•
Logistic regression
As observed
MMRM model: similar as in Section 14.2.3.
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Descriptive statistics: 
For each treatment group, descriptive statistics will be presented for absolute value, CFB and 
percent CFB value for each visit, from baseline to Week 12. 
In addition, for each SF-36 endpoint (domain scores, MCS, PCS), FACIT-Fatigue Total Score and 
, the following will be provided: 
∀the number (proportion) of subjects not worsening, and number (proportion) of subjects 
worsening, between baseline and Week 12 by treatment group. Worsening is defined as a 
decrease of 5 for SF-36 endpoints and FACIT-Fatigue Total Score, and as an increase of 5 for 
.
∀Mean score over time will be presented as a by-visit bar plot for each treatment group, with all 
treatment groups included in a single figure, and horizontal axis extending to Week 12. 
In addition, for the 
, the frequency of item administration by visit will be 
reported (ie, the items that were selected and administered by the CAT algorithm).
Probability of achieving %CFB value or higher: 
For each SF-36 endpoint (domain scores, MCS, PCS), a figure will be provided describing the
distribution of % CFB at Week 12, one curve per treatment group. The curve will display 
proportion of subjects having a value for % CFB > x at Week 12, where the range of x depends on 
the data. 
The same will be applied for FACIT-Fatigue Total Score and 
.
Logistic regression: 
Response on the SF-36 (PCS, PF, VT), FACIT-Fatigue total score and 
 will be further analyzed based on differences in proportion of responders, comparing 
each dose of evobrutinib versus placebo. 
Responder definitions will be based on minimal clinically important difference (MCID) criteria 
for improvement or deterioration as follows:
∀SF-36 - PCS:
o Improvement is defined as an increase greater or equal to 2.5 compared to baseline
o Deterioration is defined as a decrease greater or equal to 0.8 compared to baseline
∀SF-36 – domain scores:
o Improvement is defined as an increase greater or equal to 5.0 compared to baseline
o Deterioration is defined as a decrease greater or equal to 2.5 compared to baseline
∀FACIT-Fatigue Total Score:
o Improvement is defined as an increase greater or equal to 4.0 compared to baseline
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o Deterioration is defined as a decrease greater or equal to 4.0 compared to baseline
Logistic regression model for repeated measures will be applied, with adjustments for the region, 
baseline value and with treatment as a factor. An example of SAS code is available in Appendix 
18.5.
14.2.5
Exploratory Efficacy Endpoints at Week 12
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14.3
Subgroup Analysis
The following subgroup analyses will be considered: 
∀Region (Western Europe, US, ROW)
∀MRI substudy participation (Yes, No)
∀Gender (Male, Female)
The endpoints at Week 12 and the statistical analysis method are described in Table 21.  
To assess numerically the consistency of each endpoint among subgroups of subjects, the analysis 
will be performed on the mITT Analysis Set for each modality using a logistic regression model. 
The interaction between treatment group and subgroup of interest will be calculated as well.
Logistic models to be performed are summarized in Table 20.
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Table 20 : Logistic regression models for subgroup analysis 
Subgroup
Subjects to be included in the 
model
Main effects
Result to be presented in 
TLFs
•
Region
•
All subjects from mITT Set
•
Treatment, region and 
treatment by region 
interaction
P-value from the interaction 
between treatment and 
region
•
Subjects from mITT Set –
Region=Western Europe 
•
Treatment
From comparison with 
placebo: 
•
Estimated OR,
•
Two-sided 95% CI of 
the estimated OR
•
Subjects from mITT Set –
Region=US 
•
Treatment
•
Subjects from mITT Set –
Region=ROW 
•
Treatment
•
MRI 
substudy
participation
•
All subjects from mITT Set
•
Treatment, MRI 
substudy participation 
and treatment by MRI 
substudy participation 
interaction
P-value from the interaction 
between treatment and MRI 
substudy participation
•
Subjects from mITT Set –
MRI substudy participants 
only
•
Treatment, region
From comparison with 
placebo: 
•
Estimated OR,
•
Two-sided 95% CI of 
the estimated OR
•
Subjects from mITT Set –
MRI substudy 
non-participants only
•
Treatment, region
•
Gender
•
All subjects from mITT Set
•
Treatment, gender and 
treatment by gender 
interaction
P-value from the interaction 
between treatment and 
gender
•
Subjects from mITT Set –
females 
•
Treatment, region
From comparison with 
placebo: 
•
Estimated OR,
•
Two-sided 95% CI of 
the estimated OR
•
Subjects from mITT Set –
males 
•
Treatment, region
The same missing data imputation approach will be used as the primary analysis method. An 
example of SAS code is available in Appendix 18.5.
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In addition, a forest plot will be presented for each endpoint for the overall treatment effect and 
within each subgroup of interest including OR from logistic model and associated 2-sided 95% CI 
of OR.
Summary tables will be presented for each endpoint by subgroup, comparing each evobrutinib
dose group vs placebo.
Table 21 : Subgroup Analysis – Endpoints 
Endpoints
Analysis
Analysis method
Description
Missing data 
handling
•
ACR 20/50/70
•
DAS28-hsCRP < 2.6
•
DAS28-hsCRP < 3.2
•
EULAR Boolean 
Remission
•
CDAI ≤ 2.8
•
SDAI ≤ 3.3
•
EULAR Responder 
Index [good/moderate, 
vs no response]
•
Week 12
Logistic regression
Presentation of 
response rate for each 
treatment group, Δ in
response rate 
compared to placebo, 
2-sided 95% CI of Δ
(non-stratified MN), 
OR, 2-sided 95% CI 
of OR, p-value of 
interaction between 
treatment and 
subgroup of interest
LOCF-NR*
* LOCF-NR: post-baseline last observation carried forward. At Week 12, patients who discontinued from treatment are 
considered as non-responders. 
14.4
Open-label Extension 
Efficacy Data from OLE will be listed on subjects from mITT set who entered in the OLE. 
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15
Safety Evaluation
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as AEs, laboratory tests and vital signs. As detailed in Section 
7, some subjects have entered in the OLE, even if the Sponsor decided not to initiate the OLE in 
protocol V3.0. As a result, for all safety endpoints, data selection will be handled as indicated in 
Table 22.
Table 22 : Data Handling for Safety Analysis
Population
Period covered
Treatment groups
Data to be analyzed
SAF
12-week treatment 
period 
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
All Data collected during the 
12-week treatment period, safety 
follow-up included  
Subjects 
with at least 
1 dose 
during OLE
OLE period only
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg 
QD/Evobrutinib 50 mg BID
•
Evobrutinib 75 mg 
QD/Evobrutinib 50 mg BID
•
Evobrutinib 50 mg 
BID/Evobrutinib 50 mg BID
Data from OLE period only
including all Safety follow-up data
posterior to OLE (Safety follow-
up / End of Study)
15.1
Adverse Events
All analyses described in this section will be based on treatment-emergent adverse events (TEAEs)
if not otherwise specified. TEAEs will be defined according to Table 23. AEs from the OLE period 
will be listed only (those with a start date after the first intake during the OLE).
Table 23: Definition of TEAE 
Treatment group
Period covered
Definition
•
Placebo
•
Evobrutinib 25 mg 
QD 
•
Evobrutinib 75 mg 
QD
•
Evobrutinib 50 mg 
BID
12-week 
treatment period
TEAEs will be defined as: 
•
AEs starting on or after first treatment administration of 
any IMP (placebo or evobrutinib) during the 12-week 
treatment period (safety follow-up included)
•
or if it was present prior to any IMP administration but 
exacerbated after. 
Any AE which started before study first treatment administration 
of any IMP (placebo or evobrutinib), but improved during 
treatment period, will not be counted as TEAE.
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For the purpose of defining the TEAE flag, incomplete AE-related dates will be handled 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 IMP then the onset date will be replaced by the 
minimum of start of IMP 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 subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date. 
∀Further information collected after the cut-off for an analysis (such as a fatal outcome) may be 
extracted from the Safety data base and presented separately in the CSR.
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 National Cancer Institute - Common Terminology Criteria 
for Adverse Events (NCI-CTCAE version 4.03) toxicity grades. AEs with missing classification 
concerning IMP relationship will be considered related to the IMP.
15.1.1.1
3-Tier Approach
The 3-tier approach is a systematic way to summarize and analyze adverse events (AEs) in clinical 
trials (Crowe 2009). AEs in different tiers are analyzed using different levels of statistical analyses.
Tier 1 AEs are provided in Appendix 18.10. Other AEs will be classified into Tier 2 or Tier 3 
based on the Rule-of-3. If there are 3 or more subjects with the reported term in any treatment 
group, that term will be included in Tier 2. Otherwise, it will be included in Tier 3.
The Tier 1 and Tier 2 AEs will be assessed with the number and percentage of subjects having at 
least one occurrence, as well as the difference with placebo and corresponding 95% CI for 
between-group comparison. For the difference in crude rates, the CIs will be based on MN method
(Miettinen 1985). No multiplicity adjustment will be applied.
The tier 3 AEs will be assessed via summary statistics and risk differences.
For each comparison of evobrutinib group with placebo, forest trees for Tier 1 and Tier 2 AEs will 
be provided as well, displaying the incidence rate and associated 2-sided 95% CI of difference.
15.1.1.2
Overview of TEAEs
Two summary tables of TEAEs will be provided as described in Table 24.
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Table 24: Summary Tables of TEAEs
Summary
Modalities
Overview of TEAEs
∀
Any TEAE
∀
IMP related TEAE
∀
Serious TEAE
∀
IMP related serious TEAE
∀
TEAE with NCI-CTCAE grade 1
∀
IMP related TEAE with NCI-CTCAE grade 1
∀
TEAE with NCI-CTCAE grade 2
∀
IMP related TEAE with NCI-CTCAE grade 2
∀
TEAE with NCI-CTCAE grade 3
∀
IMP related TEAE with NCI-CTCAE grade 3
∀
TEAE with NCI-CTCAE grade 4
∀
IMP related TEAE with NCI-CTCAE grade 4
∀
TEAE leading to death
∀
IMP related TEAE leading to death 
Overview of TEAEs 
Actions: 
∀
Change in dose,
∀
Administration of 
medication, 
∀
Procedure,
∀
Study termination
∀
TEAE with no change of dose 
∀
IMP related TEAE with no change of dose
∀
TEAE leading to dose reduction 
∀
IMP related TEAE leading to dose reduction
∀
TEAE leading to dose increase 
∀
IMP related TEAE leading to dose increase
∀
TEAE leading to interruption of IMP 
∀
IMP related TEAE leading to interruption of IMP
∀
TEAE leading to withdrawal of IMP
∀
IMP related TEAE leading to withdrawal of IMP 
∀
TEAE leading to administration of concomitant medication 
∀
IMP related TEAE leading to administration of concomitant medication
∀
TEAE leading to concomitant procedure 
∀
IMP related TEAE leading to concomitant procedure
∀
TEAE leading to study termination 
∀
IMP related TEAE leading to study termination
15.1.1.3
Tabulation of Adverse Events by SOC and PT
The TEAE tables to be prepared are listed in Table 25. 
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Table 25: TEAE Tables to be produced 
Overall 
frequency
By primary 
SOC and 
PT
By PT 
only
By 
primary 
SOC, PT 
and 
worst 
grade
Overview of TEAEs

