A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy of Fenebrutinib in Relapsing Multiple Sclerosis
Phase: PHASE2
Conditions: Relapsing Multiple Sclerosis
Sponsor: Hoffmann-La Roche

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
Protocol GN43271, Version 3 
PROTOCOL 
PROTOCOL TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE 
THE EFFICACY OF FENEBRUTINIB IN RELAPSING 
MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: 
GN43271 
VERSION NUMBER: 
3 
ROCHE COMPOUND(S): 
Fenebrutinib (RO7010939) 
STUDY PHASE: 
Phase II 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  145957 
EUDRACT Number: 2021-003772-14 
EU Trial Number:  2022-502619-13-00
NCT Number:  NCT05119569 
SPONSOR NAME AND 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
2/Protocol GN43271, Version 3 
 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
3 
See electronic date stamp on the final 
page of this document. 
2 
13 July 2021 
1 
5 May 2021 
 
 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
3/Protocol GN43271, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol GN43271 has been amended to provide additional guidance on safety 
monitoring.  Substantive changes to the protocol, along with a rationale for each change, 
are summarized below.  
 
Per recommendations from the independent Data Monitoring Committee (iDMC), 
additional monitoring visits for liver function tests (ALT, AST, total and direct 
bilirubin) have been added to the schedule of activities (Section 1.3).  Guidance has 
been added for laboratory analysis of these blood tests.  
 
The following changes have been added to further support the additional monitoring of 
liver function tests and provide sites with more guidance regarding patient management.  
 
The exclusion criterion for ALT or AST  2 x upper limit of normal has been updated 
to no longer allow retesting for ALT or AST 23  ULN (Section 5.2).  
 
The criteria for discontinuation of study treatment have been edited to include 
participants with ALT or AST elevation between 35  ULN (inclusive) persisting for 
4 weeks and in absence of alternative etiology (Section 7.1).  
 
The safety reporting sections have been edited to clearly define the laboratory 
parameters that constitute adverse events of special interest (Sections 8.2.4 and 
8.3.8, Appendix A37.6, and Appendix A61.1).   
 
Guidance on the management of patients with elevated liver function tests, including 
re-testing requirements and/or additional laboratory tests has been clarified 
(Appendix A62.3). 
 
To build on the existing safety monitoring plan for participants, detailed monitoring 
guidelines for participants with abnormal liver biochemical and functional tests have 
been added (Appendix 7).  These revisions align with 2009 FDA regulatory 
guidance for drug induced liver injury (DILI) detection, and the 2020 Consensus by 
the CIOMS DILI Working Group.  
 
The duration of the optional open-label extension (OLE) phase was extended from 96 
weeks up to a maximum of 192 weeks.  To align with this, the following changes were 
made: 
 
The footnote for the Study Schema was updated to clarify that there currently is an 
optional OLE to provide open-label fenebrutinib to all eligible participants who 
complete the DBT phase on study treatment (Section 1.2, Figure 1).  The study 
design section has also been updated to include the duration of the OLE phase 
(Section 4.1).  
 
The OLE schedule of activities was updated to reflect that patients may remain in 
the OLE beyond 96 weeks (Section 1.3, Table 2). 
 
The collection of hepatic synthetic function tests was updated in the OLE schedule 
of activities from Weeks 36 and 96 to Weeks 12 and 24 to align with the risk period 
for potential hepatic transaminase elevations (Section 1.3, Table 2). 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
4/Protocol GN43271, Version 3 
 
The collection of lipids was changed to every 48 weeks following Week 48 to align 
with the increase in duration of the OLE phase beyond 96 weeks. 
 
The following additional changes and clarifications have been made: 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (front page and Section 8.3.10).  
Medical Monitor contact information in Section 8.3.10 has been replaced with a 
sentence indicating that this information will be provided separately to sites. 
 
The synopsis has been simplified to align with Clinical Trials Regulation (CTR) and 
other guidelines. 
 
The language regarding the timing of the Week 12 lumbar puncture was updated to 
allow for more flexibility for obtaining the sample (Sections 1.3 and 8.10.1).   
 
The primary and secondary objectives have been updated to add language on 
corresponding estimands (Section 3).  
 
Per recommendation from the U.S. Food and Drug Administration, high dose biotin 
has been added to the list of prohibited concomitant medications (Section 6.8.3.1).  
 
The exclusion criterion regarding the presence of other neurological disorders has 
been clarified to specify those conditions which could interfere with the diagnosis of 
multiple sclerosis or with the assessments of efficacy or safety during the study 
(Section 5.2).  
 
The criterion for exclusion of patients on adrenocorticotropic hormone or systemic 
corticosteroid therapy has been updated to clarify that inhaled and topical 
corticosteroids would be permitted (Section 5.2).  
 
A comprehensive list of investigational medicinal products and non-investigational/ 
auxiliary medicinal products has been added to align with CTR requirements 
(Section 6 and Appendix 11) 
 
The responsibilities of the investigator and the role of the Medical Monitor during 
study conduct have been clarified (Sections 6.3.2, 6.8, and 8.2.4; Appendix A62.2). 
 
The criteria for discontinuation of study treatment has been updated for participants 
with thrombocytopenia in alignment with the guidance provided in Table A6-1 
(Section 7.1).  
 
The criteria for discontinuation of study treatment for participants with ECG findings 
was updated to align Sections 7.1 and A6-2.4. 
 
It has been clarified that while magnetic resonance imaging scans are being 
acquired to support primary and secondary endpoints, the images will also allow for 
exploratory measurements (Section 8.1.1). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 8.10.7). 
 
The analysis sets for efficacy and biomarker endpoints have been clarified 
(Sections 9.3 and 9.4.1) 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
5/Protocol GN43271, Version 3 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Appendix A1-4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Appendix A16). 
 
The Sponsor record retention policy has been clarified (Appendix A17). 
 
Action steps for management of patients with suspected progressive multifocal 
leukoencephalopathy (PML) were edited to clarify that study treatment should be 
interrupted and the medical monitor must be notified (Appendix 8). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
6/Protocol GN43271, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11 
1. 
PROTOCOL SUMMARY ............................................................... 12 
1.1 
Synopsis .................................................................................. 12 
1.2 
Study Schema ......................................................................... 14 
1.3 
Schedule of Activities and Sample Collection Schedule .......... 15 
2. 
INTRODUCTION ........................................................................... 26 
2.1 
Study Rationale ....................................................................... 26 
2.1.1 
Overall Study Rationale ........................................................... 26 
2.2 
Background.............................................................................. 26 
2.3 
Benefit–Risk Assessment ........................................................ 27 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 28 
4. 
STUDY DESIGN ........................................................................... 31 
4.1 
Overall Design ......................................................................... 31 
4.2 
Rationale for Study Design ...................................................... 31 
4.2.1 
Rationale for Study Population ................................................ 31 
4.2.2 
Rationale for Control Group ..................................................... 32 
4.2.3 
Rationale for Blinding ............................................................... 32 
4.2.4 
Rationale for Biomarker Sample Collection Schedule ............. 32 
4.2.5 
Rationale for Endpoints ........................................................... 33 
4.2.6 
Rationale for Pharmacokinetic Sample Collection Schedule ... 33 
4.2.7 
Rationale for Stratification Factors ........................................... 33 
4.2.8 
Rationale for the Optional Cerebrospinal Fluid Substudy ........ 34 
4.3 
Justification for Dose and Schedule ......................................... 34 
4.4 
End of Study Definition ............................................................ 35 
4.5 
Duration of Participation .......................................................... 35 
5. 
STUDY POPULATION .................................................................. 35 
5.1 
Inclusion Criteria ...................................................................... 35 
5.2 
Exclusion Criteria ..................................................................... 37 
5.3 
Lifestyle Considerations ........................................................... 41 
5.3.1 
Meals and Dietary Restrictions ................................................ 41 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
7/Protocol GN43271, Version 3 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................... 41 
5.3.3 
Activity ..................................................................................... 41 
5.3.4 
Contraception Requirements ................................................... 41 
5.4 
Screen Failures ........................................................................ 41 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY ........ 41 
6.1 
Study Treatments Administered ............................................... 41 
6.1.1 
Fenebrutinib and Placebo ........................................................ 42 
6.2 
Preparation, Handling, Storage, and Accountability ................. 43 
6.3 
Treatment Assignment and Blinding ........................................ 43 
6.3.1 
Treatment Assignment ............................................................. 43 
6.3.2 
Blinding .................................................................................... 44 
6.4 
Study Treatment Compliance .................................................. 45 
6.5 
Dose Modification .................................................................... 45 
6.6 
Continued Access to Study Treatment after the End of the 
Study ....................................................................................... 46 
6.7 
Treatment of Overdose ............................................................ 46 
6.8 
Concomitant Therapy .............................................................. 46 
6.8.1 
Permitted Therapy ................................................................... 47 
6.8.1.1 
Oral Contraceptives and Hormone-Replacement Therapy ...... 47 
6.8.1.2 
Symptomatic Treatments of Multiple Sclerosis ........................ 47 
6.8.1.3 
Treatment of Relapses ............................................................ 47 
6.8.2 
Cautionary Therapy ................................................................. 47 
6.8.2.1 
Acid-Reducing Agents ............................................................. 47 
6.8.2.2 
CYP3A- and Breast Cancer Resistance Protein-Mediated 
Drug Interactions ..................................................................... 48 
6.8.2.3 
Statins ...................................................................................... 49 
6.8.2.4 
Herbal Therapies ..................................................................... 49 
6.8.3 
Prohibited Therapy .................................................................. 49 
6.8.3.1 
Other Prohibited Therapies ...................................................... 50 
6.8.4 
Prohibited Food ....................................................................... 51 
6.8.5 
Immunizations .......................................................................... 51 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............ 52 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
8/Protocol GN43271, Version 3 
7.1 
Discontinuation of Study Treatment ......................................... 52 
7.2 
Participant Discontinuation or Withdrawal from the Study ....... 53 
7.3 
Participants Lost to Follow-Up ................................................. 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 54 
8.1 
Efficacy Assessments .............................................................. 55 
8.1.1 
Magnetic Resonance Imaging ................................................. 55 
8.1.2 
Clinical Outcome Assessments ............................................... 56 
8.1.3 
MS Relapse Assessment ......................................................... 56 
8.2 
Safety Assessments ................................................................ 57 