NA
NA
NA
Overview of TEAEs actions

NA
NA
NA
All TEAEs




IMP-related TEAEs 




AEs of Special Interest (AESI)
 
 
 
 
IMP-related AESIs
 
 
 
 
Serious TEAEs


IMP-related serious TEAEs


Non-serious TEAEs*


TEAEs leading to death


IMP-related TEAEs leading to death


TEAEs leading to withdrawal of IMP


TEAEs leading to study termination


EAIR


(*): A table with all non-serious TEAEs will be first provided and then only TEAEs exceeding a frequency of 5% 
in at least one of the treatment groups (> 5%), by SOC and PT will be provided.
Specific rules for SOC/PT tabulation
All AEs recorded during the trial (ie assessed from signature of informed consent until the end of 
the Follow-up/End of Trial visit) will be coded according to the MedDRA and assigned to a SOC 
and PT. 
SOC terms will be sorted alphabetically. The combined dose of evobrutinib (25 mg QD, 75 mg 
QD and 50 mg BID) will be computed and displayed in the table. PTs within each SOC will be 
sorted by descending frequency of this combined dose of evobrutinib, and then alphabetically if 
multiple PTs have the same frequency.  
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If a subject experiences more than one occurrence of the same TEAE during the trial, the subject 
will be counted only once for that treatment (the worst severity and the worst relationship to trial 
treatment will be tabulated).
In case a subject had events with missing and non-missing grades, the maximum of the 
non-missing grades will be displayed.
Exposure adjusted incidence rates (EAIR) are calculated as number of subjects with TEAE divided 
by the sum of the individual times of all subjects in the safety population from start of treatment 
to first onset of TEAE or end of treatment period, whichever occurs first. The incidence rate 
multiplied with 1000 would give the number of TEAEs expected in 1000 subjects within 1 year. 
EAIR of TEAEs will be presented by SOC and PT.
Subject data listings
TEAEs will be also listed by treatment group and subject. A listing of TEAEs leading to 
withdrawal of IMP, a listing of TEAEs leading to study termination, if any, will be provided as 
well.
15.1.1.4
Adverse Events of Special Interest
AESIs will be summarized by SOC and PT as stated in Table 25. 
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
A summary of deaths will be provided including (clinicaltrials.gov requirement):
∀Number and percentage of (all) deaths
∀Number and percentage of the primary cause of death (categories: disease progression, adverse 
event, unknown, other) 
The tabulation of TEAEs leading to death is described in Section 15.1.1.2. A listing of deaths, if 
any, will be provided.
In case there is no death in the trial, only the summary of death required by clinicaltrials.gov will 
be performed, neither tabulation of TEAE leading to death will be edited, nor the listing of death.
15.2.2
Serious Adverse Events
The tabulation of serious TEAEs is described in Section 15.1.1.2. A subject listing of serious 
TEAEs will be provided.
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15.3
Clinical Laboratory Evaluation
The following laboratory parameters will be measured during the trial as part of the safety 
evaluation:
∀
Hematology
∀
Biochemistry, including the following supplementary liver function tests (LFT):
o
Aspartate aminotransferase,
o
Alanine aminotransferase,
o
Alkaline phosphatase,
o
γ-Glutamyl-transferase,
o
Bilirubin (total),
∀
Urinalysis
∀
Coagulation
∀
Lipid panel
∀
Hepatic panel (restricted to subjects for whom above AST or ALT withdrawal criteria are met 
and who permanently discontinue dosing due to elevated LFTs)
The clinical laboratory safety tests to be measured in this trial are provided in the protocol (refer 
to Section 7.4.3 Table 10 of the CTP). Parameters from the Section 7.4.3 of the CTP to be 
summarized and listed in the TLFs are provided in Appendix 18.8.
All laboratory data results will be presented using international system of units (SI).
Continuous protocol-specified clinical laboratory findings (hematology, biochemistry, urinalysis,
coagulation, lipid panel, hepatic panel) will be summarized by treatment using descriptive statistics 
over time (see Section 9) separately for 12-week treatment period and OLE. The descriptive 
statistics will be presented as follows: 
∀
The baseline will be presented first
∀
Then, when applicable, each scheduled time point will be presented on subjects who have 
reached this time point: absolute values, CFB and percent CFB will be displayed.
Laboratory results will be classified according to NCI-CTCAE Version 4.03 as provided by the 
central laboratory. In case a laboratory parameter has bi-directional toxicities (eg Potassium) both 
directions will be presented for the given parameter (ie Potassium Low and Potassium High). 
Laboratory results containing a modifier such as “<” or “>” will be handled case by case for 
summary statistics and will be reported both as collected in the database and imputed in subject 
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data listings. Decision for each laboratory parameter will be documented in a Note-to-File prior to 
the database lock.
A shift table of baseline versus post-baseline based on the worst NCI-CTCAE grade will be 
presented by treatment group for hematology and biochemistry. 
Subject 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 as detailed in Appendix 18.8 (eg, 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.
Boxplots of the laboratory values by treatment group and time point will be provided for the 
following parameters of Table 26:
Table 26: Laboratory Parameters
Category
Laboratory parameter
Conventional Unit
SI Units
Hematology
Hemoglobin
g/dL
g/L
Reticulocyte count
103/μL
109/L
White blood cell count
103/μL
109/L
Neutrophil count
103/μL
109/L
Lymphocyte count
103/μL
109/L
Platelet count
103/μL
109/L
Biochemistry
Albumin
g/dL
g/L
Alanine aminotransferase (ALT)
U/L
U/L
Aspartate aminotransferase (AST)
U/L
U/L
Gamma-glutamyl transferase (GGT)
U/L
U/L
Alkaline phosphatase
U/L
U/L
Total bilirubin
mg/dL
μmol/L
Amylase
U/L
U/L
Lipase
U/L
U/L
Creatinine
mg/dL
μmol/L
Blood urea nitrogen (BUN)
mg/dL
mmol/L
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Boxplots for all laboratory parameters will be displayed using the unit of measurement. If 
consistent with BOA standards, the ULN and LLN will be added to the lab parameter boxplot, for 
any lab parameter where the normal range is the same for all subjects in the analysis set. 
Listings of individual data with a flag for abnormal values will be provided, along with 
corresponding normal ranges. 
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-subject lab 
value listings will be provided:
∀
Listing of Grade ≥ 3 hematology values
∀
Listing of Grade ≥ 3 biochemistry values
∀
Listing of urinalysis values with Grade ≥ 3, value ≥ 2 times ULN (excluding values for Specific 
Gravity or pH parameters), or an increase of “++” for non-gradable parameters when 
applicable.
15.4
Vital Signs
Vital signs (height (m), weight (kg), BMI (kg/m²), body temperature (°C), SBP (mmHg), DBP 
(mmHg), respiratory rate (breaths/min) and pulse rate (beats/min)) will be summarized by 
treatment group using descriptive statistics (see Section 9).
The descriptive statistics will be presented as follows: 
∀
The baseline will be presented first
∀
Then each scheduled time point will be presented on subjects who have reached this time point: 
absolute values, CFB and percent CFB will be displayed (except Height and BMI which are 
only collected at baseline).
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Body temperature, SBP, DBP, respiratory rate and pulse rate will be analyzed with shift tables of 
maximum CFB using the categories defined in Table 27:
Table 27: Vital Signs Categories
Parameter
Unit
Shift
Baseline categories
Post-baseline categories 
(absolute change)
Temperature
°C
Increase
<37 / ≥37 - <38 / ≥38 -
<39 /≥39 - <40 / ≥ 40
≤0* / >0 - <1 / ≥1 - <2 /≥2 - <3 / 
≥3
Pulse rate
bpm
Increase
and decrease
<100 / ≥100
≤0* / >0 - ≤20 / >20 - ≤40 / >40
SBP
mmHg
Increase
and decrease
<140 / ≥140
≤0* / >0 - ≤20 / >20 - ≤40 / >40
DBP
mmHg
Increase
and decrease
<90 / ≥90
≤0* / >0 - ≤ 20 / >20 - ≤40 / >40
Respiratory rate 
breaths/min Increase
and decrease
<20 / ≥20
≤0* / >0 - ≤5 / >5 - ≤10 / >10
* This category will include the subjects with no changes or decrease/increase in the increase/decrease part of the table
respectively.
A listing of maximum CFB and a listing of all vital signs data will be provided.
15.5
12-Lead Electrocardiogram (ECG)
The 12-lead ECG data will be listed and summarized for observed values, CFB and percent CFB 
values by treatment group using descriptive statistics:
∀
RR interval (ms)
∀
PR interval (ms)
∀
QRS (ms)
∀
QT (ms)
∀
Fridericia corrected QT (QTcF) (ms).
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QTcF values will be categorized according to their calculated values into the categories
∀≤ 430 ms,
∀> 430 – 450 ms,
∀> 450 – 480 ms,
∀> 480 – 500 ms, 
∀> 500 ms
and categorized according to their CFB into the categories
∀≤ 30 ms,
∀> 30 – 60 ms,
∀> 60 msec.
A listing of ECG quantitative values, morphological and rhythm results will be produced. 
A shift table of rhythm results, from baseline to end of treatment, of the number and percentage of 
subjects for each category (Sinus rhythm, Atrial fibrillation, Other, Missing and Total) will be 
provided.
A shift table of morphological assessments, from baseline to worst on treatment observation of the 
12-week treatment period, of the number and percentage of subjects for each interpretation 
category (Normal, Abnormal NCS, Abnormal CS, Missing, and Total) will also be provided.
15.6
Physical Examination
No summary table will be provided since physical examination findings during screening will be 
recorded as medical history events and findings during the trial as AEs.
15.7
Pregnancy Test
Results of pregnancy test (serum and urine beta human chorionic gonadotropin for women only) 
will be listed.
15.8
Serum IgG, IgA, IgM Levels
Boxplot of Serum IgG, IgA and IgM levels (mg/dL) by treatment group and time point will be 
provided. Descriptive statistics by treatment group and time point will be performed as well. Serum 
IgG, IgA and IgM levels data will be listed by treatment group, subject and time point (where 
applicable). 
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15.9
B (CD19+) Cell Count
A boxplot of B (CD19+) cell count (cells/μL) by treatment group and time point will be provided. 
Descriptive statistics by treatment group and time point will be performed as well. B (CD19+) cell
count data will be listed by treatment group, subject and time point (where applicable). 
15.10
Urinalysis Microscopic Evaluation
Urinalysis Microscopic Evaluation data will be listed by treatment group and time point (where 
applicable). Parameters are listed in Appendix 18.8.
15.11
HBV DNA
Hepatitis B Virus (HBV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) testing 
results will be listed by treatment group and time point (where applicable). A shift table from 
baseline to worst post-baseline values including the categories < 20 IU/mL versus ≥ 20 IU/mL will 
be provided.
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Analyses of Other Endpoints
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Anderson J, Caplan L, Yazdany J, et al. Rheumatoid Arthritis Disease Activity Measures: 
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18
Appendices
18.1
Definitions of Efficacy Endpoints
ACR20 - The ACR20 is a primary efficacy measure for which a subject must have at least 
20% improvement in the following ACR Core Set values:
∀TJC (being the number of joints assessed as “Pain/Tender only” or “Pain/Tender and Swollen” 
among the 68-joint count) and
∀SJC (being the sum of joints assessed as “Swollen only” or “Pain/Tender and Swollen” among 
the 66-joint count) and
∀An improvement of at least 20% in at least 3 of the following 5 assessments:
-
Subject’s Global Assessment of Disease Activity 
-
Subject’s Assessment of Pain
-
Subject’s Assessment of Physical Function as measured by the HAQ-DI
-
Physician’s Global Assessment of Disease Activity
-
Acute phase reactant as measured by hsCRP.
In this trial, ACR20 response calculations will use the HAQ-DI for the subject’s assessment of 
physical function and hsCRP as the measure of acute phase reactant.
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Improvement of at least 20% of these assessments is defined as follows:
∀TJC (68 joint count): a decrease of at least 20% of the number of tender joints compared to 
baseline
∀SJC (66 joint count): a decrease of at least 20% of the number of swollen joints compared to 
baseline 
∀Subject’s Global Assessment of Disease Activity: a decrease of at least 20% on the VAS 
compared to baseline. Note: The scale has been scored from 100 [very well] to 0 [very poor]
during the data collection. As a result, for analyses, the parameter is derived as 100 – the 
original value to correctly assess the subject’s global assessment of disease activity and 
calculate the improvement from baseline. 
∀Subject’s Assessment of Pain: a decrease of at least 20% on the VAS compared to baseline.
∀Subject’s Assessment of Physical Function: a decrease of at least 20% of the HAQ-DI score 
compared to baseline.
∀Physician’s Global Assessment of Disease Activity: a decrease of at least 20% on the VAS 
compared to baseline
∀Acute phase reactant: a decrease of at least 20% of hsCRP measurement compared to baseline
ACR50, ACR70 - ACR50 and ACR70 are defined in the same way as the ACR20 using at least 
50% and 70% improvement, respectively.
DAS28-hsCRP - The DAS28-hsCRP is a measure of disease activity in 28 joints that consists of 
a composite numerical score of the following variables: TJC, SJC, hsCRP, and Patient’s Global 
Assessment of Disease Activity (Vander Cruyssen 2005).
For DAS28-hsCRP, the 28 joints to be examined and assessed as tender or not tender for TJC and
to be examined and assessed as swollen or not swollen for SJC include 14 joints on each side of 
the subject’s body: 2 shoulders, 2 elbows, 2 wrists, 10 MCP joints, 2 interphalangeal joints of the 
thumb, 8 proximal interphalangeal joints, and 2 knees (Smolen 1995).
In this trial, the acute phase reactant for computing DAS28 is the hsCRP. DAS28-hsCRP will be 
derived using the following formula from the DAS28 website (DAS28 2016):
DAS28-hsCRP =  0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.014 × GH + 0.36 × ln(hsCRP + 1) +
0.96
Where:
∀TJC28 = 28 joint count for tenderness
∀SJC28 = 28 joint count for swelling
∀ln(hsCRP) = natural logarithm of hsCRP
GH = the general health component of the Disease Activity Score (DAS) (i.e., Patient’s Global 
Assessment of Disease Activity).
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ACR Hybrid - The ACR hybrid score was developed to provide a quasi-continuous score that can 
detect smaller changes between treatments than the categorical ACR20/50/70 scores by combining 
the continuous score of the mean improvement in the core set measures combining the ACR20, 
ACR50, and ACR70 scores with the mean percent change from Baseline in all 7 ACR response 
core set components (Felson 2007, American College of Rheumatology Clinical Trial Priorities 
and Design Conference 2010, van Vollenhoven 2011). ACR hybrid, along with the DAS28, is 
recommended by the FDA regulatory guidance as a way to support dose-response assessment. It 
is calculated according to Table 28:
Table 28: Scoring Method for the Hybrid American College of Rheumatology Response 
Measure
ACR Status
Mean % Change in Core Set Measures
< 20
≥20, < 50
≥50, < 70
≥70
Not ACR20
Mean % change
19.99
19.99
19.99
ACR20 but not ACR50
20
Mean % change
49.99
49.99
ACR50 but not ACR70
50
50
Mean % change
69.99
ACR70
70
70
70
Mean % change
Source: Felson 2007.
ACR = American College of Rheumatology, ACR20 = American College of Rheumatology 20% Response Criteria, 
ACR50 = American College of Rheumatology 50% Response Criteria, ACR70 = American College of Rheumatology 
70% Response Criteria.
Note: 1) Calculate the average percentage change in core set measures. For each core set measure, subtract score 
after treatment from Baseline score and determine percentage improvement in each measure. Next, if a core set 
measure worsened by > 100%, limit that percentage change to 100% (a - 100% bound). Then average the 
percentage changes for all core set measures. 2) Determine whether the subject has achieved ACR20, ACR50, or 
ACR70. 3) Using the table above, obtain the Hybrid ACR response measure. To use the table, take the ACR20, 
ACR50, or ACR70 status of the subject (left column) and the mean percentage improvement in core set items; the 
Hybrid ACR score is where they intersect in the table.
EULAR Responder index – Assessments of subjects with RA by EULAR response criteria will 
be used to categorize subjects as having had no response, moderate response, good response, or 
any response (moderate + good responders) according to Table 29.
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Table 29: Categorization of Subject Responses as No Response, Moderate Response, or 
Good Response Based on EULAR Response Criteria
Post-baseline Level of 
DAS28
Improvement Since Baseline in DAS28
> 1.2
≤1.2 and > 0.6
≤0.6
DAS28 ≤3.2
Good response
3.2 < DAS28 ≤5.1
Moderate response
DAS28 > 5.1
No response
Source: van Gestel 1996 and van Gestel 1998.
DAS28 = Disease Activity Score modified to include the 28 diarthrodial joint count.
SDAI – The SDAI is the numerical sum of 5 outcome parameters: TJC and SJC (based on a 28-
joint assessment), the Patient’s and the Physician’s Global Assessments of disease activity (0–
10 cm VAS), and level of CRP (expressed in units of mg/dL). The SDAI is a valid and sensitive 
assessment of disease activity (Aletaha 2005, Smolen 2014) and treatment response that is 
comparable with the DAS28 and ACR response criteria; it is easy to calculate and therefore a 
viable tool for day-to-day clinical assessment of RA treatment (Fransen 2005, Smolen 2014). The 
ACR/EULAR 2011 Index-based definition of remission is based on SDAI (SDAI ≤3.3), and is 
being assessed as a secondary endpoint (Felson 2011, Smolen 2014).
CDAI – The CDAI is a composite index (without acute-phase reactant) for assessing disease 
activity. CDAI is based on the simple summation of the count of SJC and TJC of 28 joints along 
with the Patient’s and Physician’s Global Assessments (0–10 cm VAS) for estimating disease 
activity. The greater advantage associated with CDAI is its potential to be employed in evaluation 
of subjects with RA consistently with close frequency and independently of any calculating device; 
therefore, it can essentially be used everywhere and anytime for disease activity assessment in 
subjects with RA (Aletaha 2005, Smolen 2014). Thresholds for disease severity grading are 
included in Anderson (Anderson 2012). Remission based on CDAI is also being assessed as a 
secondary endpoint.
EULAR/ACR Boolean Remission – Following the Boolean-based definition of remission of 
ACR/EULAR, at any time point, a subject must satisfy all of the following: tender joint count 
TJC ≤1, SJC ≤1, CRP ≤1 mg/dL and Patient’s Global Assessment ≤1 (on a 0–10 scale). The 
Patient’s Global Assessment must be elicited as follows: “Considering all of the ways your arthritis 
has affected you, how do you feel your arthritis is today? (0–10, where 0 = very well and 10 = very 
poorly)”. The Boolean criteria appear more stringent than the DAS28 remission and have been 
specifically created for use in clinical trials (Bykerk 2012, Felson 2011).
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18.2
HAQ-DI Scoring
The HAQ-DI is a subject-reported questionnaire that consists of 24 questions referring to 8 
domains: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. 
The questionnaire scores the subject’s self-perception (20 questions): 0=without any difficulty, 
1=with some difficulty, 2=with much difficulty, 3=unable to do, and reports use of special aids or 
devices and/or the need for assistance from another person as indicated in Table 30.
Table 30: List of Questions from HAQ-DI Questionnaire
Domains
Questions
Dressing and 
grooming
1. Dress yourself, including tying shoelaces and doing buttons?
2. Shampoo your hair?
Arising
3. Stand up from a straight chair?
4. Get in and out of bed?
Eating
5. Cut your meat?
6. Lift a full cup or glass to your mouth?
7. Open a new milk carton?
Walking
8. Walk outdoors on flat ground?
9. Climb up five steps?
Check any aids or devices that you usually use for any of the above activities (questions 1 to 9):
Devices used for dressing (button hook, zipper pull, etc.) / Special or built up chair / Built up or 
special utensils / Cane / Walker / Crutches / Wheelchair / Other
Check any categories for which you usually need help from another person (questions 1 to 9):
Dressing and grooming / Arising / Eating / Walking
Hygiene
10. Wash and dry your body?
11. Take a tub bath?
12. Get on and off the toilet?
Reach
13. Reach and get down a 5 pound object (such as a bag of sugar) from just above your head?
14. Bend down to pick up clothing from the floor?
Grip
15. Open car doors?
16. Open jars which have been previously opened?
17. Turn faucets on and off?
Activities
18. Run errands and shop?
19. Get in and out of a car?
20. Do chores such as vacuuming or yard work?
Check any aids or devices that you usually use for any of the above activities(questions 10 to 
20):
Raised toilet seat / bathtub seat / bathtub bar / long-handled appliances in bathroom / long-
handled appliances for reach / jar opener ( for jar previously opened) / Other
Check any categories for which you usually need help from another person (questions 10 to 20):
Hygiene / Reach / Gripping an opening things / Errands and Chores
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The highest score for any component question of each of the eight domains determines the score 
for that domain. Each domain must have at least one question answered. Otherwise, the domain 
score is set to missing. 
The non-missing domain scores are adjusted, based upon the patient’s use of any aid, device or 
assistance (multiple aids, devices, or assistance could be checked). The relationship between aids, 
devices help from another person and the disability domain is shown in Table 31.
Table 31: HAQ-DI: Relationship between Aids, Devices Help from Another Person and the 
Disability Domain
Domains
Aids or devices
Help from another 
person
Dressing and 
grooming
Devices used for dressing / Other
Dressing and grooming
Arising
Special or built up chair / Other
Arising
Eating
Built up or special utensils / Other
Eating
Walking
Cane / Walker / Crutches / Wheelchair / Other
Walking
Hygiene
Raised toilet seat / bathtub seat / bathtub bar / long-handled 
appliances in bathroom / Other
Hygiene
Reach
long-handled appliances for reach / Other
Reach
Grip
jar opener / Other
Gripping and opening 
things
Activities
Other
Errands and Chores
If either aid or device and/or help from another person are checked for a domain or ‘other’ 
aid/device/assistance was needed, then the score for that domain is raised from 0 or 1 to 2 and 
unchanged if already scored at 2 or 3. If no aid, device and assistance were needed, the score for 