8.2.1 
Physical Examinations ............................................................. 57 
8.2.2 
Vital Signs ................................................................................ 57 
8.2.3 
Electrocardiograms .................................................................. 57 
8.2.4 
Clinical Safety Laboratory Assessments .................................. 58 
8.2.5 
Pregnancy Testing ................................................................... 59 
8.2.6 
Monitoring for Suicidal Ideation and Behavior.......................... 59 
8.3 
Adverse Events, Serious Adverse Events, and Other 
Safety Reporting ...................................................................... 60 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 60 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 61 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 61 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 61 
8.3.5 
Pregnancy................................................................................ 62 
8.3.6 
Cardiovascular and Death Events ........................................... 62 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting ..... 62 
8.3.8 
Adverse Events of Special Interest .......................................... 62 
8.3.9 
Medical Monitors and Emergency Medical Contacts ............... 63 
8.4 
Pharmacokinetics .................................................................... 63 
8.5 
Pharmacodynamics ................................................................. 64 
8.6 
Genetics .................................................................................. 64 
8.7 
Biomarker Assessments .......................................................... 64 
8.8 
Immunogenicity Assessments ................................................. 65 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
9/Protocol GN43271, Version 3 
8.9 
Health Economics and Medical Resource Utilization ............... 65 
8.10 
Additional Assessments and Procedures 
Requiring Separate Consent.................................................... 65 
8.10.1 
Lumbar Punctures and CSF Substudy .................................... 65 
8.10.2 
Samples for Research Biosample Repository.......................... 67 
8.10.2.1 
Overview of the Research Biosample Repository .................... 67 
8.10.3 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 68 
8.10.4 
Sample Collection .................................................................... 68 
8.10.5 
Confidentiality .......................................................................... 69 
8.10.6 
Consent to Participate in the Research Biosample 
Repository................................................................................ 69 
8.10.7 
Withdrawal from the Research Biosample Repository ............. 70 
8.10.8 
Monitoring and Oversight ......................................................... 70 
9. 
STATISTICAL CONSIDERATIONS .............................................. 70 
9.1 
Statistical Hypotheses ............................................................. 70 
9.2 
Sample Size Determination ..................................................... 71 
9.3 
Analysis Sets ........................................................................... 71 
9.4 
Statistical Analyses .................................................................. 71 
9.4.1 
General Considerations ........................................................... 71 
9.4.2 
Primary Endpoint(s) ................................................................. 71 
9.4.3 
Secondary Endpoints ............................................................... 73 
9.4.4 
Exploratory Endpoints .............................................................. 74 
9.4.5 
Other Safety Analyses ............................................................. 74 
9.4.6 
Other Analyses ........................................................................ 74 
9.4.6.1 
Summaries of Conduct of Study .............................................. 74 
9.4.6.2 
Summaries of Treatment Group Comparability ........................ 74 
9.4.6.3 
Pharmacokinetic Analyses ....................................................... 74 
9.5 
Interim Analysis ....................................................................... 74 
9.6 
Independent Data Monitoring Committee ................................ 74 
10. 
REFERENCES.............................................................................. 75 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
10/Protocol GN43271, Version 3 
LIST OF TABLES 
Table 1
Schedule of Activities .................................................................. 15
Table 2
Schedule of Activities:  Open-Label Extension Phase ................ 20
Table 3
Schedule of Pharmacokinetic Samples for Double-Blind 
Treatment.................................................................................... 25
Table 4
Primary and Secondary Objectives and Corresponding 
Estimands ................................................................................... 29
Table 5 
Other Secondary and Exploratory Objectives and Endpoints ..... 30
Table 6
Study Treatment Description ....................................................... 42
Table 7
List of Prohibited Medicines Due to CYP3A-Mediated Drug 
Interactions ................................................................................. 50
Table 8
 Schedule of CSF Substudy Pharmacokinetic and Biomarker 
Samples for Double-Blind Treatment .......................................... 67
LIST OF FIGURES 
Figure 1
Study Schema ............................................................................. 14
LIST OF APPENDICES 
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations ........... 77
Appendix 2
Clinical Safety Laboratory Tests ................................................. 84
Appendix 3
Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................... 86
Appendix 4
Contraceptive and Barrier Guidance ......................................... 104
Appendix 5
Genetics:  Use and Analysis of DNA ......................................... 107
Appendix 6
Safety Plan:  Management of Identified and Potential Risks ..... 108
Appendix 7 
Guidance for Recording Information in eCRFs for 
Participants with Abnormal Liver Enzyme and Function 
Tests.......................................................................................... 119
Appendix 8 Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ............................................................... 125
Appendix 9 Columbia-Suicide Severity Rating Scale 
Baseline/Screening Version and Since Last Visit Version ........ 130
Appendix 10 Telephone Interviews ................................................................... 136
Appendix 11 Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ...................................... 137
Appendix 12 Protocol Amendment History ....................................................... 138
Appendix 1 Abbreviations ............................................................................... 140