that domain will remain as raw score.
The disability index is the mean of the eight domain scores. If at least two of the domains are 
missing, the disability index cannot be obtained. If fewer than 2 of the domain scores are missing, 
divide the sum of the domains by the number of answered domains. The disability scores between 
0 and 3, with higher score indicating greater disability.
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18.3
36-Item Short Form Survey (SF-36) Scoring Instructions
The SF-36 is a validated 36-item, subject-reported indication of overall health status not specific 
to any age, disease, or treatment group (Ware 1992). The SF-36 has been extensively studied in 
RA, and a significant association has been shown between the physical functioning score of the 
SF-36 and the HAQ-DI score, as well as with other measures of disease activity and severity, and 
co-morbidities (Fries 1980). 
The SF-36 includes multi-item scales
measuring each of the following 8 health 
concepts: (1) physical functioning; (2) role limitations because of physical health problems; 
(3) bodily pain; (4) social functioning; (5) general mental health (psychological distress and 
psychological wellbeing); (6) role limitations because of emotional problems; (7) vitality 
(energy/fatigue); and (8) general health perceptions (see Table 32). These are summarized in two 
summary measures of physical and mental health: the PCS and MCS.
Questions in the standard version of the SF-36 refer to a 4-week time period. Scales are scored 
according to the Likert method. Lower scores equate to higher disability and higher scores equate 
to lower disability.
The SF-36v2 multi-item scales yield a health profile (8 scores) or can be aggregated into two 
summary scores, the PCS score and MCS score obtained through a linear combination of weighted 
transformed scores from the 8 subscales. PCS and MCS are standardised, with an average of 50 
and a standard deviation of 10 in the general American population. PCS and MCS are computed 
only if all of the 8 scale scores are available. This Appendix details how these two scores should 
be calculated, as described in Ware 2007.
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Table 32: SF-36 – Abbreviated Item Content for the SF-36v2 Health Domain Scales
Scale
Original 
item#
Item# in the 
MS200527-0060 
study
Abbreviated Item Content
Physical 
Functioning (PF)
3a
3
Vigorous activities, such as running, lifting heavy objects, 
or participating in strenuous sports
3b
4
Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf
3c
5
Lifting or carrying groceries
3d
6
Climbing several flights of stairs
3e
7
Climbing one flight of stairs
3f
8
Bending, kneeling, or stooping
3g
9
Walking more than a mile
3h
10
Walking several hundred yards
3i
11
Walking one hundred yards
3j
12
Bathing or dressing oneself
Role-Physical (RP)
4a
13
Cut down the amount of time spent on work or other 
activities
4b
14
Accomplished less than you would like
4c
15
Limited in kind of work or other activities
4d
16
Had difficulty performing work or other activities (eg, it 
took extra effort)
Bodily Pain (BP)
7
21
Intensity of bodily pain
8
22
Extent pain interfered with normal work
General Health 
(GH)
1
1
Is your health: excellent, very good, good, fair, poor
11a
33
Seem to get sick a little easier than other people
11b
34
As healthy as anybody I know
11c
35
Expect my health to get worse
11d
36
Health is excellent
Vitality (VT)
9a
23
Feel full of life
9e
27
Have a lot of energy
9g
29
Feel worn out
9i
31
Feel tired
Social Functioning 
(SF)
6
20
Extent health problems interfered with normal social 
activities
10
32
Frequency health problems interfered with social activities
Role-Emotional 
(RE)
5a
17
Cut down the amount of time spent on work or other 
activities
5b
18
Accomplished less than you would like
5c
19
Did work or other activities less carefully than usual
Mental Health 
(MH)
9b
24
Been very nervous
9c
25
Felt so down in the dumps that nothing could cheer you up
9d
26
Felt calm and peaceful
9f
28
Felt downhearted and depressed
9h
30
Been happy
Self-Evaluated 
Transition (SET)
2
2
How health is now compared to 1 year ago
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Step 1: Recoding Item Response Values
Some of the SF-36v2 items will be re-coded so that across all questions, a higher score will indicate 
a better health state.  Questions 2, 3a-3j, 4a-4d, 5a-5c, 9b, 9c, 9f, 9g, 9i, 10, 11a, 11c will be scored 
as recorded; the other questions will have the scores transformed as shown in Table 33. If multiple 
answers are given to the same item, then the item score will be left as missing.
Table 33: SF-36 – Recoding
Question
Original code and re-code response
Question number: 1
    Original response
1
2
3
4
5
    Re-coded response
5
4.4
3.4
2
1
Questions numbers:  6, 11b, 11d 
    Original response
1
2
3
4
5
    Re-coded response
5
4
3
2
1
Question number:  7
    Original response
1
2
3
4
5
6
    Re-coded response
6
5.4
4.2
3.1
2.2
1
Question number:  8 (if question number 7 is answered)
    Original response to #8
1
1
2
3
4
5
    Original response to #7
1
2-6
1-6
1-6
1-6
1-6
    Re-coded response
6
5
4
3
2
1
Question number:  8 (if question number 7 is NOT answered)
    Original response
1
2
3
4
5
    Re-coded response
6
4.75
3.5
2.25
1
Questions number:  9a, 9d, 9e, 9h
    Original response
1
2
3
4
5
    Re-coded response
5
4
3
2
1
Step 2: Determining Health Domain Scale Scores (0-100 Scores)
After item recoding, a total raw score is computed for each health domain scale. The total raw 
score is the simple algebraic sum of the final response values for all items in a given scale, as 
shown in Table 34. The total raw score for each scale is transformed to a 0-100 scale score using 
the following formula:
 h  = 100 × (Raw score – Lowest possible raw score)
Possible raw score range
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Table 34: SF-36 – Values used in transforming SF-36v2 Health Survey Health Domain 
Scale Total Raw Scores on the 0-100 Scale
Scale
Sum of Final Response Values
Lowest and highest
possible total raw 
scores
Possible total raw 
score range
PF
3a+3b+3c+3d+3e+3f+3g+3h+3i+3j
10, 30
20
RP
4a+4b+4c+4d
4, 20
16
BP
7+8
2, 12
10
GH
1+11a+11b+11c+11d
5, 25
20
VT
9a+9e+9g+9i
4, 20
16
SF
6+10
2, 10
8
RE
5a+5b+5c
3, 15
12
MH
9b+9c+9d+9f+9h
5, 25
20
Raw and transformed scale scores are not calculated for the Reported Health Transition (HT) item.
As recommended by the developers of the questionnaire, missing item responses will be treated 
using the “Half-scale rule”, which states that a score can be calculated if the respondent answers 
at least 50% of the items in a multi-item scale. In such cases, the missing item data will be replaced 
by the mean of the answered items of its scale. If more than 50% of the items are missing within a 
scale, the scale score will be missing.
Step 3: Calculating Normalized Health Domain Scores
The normalized scale scores will then be calculated using the following formulas:
Zℎ(!,  ¡ = (Zℎ(!,wW@ww ¢£¤a¥ – )
+
i
*!¦ Zℎ(!,  = 50 + (Zℎ(!,  ¡ × 10)
where a and b are the Mean and Standard Deviation of the Health Domain scale in the 1998 U.S. 
general population as shown in Table 35.
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Table 35: SF-36 – 1998 General US Population Means and Standard Deviations used to 
Calculate Normalized Health Domain Scores
Health Domain Scales
Mean
Standard Deviation
PF
83.29094
23.75883
RP
82.50964
25.52028
BP
71.32527
23.66224
GH
70.84570
20.97821
VT
58.31411
20.01923
SF
84.30250
22.91921
RE
87.39733
21.43778
MH
74.98685
17.75604
The advantages of the normalization of the eight health domain scales are that results for one health 
domain scale can be meaningfully compared with those from the other scales and that domain 