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
11/Protocol GN43271, Version 3 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO INVESTIGATE 
THE EFFICACY OF FENEBRUTINIB IN RELAPSING 
MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: 
GN43271 
VERSION NUMBER: 
3 
ROCHE COMPOUND(S): 
Fenebrutinib (RO7010939) 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy of 
the signed form as instructed by the CRO. 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
12/Protocol GN43271, Version 3 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO INVESTIGATE THE EFFICACY OF FENEBRUTINIB IN 
RELAPSING MULTIPLE SCLEROSIS  
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  145957 
EUDRACT Number: 2021-003772-14 
EU Trial Number:  2022-502619-13-00 
NCT Number:  NCT05119569 
  
STUDY RATIONALE 
The purpose of this study is to assess the efficacy, safety, and pharmacokinetics of fenebrutinib, 
a highly selective, orally administered, adenosine triphosphate- competitive, reversible inhibitor 
of Bruton tyrosine kinase (BTK), compared with placebo in participants with relapsing multiple 
sclerosis (RMS).  The BTK inhibition with fenebrutinib has the potential to reduce disease 
activity in multiple sclerosis by inhibiting B-cell and myeloid cell activation.  
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of fenebrutinib compared 
with placebo in participants with RMS.  Specific objectives and corresponding endpoints for the 
study are outlined below. 
Primary Objective 
Corresponding Endpoint  
 To evaluate the efficacy of fenebrutinib 
compared with placebo on the total 
number of new gadolinium-enhancing 
T1 MRI lesions 
 Total number of new gadolinium-enhancing 
T1 lesions observed on MRI scans of the brain at 
Weeks 4, 8, and 12 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the effect of fenebrutinib 
on MRI lesions 
 Total number of new or enlarging T2-weighted 
lesions observed on brain MRI at Weeks 4, 8, and 12  
 Proportion of participants free from any new 
gadolinium-enhancing T1 lesions and new or 
enlarging T2-weighted lesions observed on brain 
MRI at Weeks 4, 8, and 12. 
 To evaluate the safety of fenebrutinib 
compared with placebo 
 Incidence and severity of adverse events 
 Change from baseline in vital signs 
 Change from baseline in targeted clinical laboratory 
test results 
 Proportion of participants with suicidal ideation or 
behavior, as assessed by Columbia-Suicide Severity 
Rating Scale (Appendix 9) 
 To characterize the fenebrutinib PK 
profile 
 Plasma concentration of fenebrutinib at specified 
timepoints 
MRI  magnetic resonance imaging; PK  pharmacokinetic. 
  

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
13/Protocol GN43271, Version 3 
Primary and selected secondary objectives for the study are expressed using the estimand 
framework in accordance with the International Conference on Harmonization E9 (R1) statistical 
principles for clinical trials (ICH 2020) in Section 3. 
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase II, double-blind, placebo-controlled, randomized study with a primary efficacy 
objective of evaluating the effect of fenebrutinib on the total number of new 
gadolinium -enhancing T1 brain magnetic resonance imaging lesions in participants with RMS.  
The safety and pharmacokinetics of fenebrutinib will also be evaluated in the study.  
Several key aspects of the study design and study population are summarized below. 
 
Phase: 
Phase II 
Population Type: 
Adult patients 
 
Control Method: 
Placebo 
Population Diagnosis 
or Condition: 
RMS 
Interventional 
Model: 
Parallel group 
 
Population Age: 
1855 years 
Test Compound{s}: Fenebrutinib 
 
Site Distribution: 
Multi-site 
 
Active Comparator: Not applicable 
Study Intervention 
Assignment Method: 
Randomization 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 102 
  
STUDY TREATMENT 
The investigational medicinal product for this study is fenebrutinib. 
Participants will take two 100 mg tablets by mouth twice a day for a total dose of 400 mg of 
fenebrutinib (or placebo) every day.  Participants will self-administer two 100 mg tablets in the 
morning and two 100 mg tablets in the evening by mouth.  The tablet should be swallowed 
whole with some water, can be taken with or without food, and should be taken at the same 
time each day.  Participants should be instructed that a missed fenebrutinib (or matching 
placebo) dose should not be taken with the next scheduled dose.  Administration of fenebrutinib 
(or matching placebo) should be staggered with antacid use (i.e., study drug should be taken 2 
hours before or 2 hours after antacid administration). 
DURATION OF PARTICIPATION 
The duration of participation for each individual is expected to be 12 weeks (approximately 3 
months) plus 4 weeks of safety follow up, if applicable.  This will be followed by participation in 
an optional open-label extension (OLE) period. 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee 
Other Committees: 
Not Applicable 
 
 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
15/Protocol GN43271, Version 3 
 
1.3 
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION SCHEDULE 
Table 1 
Schedule of Activities 
Visit 
SCR a 
Double-Blind Treatment 
UV c 
Early D/C 
Visit d 
Safety Follow-Up Visit e 
1 
2 
3 
4 
5 
6 
7 
8 
Study week 
 
0 
2 b 
4 
6 b 
8 
10 b 
12 
16 (or 4 weeks after 
Early D/C) 
Window in Days 
–28 to –1 
NA 
±2 
±2 
±2 
±2 
±2 
±2 
NA 
NA 
2 
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
 
Review of eligibility criteria 
x 
x 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline conditions 
x 
 
 
 
 
 
 
 
 
 
 
Review of contraception methods 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
C-SSRS 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
Vital signs g 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Weight 
 
x 
 
 
 
 
 
x 
 
x 
x 
Height 
 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination h 
x 
x 
 
 
 
 
 
x 
(x) 
x 
 
Neurological examination i 
x 
x 
 
 
 
 
 
x 
(x) 
x 
 
Query for potential unreported relapses 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
EDSS j 
x 
x 
 
 
 
 
 
x 
(x) 
x 
 
12-lead ECG k 
x 
x 
 
x 
 
 
 
x 
 
x 
 
Blood tests:l 
Hematology and full chemistry panel 
x 
x 
 
x 
 
x 
 
x 
(x) 
x 
x 

Table 1 
Schedule of Activities (cont.) 
 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
16/Protocol GN43271, Version 3 
 
 
Visit 
SCRa 
Double-Blind Treatment 
UV c 
Early D/C 
Visit d 
Safety Follow-Up 
Visit e 
1 
2 
3 
4 
5 
6 
7 
8 
Study week 
 
0 
2 b 
4 
6 b 
8 
10 b 
12 
16 (or 4 weeks 
after Early D/C) 
Window in Days 
–28 to 
–1 
NA 
±2 
±2 
±2 
±2 
±2 
±2 
NA 
NA 
±2 
Limited chemistry panel: ALT, AST, total and 
direct bilirubin testing 
 
 
x 
 
x 
 
x 
 
 
 
 
Hepatic synthetic function testing (PT, INR, aPTT) 
x 
 
 
 
 
 
 
x 
(x) 
 
 
Lipids 
 
x 
 
 
 
 
 
x 
 
x 
 
Flow cytometry m 
x 
xn 
 
x 
 
x 
 
x 
 
x 
x 
Total Ig, IgG, IgA, IgM  
x 
 
 
x 
 
x 
 
x 
 
x 
x 
Hepatitis B screening o 
x 
 
 
 
 
 
 
 
 
 
 
Hepatitis B virus DNA 
x 
 
 
(x) 
 
 
 
(x) 
 
(x) 
 
Hepatitis C screening p 
x 
 
 
 
 
 
 
 
 
 
 
HIV screening 
x 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Test (QuantiFERON®-TB Gold) 
x 
 
 
 
 
 
 
 
 
 
 
Plasma PK sample q 
 
x 
 
x 
 
x 
 
x 
(x) 
x 
 
Additional intensive PK sampling (optional) q 
 
x 
 
x 
 
 
 
 
 
 
 
Serum and plasma biomarkers r 
x 
xn 
 
x 
 
x 
 
x 
 
x 
x 
RNA collection (PAXgene tube) 
x 
xn 
 
 
 
 
 
x 
 
x 
x 
In clinic pregnancy test s 
x 
x 
 
x 
 
x 
 
x 
(x) 
x 
x 
    Urinalysis 
 
x 
 
x 
 
 
 
x 
(x) 
x 
x 

Table 1 
Schedule of Activities (cont.) 
 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
17/Protocol GN43271, Version 3 
 
 
SCR a 
Double-Blind Treatment 
UV c 
Early D/C 
Visit d 
Safety Follow-Up 
Visit e 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Study week 
 
0 
2 b 
4 
6 b 
8 
10 b 
12 
16 (or 4 weeks after 
Early D/C) 
Window in Days 
–28 to –1  
NA 
±2 
±2 
±2 
±2 
±2 
±2 
NA 
NA 
±2 
CSF collection (optional) t 
x 
 
 
 
 
 
 
x 
 
 
 
MRI u 
x 
 
 
x 
 
x 
 
x 
(x) 
(x) 
 
Concomitant medications  
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Adverse events 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Study treatment dispensation 
 
x 
 
x 
 
x 
 
x v 
 
 
 
Study treatment compliance 
 
 
 
x 
 
x 
 
x 
 
x 
 
RBR: RNA, serum and plasma samples (optional) w 
x 
xn 
 
x 
 
x 
 
x 
 
x 
x 
RBR: DNA (optional) w 
 
x x 
 
 
 
 
 
 
 
 
 
C-SSRS   Columbia-Suicide Severity Rating Scale; CSF  cerebrospinal fluid; DBT   double-blind treatment; D/C   discontinuation; 
eCRF    electronic Case Report Form; EDSS   Expanded Disability Status Scale; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface 
antigen; Ig   immunoglobulin; MRI  magnetic resonance imaging; OLE   open-label extension; PK   pharmacokinetic; RBR  research biosample 
repository; SCR.   screening; TB   tuberculosis;ULN  upper limit of normal; UV   unscheduled visit; x required, (x) not always required.  

Table 1 
Schedule of Activities (cont.) 
 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
18/Protocol GN43271, Version 3 
a Participants are permitted one re-screening.  As a general guideline, MRI scan, EDSS, RBR, hematology, chemistry, urinalysis, CD4, ECG, 
immunoglobulins, hepatitis B, C, HIV, hepatic synthetic function testing, lipids, flow cytometry, and TB screening and biomarkers samples should 
be repeated if there is more than 6 weeks between the screening assessment date and re-screening assessment date.  All other procedures listed 
in the schedule of activities for the screening visit should be repeated at the re-screening visit.  Any screening assessment may be repeated at a 
re-screening visit if judged by the investigator to be clinically necessary. 
b It is preferred that the blood tests performed at these visits are analyzed by the central laboratory  during a clinic visit.  However, if these are 
performed by an accredited local laboratory, the results and reference ranges must be added to the appropriate adverse event eCRF form when 
applicable. 
c UV may be performed, as clinically appropriate. It must be performed in the following situations: 1) if the patient is experiencing neurological 
worsening, 2) if the patient has  3  ULN AST or ALT, or 3) if the patient is experiencing symptoms that could be associated with worsening liver 
function.  Assessments at UVs may be performed as clinically indicated. In the case of abnormalities in transaminase levels or clinical indications 
of worsening liver function, additional laboratory testing may be required per medical monitor guidelines (see Table A6-1).   
d Participants who discontinue from the study prior to completion should be encouraged to return to the clinic for an Early D/C visit.  If a patient 
states intention to discontinue participation at the Week 4, Week 8, or an UV prior to Week 12, that visit should be converted to an Early D/C 
Visit. 
e A Safety Follow-up Visit should be performed in 2 situations:  1) 4 weeks after early discontinuation of study drug, or 2) for participants that 
complete the double-blind treatment period (Week 12) who do not elect to participate in the OLE, in which the visit should be performed at 
Week 16. 
f Informed consent must be documented before any study-specific screening procedure is performed.   
g Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and temperature. 
Temperature should be noted in the participant’s notes only. 
h Includes an evaluation of the head, eyes, ears, nose, and throat and evaluation of the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems; genitourinary examinations may be performed if clinically indicated.  
i A separate neurological examination should be performed by the treating physician if the treating physician is not performing the EDSS.  During 
an UV, the neurological examination must be performed if the participant is experiencing neurological worsening between scheduled visits. 
j The EDSS can performed by either the treating investigator or a separate examining investigator.  The person performing the EDSS must have a 
valid Level C Neurostatus certification. 
k ECG recordings must be performed after the participant has been resting in a supine position for at least 10 minutes.   
l Participants should fast prior to the blood draws for Visits 2, 3, 4, and 5. 
m Flow cytometry: Analysis may include, but is not limited to, the determination of B-cell and T-cell numbers and other lymphocyte subsets. 
n Biomarker and RBR samples should be collected prior to the administration of study drug (predose). 