scores have a direct interpretation in relation to the distribution of scores in the 1998 U.S. general 
population.
Step 4: Scoring the Physical and Mental Component Summary Measures
The Physical Component Summary (PCS) and Mental Component Summary (MCS) measures are 
scored using a three-step procedure:
1. First, the 8 health domain scale scores are standardized using means and standards 
deviations from the 1998 U.S. general population (see Table 35). 
2. Second, these Z-scores are aggregated using weights (factor score coefficient) from the 
1990 U.S general population. 
3. Third, aggregate PCS and MCS scores are standardized by multiplying the standardized 
scale by 10 and adding 50. 
U.S. general population statistics used in the standardization and in the aggregation of SF-36v2 
Health Survey health domain scale scores are presented in Table 36.
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Table 36: SF-36 – Factor Score Coefficients used to Calculate PCS and MCS Scores for the 
SF-36v2
Summary component measure factor score coefficients
Scales
PCS
MCS
PF
0.42402
-0.22999
RP
0.35119
-0.12329
BP
0.31754
-0.09731
GH
0.24954
-0.01571
VT
0.028877
0.23534
SF
-0.00753
0.26876
RE
-0.19206
0.43407
MH
-0.22069
0.48581
Example:
Let’s consider the following answers from a subject: 
Table 37: SF-36 – Numerical Example – Raw Data
#
Item description
Answer
1
In general, would you say your health is:
1 – Excellent 
2
Compared to one year ago, how would you rate your health in general now?
2 – Somewhat better now 
than one year ago
3
Vigorous activities, such as running, lifting heavy objects, participating in strenuous 
sports
2 – Yes, limited a little
4
Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or 
playing golf
2 – Yes, limited a little
5
Lifting or carrying groceries
2 – Yes, limited a little
6
Climbing several flights of stairs
2 – Yes, limited a little
7
Climbing one flight of stairs
2 – Yes, limited a little
8
Bending, kneeling or stooping
1 – Yes, limited a lot
9
Walking more than a mile
2 – Yes, limited a little
10
Walking several hundred yards
2 – Yes, limited a little
11
Walking one hundred yards
2 – Yes, limited a little
12
Bathing or dressing yourself
2 – Yes, limited a little
13
Cut down on the amount of time you spent on work or other activities
2 – Most of the time
14
Accomplished less than you would like
3 – Some of the time 
15
Were limited in the kind of work or other activities
2 – Most of the time
16
Had difficulty performing the work or other activities (for example, it took extra effort)
3 – Some of the time 
17
Cut down on the amount of time you spent on work or other activities
2 – Most of the time
18
Accomplished less than you would like 
3 – Some of the time 
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19
Don’t do work or other activities as carefully as usual
2 – Most of the time
20
During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbours, or 
groups?
2 – Slightly 
21
How much bodily pain have you had during the past 4 weeks?
3 – Mild 
22
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)?
2 – A little bit
23
Did you feel full of life?
4 – A little of the time
24
Have you been a very nervous person?
3 – Some of the time 
25
Have you felt so down in the dumps that nothing could cheer you up?
2 – Most of the time
26
Have you felt calm and peaceful?
4 – A little of the time
27
Did you have a lot of energy?
3 – Some of the time 
28
Have you felt downhearted and low?
2 – Most of the time
29
Did you feel worn out?
4 – A little of the time
30
Have you been a happy person?
3 – Some of the time 
31
Did you feel tired?
2 – Most of the time
32
During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, 
etc.)?
4 – A little of the time
33
I seem to get ill more easily than other people
3 – Don’t know
34
I am as healthy as anybody I know
2 – Mostly true
35
I expect my health to get worse
3 – Don’t know
36
My health is excellent
2 – Mostly true
After having recoded the answers, the 8 domain scores are equal to:
Table 38: SF-36 – Numerical Example – Domain Scores
Raw 
Score
Raw Score0-100
Health Domain Z-Score
Normalized Health 
Domain Z-Score
PF
19 
100 x (19-10) /20 = 45
45 - 83.29094 / 23.75883 = -1.61
-1.61 x 10 + 50 = 33.9 
RP
10
100 x (10-4) /16 = 37.5
37.5 - 82.50964 / 25.52028 = -1.76
-1.76 x 10 + 50 = 32.4
BP
8.2
100 x (8.2-2) /10 = 62
62 - 71.32527 / 23.66224 = -0.39
-0.39 x 10 + 50 = 46.1
GH
19
100 x (19-5) /20 = 70
70 - 70.84570 / 20.97821 = -0.04
-0.04 x 10 + 50 = 49.6
VT
11
100 x (11-4) /16 = 43.75
43.75 - 58.31411 / 20.01923 = -0.73
-0.73 x 10 + 50 = 42.7
SF
8
100 x (8-2) / 8 = 75
75 - 84.30250 / 22.91921 = -0.41
-0.41 x 10 + 50 = 45.9
RE
7
100 x (7-3) / 15 = 27
27 - 87.39733 / 21.43778 = -2.82
-2.82 x 10 + 50 = 21.8
MH
12
100 x (12-5) / 20 = 35
35 - 74.98685 / 17.75604 = -2.25
-2.25 x 10 + 50 = 27.5
Finally, PCS and MCS are provided below using Table 36: 
∀
PCS = -1.61 x 0.42402 + … + -2.25 x -0.22069 = -0.41
∀
Normalized PCS = 10 x PCS + 50 = 45.9
∀
MCS = -1.61 x -0.22999 + … + -2.25 x 0.48581 = -2.62
∀
Normalized MCS = 10 x MCS + 50 = 23.8
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18.4
FACIT-Fatigue Scoring Instructions
FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon 
daily activities and function (Wolfe 1996). It uses a 5-point Likert-type scale (0 = not at all; 1 = a 
little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). As each of the 13 items of the 
FACIT-Fatigue scale ranges from 0–4, the range of possible scores is 0–52, with 0 being the worst 
possible score and 52 the best. To obtain the 0–52 score, each negatively worded item response is 
recoded so that 0 is a bad response and 4 is good response. All responses are added with equal 
weight to obtain the total score.
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18.5
SAS/R Sample Code
This Appendix details how the statistical methods will be implemented with either SAS or R 
software applications.
Logistic regression: PROC LOGISTIC with SAS
The logistic regression can be implemented using the following SAS code: 
proc logistic data=<dataset>;
class TreatmentGroup(ref='Placebo') Region;
model AVALC(event="Y") = TreatmentGroup Region / alpha=0.05;
ods output ParameterEstimates=ParameterEstimates OddsRatios=OddsRatios ;
run ;
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
101/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
102/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
103/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
104/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
105/130
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
106/130
MMRM: PROC MIXED with SAS
A mixed model can be performed with SAS using the following code below. This sample code 
assumes the treatment group is assigned in the following order: 
∀
1 = Placebo
∀
2 = Evobrutinib 25 mg QD
∀
3 = Evobrutinib 75 mg QD
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
107/130
∀
4 = Evobrutinib 50 mg BID
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
108/130
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
109/130
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
110/130
Table 43: Time Windows for Urinalysis
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date 
of first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 70 )
Week 8 – Day 56
[ 70 ; 91 )
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg 
BID
•
Evobrutinib 25 mg 
QD/Evobrutinib 50 mg BID 
•
Evobrutinib 75 mg 
QD/Evobrutinib 50 mg BID
•
Evobrutinib 50 mg 
BID/Evobrutinib 50 mg BID
OLE period
1
Day 1 – OLE
[ 2 ; 45 )
Month 1 – OLE
[ 45 ; 75 )
Month 2 – OLE
[ 75 ; 105 )
Month 3 – OLE
[ 105 ; 150 )
Month 4 – OLE
[ 150 ; 225 ) 
Month 6 – OLE
[ 225 ; 315 ) 
Month 9 – OLE
[ 315 ; 367 ) 
Month 12 – OLE
  