Table 1 
Schedule of Activities (cont.) 
 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
19/Protocol GN43271, Version 3 
o Tests required for hepatitis B screening: HBsAg, total HBcAb, and viral DNA PCR.  Participants with a positive HBsAg must be excluded. 
Participants with a positive HBcAb are permitted provided viral DNA PCR is negative.  Participants with a positive HBcAb but negative HBV DNA 
PCR will have their hepatitis B viral DNA monitored as per the schedule of activities. 
p Hepatitis C screening: HCAb must be negative. 
q Please refer to Table 3 for more details. 
r Biomarker samples should be collected ±3.5 days from MRI scan.  Note: Not all biomarker samples will be collected at each MRI visit; however, 
those that are collected should be collected as close to the MRI scan as possible.    
s All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specific 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t The Day 1 CSF collection by lumbar puncture should only be performed once other screening tests confirm that the patient qualifies for the 
study.  Lumbar puncture can be performed anytime during the screening period or at Day 1 prior to dosing.  The Week 12 lumbar puncture 
should to be performed between 1 to 2 hours after the administration of study drug in clinic.  A contemporaneous plasma PK sample should be 
collected at the time of CSF collection to enable comparison of CSF and serum drug levels. If the Week 12 lumbar puncture is missed, it can be 
performed at a later visit, including an OLE visit. 
u MRI scans should be obtained as close to the scheduled visit as possible (3 days) and may be obtained at UV if medically warranted.  MRI 
scan may not be performed earlier than 3 weeks after IV corticosteroid treatment for MS relapses.  At the study D/C visit, an MRI scan should be 
obtained if an MRI scan was not performed during the prior 4 weeks. 
v Study treatment will only be dispensed for participants continuing in the optional OLE. 
w RBR: Not applicable at a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
x A single, DNA sample will be collected for RBR at the baseline visit.  If the DNA sample is not taken at Visit 2 (baseline), the sample may be 
taken at any subsequent timepoint during the trial.  
 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
20/Protocol GN43271, Version 3 
 
Table 2 
Schedule of Activities:  Open-Label Extension Phase 
Visit 
Baseline a 
Open-Label Extension Phase 
UV c 
Early 
D/C 
Visit d 
SFU 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 13, 
15, etc.  
12, 14, 16, 
etc.  
Study week 
0 
2  
4 
6 b 
8 
10 b 
12 
14b 
16b 
20b 
24 
36+ every 
24 weeks 
thereafter 
48 + every 
24 weeks 
thereafter 
+4 
weeks e 
Window in Days 
 
±2 
±5 
 
±5 
5 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of contraception 
methods 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
C-SSRS 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
x 
Vital signs f 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
Complete physical 
examination g 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
(x) 
x 
x 
Query for potential 
unreported relapses 
x 
 
 
 
 
 
x 
 
 
 
x 
 
 
(x) 
x 
 
EDSS h 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
(x) 
x 
 
12-lead ECG i 
x 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 

Table 2 Schedule of Activities:  Open-Label Extension Phase (cont.) 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
21/Protocol GN43271, Version 3 
Visit 
Baseline a 
Open-Label Extension Phase 
UV c 
Early 
D/C 
Visit d 
SFU 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 13, 
15, etc.  
12, 14, 16, 
etc.  
Study week 
0 
2  
4 
6 b 
8 
10 b 
12 
14b 
16b 
20b 
24 
36+ every 
24 weeks 
thereafter 
48 + every 
24 weeks 
thereafter 
+4 
weeks e 
Window in Days 
 
±2 
±5 
 
±5 
5 
Blood tests j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and 
full chemistry 
panel 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
(x) 
x 
x 
Limited chemistry 
panel: ALT, AST, 
total and direct 
bilirubin testing 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
 
 
 
 
Hepatic synthetic 
function testing 
(PT, INR, aPTT) 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
Total Ig, IgG, IgA, 
IgM 
x 
 
x 
 
x 
 
x 
 
 
 
x 
x 
x 
 
x 
x 
Hepatitis B virus 
DNA k 
(x) 
 
 
 
 
 
(x) 
 
 
 
(x) 
 
(x) 
 
 
 
Plasma PK sample 
l 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
(x) m  
x 
 
Serum and plasma 
biomarkers n 
x 
 
 
 
 
 
x 
 
 
 
x 
 
[x] 
 
x 
x 

Table 2 Schedule of Activities:  Open-Label Extension Phase (cont.) 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
22/Protocol GN43271, Version 3 
Visit 
Baseline a 
Open-Label Extension Phase 
UV c 
Early 
D/C 
Visit d 
SFU 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11, 13, 
15, etc.  
12, 14, 16, 
etc.  
Study week 
0 
2  
4 
6 b 
8 
10 b 
12 
14b 
16b 
20b 
24 
36+ every 
24 weeks 
thereafter 
48 + every 
24 weeks 
thereafter 
+4 
weeks e 
Window in Days 
 
±2 
±5 
 
±5 
5 
Flow cytometry o 
 
 
 
 
 
 
 
 
 
 
x 
 
[x] 
 
x 
 
Lipids 
 
 
 
 
 
 
 
 
 
 
x 
 
[x] 
 
x 
 
At home pregnancy test 
 
Monthly testing 
 
 
 
Urine tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In clinic pregnancy 
test p 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
(x) 
x 
x 
Urinalysis 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
(x) 
x 
x 
MRI q 
x 
 
 
 
 
 
 
 
 
 
 
 
[x] 
(x) 
(x) 
 
Concomitant 
medications 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Study treatment 
dispensation 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
 
 
Study treatment 
compliance 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
RBR RNA, serum and 
plasma samples 
(optional) r 
x 
 
 
 
 
 
x 
 
 
 
x 
 
[x] 
 
x 
x 
Telephone interviews s 
 
Every 6 weeks (±3 days) 
 
 
 

Table 2 Schedule of Activities:  Open-Label Extension Phase (cont.) 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
23/Protocol GN43271, Version 3 
C-SSRS  Columbia-Suicide Severity Rating Scale; D/C  discontinuation; eCRF  electronic Case Report Form; EDSS  Expanded Disability 
Status Scale; HBV  hepatitis B virus; Ig  immunoglobulin; MRI  magnetic resonance imaging; OLE  open-label extension; 
PK  pharmacokinetic; SFU  safety follow-up; UV unscheduled visit; x required, (x) not always required; [x] = assessment will be carried out 
every 48 weeks after week 48. 
a The baseline visit in the OLE is the same as the Week 12 visit in the DBT phase.  Activities performed at the final visit of the randomized 
controlled period do not need to be repeated. 
b It is preferred that the blood tests performed at these visits are analyzed by the central laboratory during a clinic visit.  However, if these are 
performed by an accredited local laboratory, the results and reference ranges must be added to the appropriate adverse event eCRF when 
applicable.  When treatment codes become available, patients who received fenebrutinib during the DBT phase do not need to perform 
these visits. 
c UV may be performed, as clinically appropriate. It must be performed in the following situations: 1) if the patient is experiencing neurological 
worsening, 2) if the patient has    3   ULN AST or ALT, or 3) if the patient is experiencing symptoms that could be associated with worsening 
liver function.  Assessments at UVs may be performed as clinically indicated. In the case of abnormalities in transamine levels or clinical 
indications of worsening liver function,  additional lab testing may be required per medical monitor guidelines (see Table A6-1).  
d Participants who discontinue from the study prior to completion should be encouraged to return to the clinic for an Early D/C visit.  
 
e A SFU visit should be performed 4 weeks after early discontinuation of study drug. 
f Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and temperature. 
Temperature should be noted in the participant’s notes only. 
g Includes an evaluation of the head, eyes, ears, nose, and throat and evaluation of the cardiovascular, dermatologic, musculoskeletal, respiratory, 
and gastrointestinal systems; genitourinary examinations may be performed if clinically indicated.  A separate neurological examination should 
be performed by the treating physician if the treating physician is not performing the EDSS.  During an UV, the neurological examination must be 
performed if the participant is experiencing neurological worsening between scheduled visits. 
h The EDSS can performed by either the treating investigator or a separate examining investigator.  The person performing the EDSS must have a 
valid Level C Neurostatus certification. 
i ECG recordings must be performed after the participant has been resting in a supine position for at least 10 minutes. 
j Participants should fast before the blood draws. 
k Participants with a positive HBcAb but negative HBV DNA PCR will have their hepatitis B viral DNA monitored as per the schedule of activities. 
l To be collected predose except for the UV and Early D/C visit where sample timing is flexible. 
m This sample is optional per the investigator’s discretion 
n Biomarker samples should be collected  3.5 days from MRI scan.  Note:  Not all biomarker samples will be collected at each MRI visit; however, 
those that are collected should be collected as close to the MRI scan as possible.   
o Flow cytometry:  Analysis may include, but is not limited to, the determination of B-cell and T-cell numbers and other lymphocyte subsets. 

Table 2 Schedule of Activities:  Open-Label Extension Phase (cont.) 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
24/Protocol GN43271, Version 3 
p All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
q MRI scans should be obtained as close to the scheduled visit as possible (3 days) and may be obtained at an UV if medically warranted. 
MRI scan may not be performed earlier than 3 weeks after IV corticosteroid treatment for MS relapses.  At the Study D/C visit, an MRI scan 
should be obtained if an MRI scan was not performed during the prior 4 weeks. 
r RBR:  Not applicable at a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate. 
s Semi-structured telephone interviews will be conducted every 6 weeks (3 days) between study visits (when there are dates overlapping with site 
visits, telephone calls will not occur).  Please see $SSHQGL[  for more details.  If the participant answers YES to any question during the semi-
structured telephone interview, the answer should be discussed and reviewed by the investigator.  If warranted, the participant should return 
for an UV.  If an unplanned pregnancy is suspected, an UV to confirm the pregnancy is required.