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MS200527-0060
14 October 2019 / Version 2.0
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Table 44: Time Windows for Vital Signs, Serum IgA, IgG, IgM, Total B cell counts, 
Plasma/serum collection for 
, Hematology and Biochemistry 
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date of 
first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 21 )
Week 2 – Day 14
[ 21 ; 42 )
Week 4 – Day 28
[ 42 ; 70 )
Week 8 – Day 56
[ 70 ; 91 )
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg
BID
•
Evobrutinib 25 mg 
QD/Evobrutinib 50 mg BID 
•
Evobrutinib 75 mg 
QD/Evobrutinib 50 mg BID
•
Evobrutinib 50 mg 
BID/Evobrutinib 50 mg BID
OLE period
1
Day 1 – OLE
[ 2 ; 45 )
Month 1 – OLE
[ 45 ; 75 )
Month 2 – OLE
[ 75 ; 135 )
Month 3 – OLE
[135 ; 225 ) 
Month 6 – OLE
[ 225 ; 315 ) 
Month 9 – OLE
[ 315 ; 367 ) 
Month 12 – OLE
Note: Plasma/serum collection for 
 are not collected during OLE
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
112/130
Table 45: Time Windows for B cell subsets
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date of 
first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 56 )
Week 4 – Day 28
[ 56 ; 91 )
Week 12 – Day 84
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
113/130
Table 46: Time Windows for ECG 
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date 
of first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 70 )
Week 8 – Day 56
[ 70 ; 91 )
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg QD/Evobrutinib 
50 mg BID 
•
Evobrutinib 75 mg QD/Evobrutinib 
50 mg BID
•
Evobrutinib 50 mg BID/Evobrutinib 
50 mg BID
OLE period
1
Day 1 – OLE
[2 ; 270 ) 
Month 6 – OLE
[ 270 ; 367 ) 
Month 12 – OLE
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MS200527-0060
14 October 2019 / Version 2.0
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Table 47: Time Windows for ACR components 
Treatment groups
Period covered
Interval (days)
[Date of assessment –
Date of first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 21 )
Week 2 – Day 14
[ 21 ; 42 )
Week 4 – Day 28
[ 42 ; 70 )
Week 8 – Day 56
[ 70 ; 98 ]
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg QD/Evobrutinib 
50 mg BID 
•
Evobrutinib 75 mg QD/Evobrutinib 
50 mg BID
•
Evobrutinib 50 mg BID/Evobrutinib 
50 mg BID
OLE period
1
Day 1 – OLE
[2 ; 270 ) 
Month 6 – OLE
[ 270 ; 367 ) 
Month 12 – OLE
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14 October 2019 / Version 2.0
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Table 48: Time Windows for SF-36, FACIT-Fatigue and 
Treatment groups
Period covered
Interval (days)
[Date of assessment –
Date of first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
1
Day 1
[ 2 ; 42 )
Week 4 – Day 28
[ 42 ; 70 )
Week 8 – Day 56
[ 70 ; 98 ]
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg BID
•
Evobrutinib 25 mg QD/Evobrutinib 
50 mg BID 
•
Evobrutinib 75 mg QD/Evobrutinib 
50 mg BID
•
Evobrutinib 50 mg BID/Evobrutinib 
50 mg BID
OLE period
1
Day 1 – OLE
[2 ; 270 ) 
Month 6 – OLE
[ 270 ; 367 ) 
Month 12 – OLE
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
116/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
117/130
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
118/130
Table 51: Time Windows for MRI assessments 
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date 
of first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
[ -35 ; 1 ]
Day 1
[ 2 ; 56 )
Week 4 – Day 28
[ 56 ; 98 ]
Week 12 – Day 84
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
119/130
Table 52: Time Windows for HBV DNA assessments 
Treatment groups
Period covered
Interval (days)
[Date of assessment – Date of 
first dose + 1]
Analysis Visit
•
Placebo
•
Evobrutinib 25 mg QD 
•
Evobrutinib 75 mg QD
•
Evobrutinib 50 mg BID
12-week treatment 
period
[ 1 ; 42 )
Week 4 – Day 28
[ 42 ; 70 )
Week 8 – Day 56
[ 70 ; 91 )
Week 12 – Day 84
•
Placebo/Evobrutinib 50 mg 
BID
•
Evobrutinib 25 mg 
QD/Evobrutinib 50 mg BID 
•
Evobrutinib 75 mg 
QD/Evobrutinib 50 mg BID
•
Evobrutinib 50 mg 
BID/Evobrutinib 50 mg BID
OLE period
1
Day 1 – OLE
[ 2 ; 45 )
Month 1 – OLE
[ 45 ; 75 )
Month 2 – OLE
[ 75 ; 135 )
Month 3 – OLE
[135 ; 225 ) 
Month 6 – OLE
[ 225 ; 315 ) 
Month 9 – OLE
[ 315 ; 367 ) 
Month 12 – OLE
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
120/130
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Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
121/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
122/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
123/130
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Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
124/130
18.8
Laboratory Parameters to be summarized in the TLFs
Table 53: Laboratory Parameters to be Summarized in the TLFs
Names of Clinical Safety 
Laboratory Evaluations in Protocol 
version 3.0
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
Amylase
Serum amylase increased
HIGH
Lipase
Lipase increased
HIGH
Total carbon dioxide
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
HIGH
Hematology
Hematocrit
LOW/HIGH
Hemoglobin
Hemoglobin increased
HIGH
Hemoglobin
Anemia
LOW
Hemoglobin A1C
HIGH
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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14 October 2019 / Version 2.0
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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
Specific Gravity 
NA
Coagulation
International normalized ratio
NA
Partial thromboplastin time
NA
Urine 
Microscopy
White blood cells
HIGH
Red blood cells
HIGH
Casts (Granular and Hyaline)
NA
Lipid Panel
HDL-C
LDL-C
Total Cholesterol
Total Cholesterol increased
HIGH
Triglycerides
Hypertriglyceridemia
HIGH
Reflex Testing 
for HBV DNA
HBV DNA
HIGH
Hepatic Panel
International normalized ratio
Partial thromboplastin time
Partial thromboplastin time 
prolonged
HIGH
Fibrinogen
Fibrinogen decreased
LOW
hsCRP
HIGH
Hepatitis serology: anti hepatitis A 
Virus IgG, anti-hepatitis A Virus 
IgM, HBsAg, anti hepatitis B core 
antigen, anti HBsAg, anti HCV, anti 
hepatitis E Virus IgG and IgM, anti 
viral capsid antigen IgG and IgM, 
anti early antigen IgG, anti Epstein 
NA
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14 October 2019 / Version 2.0
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Barr nuclear antigen IgG, anti 
cytomegalovirus IgG and IgM
Antinuclear antibody, anti smooth 
muscle antibody, antibody to liver 
kidney microsomal antibody
NA
Albumin
Hypoalbuminemia
LOW
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14 October 2019 / Version 2.0
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18.9
Justification for the MCPMOD parameters 
The primary endpoint of the MS200527-0086 study, total number of Gd+ T1 lesions at Weeks 12, 
16, 20, and 24, was significantly lower in the evobrutinib 75 mg once daily and evobrutinib 75 mg 
twice daily groups when compared to placebo, and the primary objective of the study was met for 
these 2 treatment groups.
A monotonic dose-response relationship between ordered dose groups (placebo, evobrutinib 
25 mg once daily, evobrutinib 75 mg once daily, and evobrutinib 75 mg twice daily) and ordered 
categories of Gd+ T1 lesion count for Weeks 12, 16, 20, and 24, was assessed via the 
Jonckheere-Terpstra trend test. The results demonstrated that the location of the lesion count 
distribution is ordered (from largest value to smallest) according to increasing dose group 
(p<0.0001). Results are provided in Table .
Table 54: Results from Jonckheere-Terpstra trend test
Response
Category
Placebo
N=53 
(100%)
Evobrutinib
25 mg QD
N=50 
(100%)
Evobrutinib
75 mg QD
N=51 
(100%)
Evobrutinib
75 mg BID
N=53 
(100%)
Tecfidera
N=54 
(100%)
Number of subjects with 
total number Gd+ T1 
lesions, n (%)
0
20
(37.7)
24
(48.0)
37
(72.5)
36
(67.9)
31
(57.4)
[1, 2)
6
(11.3)
8
(16.0)
4
( 7.8)
8
(15.1)
11
(20.4)
[2, 3)
6
(11.3)
6
(12.0)
2
( 3.9)
2
( 3.8)
3
( 5.6)
≥ 3
21
(39.6)
12
(24.0)
8
(15.7)
7
(13.2)
9
(16.7)
Jonckheere-Terpstra trend 
test*
Statistic (Z)
-4.08
P-Value 
(asymptotic)
<.0001
Tecfidera treatment group is not included in inferential analyses.                                                       
Prior to defining suitable categories for Gd+ T1 lesion count for wks 12, 16, 20, 24, missing scan data for a subject will be
imputed using average of available scan data for that subject. Scans collected within 3 weeks of high dose corticosteroid use are 
considered missing. If a subject lacks any post-baseline evaluable MRI assessment, lesion count is imputed as the product of 
“4” and the median lesions per scan, where the median is among subjects with available post-baseline scans, who are in the 
same treatment group, and who have the same value for the categorical baseline covariate.                                                             
*Jonckheere-Terpstra monotonic trend test: unstratified test for decreasing ordinal total number Gd+ T1 lesions with increasing 
ordinal dose.                                                                                  
In addition to the nonparametric test of monotonic dose-response, a model-based test of linear
trend in log lesion rate with increasing dose suggests that the log lesion rate decreased linearly 
with increasing dose group order. Results from this model-based test are provided in Table .
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Table 55: Results from negative binomial and Poisson models
Placebo
N=53 
(100%)
Evobrutinib
25 mg QD
N=50 
(100%)
Evobrutinib
75 mg QD
N=51 
(100%)
Evobrutinib
75 mg BID
N=53 
(100%)
Tecfidera
N=54 
(100%)
Total number of Gd+ T1 lesions at Weeks 
12, 16, 20, 24
   Subjects with 0 lesions, n (%)
20 (37.7)
24 (48.0)
37 (72.5)
36 (67.9)
31 (57.4)
                        1 lesion, n (%)
8 (15.1)
8 (16.0)
4 (7.8)
8 (15.1)
11 (20.4)
                          2 lesions, n (%)
5 (9.4)
6 (12.0)
2 (3.9)
4 (7.5)
3 (5.6)
                          3 lesions, n (%)
3 (5.7)
1 (2.0)
1 (2.0)
2 (3.8)
1 (1.9)
Total number of scans
   Subjects with 1 scan, n (%)
2 (3.8)
2 (4.0)
2 (3.9)
4 (7.5)
1 (1.9)
                         2 scans, n (%)
1 (1.9)
1 (2.0)
0 (0.0)
1 (1.9)
2 (3.7)
                         3 scans, n (%)
8 (15.1)
12 (24.0)
2 (3.9)
7 (13.2)
6 (11.1)
                          4 scans, n (%)
42 (79.2)
35 (70.0)
47 (92.2)
41 (77.4)
45 (83.3)
Gd+ T1 lesion rate (subject level)
   n (%)
53 (100.0)
50 (100.0)
51 (100.0)
53 (100.0)
54 (100.0)
   Mean ±SD
1.02 ±1.439
1.31 ±3.130
0.42 ±1.173
0.33 ±0.961
1.45 ±7.293
   Median
0.50
0.25
0.00
0.00
0.00
   Q1; Q3
0.00; 1.50
0.00; 0.67
0.00; 0.25
0.00; 0.25
0.00; 0.25
   Min; Max
0.00; 6.00
0.00; 19.00
0.00; 6.75
0.00; 6.25
0.00; 53.33
Lesion RR based on NB model (*) [95% 
CI]
1.45
[0.72, 2.91]
0.30
[0.14, 0.63]
0.44
[0.21, 0.93]
P-value (Evobrutinib vs placebo)
0.2947
0.0015
0.0313
Hochberg adjusted P-value
0.3157
0.0046
0.0648
Linear trend test P-value
   Based on Likelihood Ratio Test
0.0011
   Based on Wald Test
0.0007
Conditional Lesion RR based on 
longitudinal Poisson model (**) [95% CI]
1.44
[0.81, 2.58]
0.49
[0.22, 1.09]
0.31
[0.13, 0.77]
P-value (Evobrutinib vs placebo)
0.2173
0.0793
0.0112
Tecfidera treatment group is not included in inferential analyses.                                                       
(*) Negative binomial model for lesion count (summed over scans) includes treatment and covariate presence/absence of Gd+ 
T1 lesions at baseline, with offset equal to the log of number of scans performed. A lesion rate ratio (RR) < 1 favors the active 
treatment. Subjects with missing scans or discontinuing early are analyzed according to the available number of scans and lesion 
counts. Scans collected within 3 weeks of high dose corticosteroid use are considered missing. Linear trend test assesses linearly 
decreasing trend of log lesion rate with increasing dose.                   
(**) Poisson Generalized Linear Mixed Model (GLMM) for lesion count at a single scan includes fixed effects for treatment 
and scan time point, a covariate for presence/absence of Gd+ T1 lesions at baseline, zero offset, and CS covariance structure for 
repeated measures. Same handling of early discontinuers, and consideration of scans collected within 3 weeks of high dose 
corticosteroid use as in first model. Lesion RR is conditional on random effects.            
- Lesion rate on the subject level is the Total # of Gd+ T1 lesions for the subject (summed over all scans), divided by the Total 
# of scans for the subject. 
- Summary and inferential statistics are based on data where imputation is performed only for those subjects in the mITT analysis 
set who are missing all post-baseline scans.
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Therefore, a dose-response relationship was observed. However, the negative binomial model 
showed a lower lesion rate ratio in the evobrutinib 75 mg once daily group when adjusted on the 
number of scans, but the conditional lesion rate ratio based on longitudinal Poisson model showed 
an ordered dose-response relationship, as indicated in Table .
As a result, since the evobrutinib 75 mg once daily dose is common from both studies 
MS200527-0060 and MS200527-0086, it has been decided to use the conditional lesion rate ratio
based on longitudinal Poisson model to assess the percentage of maximum effect observed. As the 
maximum effect was obtained in the evobrutinib 75 mg twice daily group with a lesion rate ratio 
of 0.31, the percentage of maximum effect observed for the evobrutinib 75 mg once daily group 
was estimated as follows: 
%  !$! !  = 0.51
0.69 × 100 = 74%
Based on this percentage of maximum effect in the evobrutinib 75 mg once daily group, the 
parameters of the models for the MCPMOD were assessed using the following R statements: 
R> ## load package
R> library(DoseFinding)
R> # assign doses in mg
R> doses <- c(0, 25, 75, 100)
R> emax<-guesst(d=75, p=0.74, model="emax")
R> emax[1]
R> quad<-guesst(d=75, p=1, "quadratic")
R> quad[1]
R> logi<-guesst(d=c(75,100), p=c(0.74,0.9999999), "logistic")
R> logi[1]
R> logi[2]
It provides the parameters described in Table 14.
  
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CCI


Evobrutinib
Phase IIb in Rheumatoid Arthritis
MS200527-0060
14 October 2019 / Version 2.0
130/130
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CCI
CCI


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