 
Fenebrutinib—F. Hoffmann-La Roche Ltd  
25/Protocol GN43271, Version 3 
Table 3 
Schedule of Pharmacokinetic Samples for Double-Blind 
Treatment  
Visit 
Timepoint 
Sample Type 
Day 1 (Week 0) 
and 29 (Week 4) 
Prior to the morning dose, 
fasted a  
PK (plasma) 
12 hours after dosing, 
fasted 
PK (plasma) 
Day 1 (Week 0) 
and Day 29 (Week 
4) (if applicable) b 
Prior to the morning dose, 
fasted a 
PK (plasma 
1 hour ( 10 minutes) after 
dosing, fasted 
PK (plasma) 
2 hours ( 10 minutes) 
after dosing, fasted 
PK (plasma) 
4, 6, and 8 hours 
( 10 minutes) after 
dosing c 
PK (plasma) 
Day 57 (Week 8) 
Predose a 
PK (plasma) 
Day 85 (Week 12) Predose a 
PK (plasma) 
Unscheduled visit d NA 
PK (plasma) 
Early D/C visit 
NA 
PK (plasma) 
D/C  discontinuation; NA  not applicable; PK  pharmacokinetic; PPI  proton pump inhibitor. 
Notes:   
Morning clinic visits are preferred for all visits but are required on Days 1, 15, and 29.  Prior to 
each morning clinic visit, participants should be instructed not to take their morning dose and to 
bring their study medication with them to their clinic visit.  The dates and times of the most 
recent prior meal, last dose of oral study drug (prior to the clinic visit), and timing of oral study 
drug administration in the clinic should be recorded at each clinic visit.  Use of PPIs, H2-receptor 
antagonists, and/or other antacids (e.g., bismuth subsalicylate, calcium carbonate, aluminum-
magnesium hydroxide) should be recorded as concomitant medications, including the date and 
time of last administration at each clinic visit. 
Single-dose acid-reducing agents are not permitted on the day of an in-clinic visit with 
PK assessments. 
a Participants should be fasting for  6 hours overnight prior to the sample collection, which 
must be performed at the clinic in the morning.  The PK samples should be collected 
530 minutes prior to the fenebrutinib dose. 
b For participants participating in the intensive PK sample collection only. 
c Fasting is not required for these samples. 
d This sample is optional per the investigator’s discretion. 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
26/Protocol GN43271, Version 3 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
2.1.1 
Overall Study Rationale 
The purpose of this study is to assess the efficacy, safety, and pharmacokinetics of 
fenebrutinib, a highly selective, orally administered, adenosine triphosphate 
(ATP)-competitive, reversible inhibitor of Bruton’s tyrosine kinase (BTK), compared with 
placebo in participants with relapsing multiple sclerosis (RMS).  The BTK inhibition with 
fenebrutinib has the potential to reduce disease activity in multiple sclerosis (MS) by 
inhibiting B-cell and myeloid cell activation.  
2.2 
BACKGROUND 
MS is a chronic, inflammatory, demyelinating, and degenerative disease of the CNS that 
affects approximately 900,000 people in the United States (Wallin et al. 2019) and 
2.3 million people worldwide (GBD 2016 Multiple Sclerosis Collaborators 2019).  
Traditionally, MS has been classified into three clinical phenotypes: relapsing remitting 
MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) 
(Lublin et al. 2014).  SPMS and PPMS are further subdivided into active and non-active 
forms based on the presence or absence of disease activity (DA), defined by the 
presence of clinical relapses and/or T1-weighted gadolinium-enhancing (T1Gd) lesions 
on magnetic resonance imaging (MRI) scan or new/enlarging T2-weighted lesions on 
MRI scan. 
Available evidence suggests that despite the potential heterogeneity of the clinical 
expression of the disease, PPMS, SPMS, and RRMS belong to the same disease 
spectrum and that pathological mechanisms responsible for relapses/DA and 
progression biology are largely identical across the MS spectrum (Lassmann 2019). 
Disability progression across the spectrum of MS might occur as the result of two 
concurrent inflammatory mechanisms: active inflammation and chronic 
compartmentalized inflammation.  Active inflammation is responsible for the acute 
inflammation that can be observed on an MRI scan (as T1Gd lesions or new/enlarging 
T2 lesions) and/or that might manifest clinically as MS relapses and/or 
relapse -associated worsening when recovery from a previous relapse is incomplete. 
RMS is associated with an active inflammatory mechanism characterized by focal, bulk 
T-cell, and B-cell invasion and blood brain barrier leakage that give rise to classic active 
demyelinating plaques in the white matter. 
Increasing evidence suggests that B cells (Hauser et al. 2017; Montalban et al. 2017) 
and myeloid cells/microglia (Howell et al. 2010) are central to the immunopathology of 
MS, a chronic, inflammatory and degenerative demyelinating disease of the human CNS 
leading to a health-related loss of quality of life due to accumulating neurological 
disability. 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
27/Protocol GN43271, Version 3 
Approved disease modifying MS therapies primarily address the prevention of relapses 
with variable levels of efficacy.  Disease modifying therapies, which include 
immunomodulatory, anti-inflammatory, and immunosuppressive drugs, can also, to a 
lesser and highly variable degree slow the development of MS-related neurological 
disability progression.  Despite the availability of several treatments for relapsing forms 
of MS (RMS), ocrelizumab is to date the only drug approved in European Union and 
United States for participants with both RMS and PPMS.  Preventing worsening of 
disability, especially in PMS, remains a critical unmet need (Thompson et al. 2018). 
Fenebrutinib is a highly selective, orally administered, ATP-competitive, reversible 
inhibitor of BTK that is being developed by F. Hoffmann-La Roche Ltd (hereafter referred 
to as Roche) as a potential therapeutic agent for MS and other autoimmune diseases.  
In vitro cell-based experiments suggest that antagonism of BTK with fenebrutinib leads 
to inhibition of BCR-dependent B-cell proliferation and a reduction of inflammatory 
cytokine production from myeloid cells (including tumor necrosis factor- [TNF-]).  
Myeloid effector functions are triggered by immune complexes in vitro, and increasing 
evidence suggests that B cells and myeloid/microglia are central to the 
immunopathology of MS. 
Detailed information on fenebrutinib is provided in the Fenebrutinib 
Investigator's Brochure. 
2.3 
BENEFIT–RISK ASSESSMENT 
The purpose of this study is to assess the efficacy and safety of fenebrutinib, a highly 
selective, orally administered, ATP-competitive, reversible inhibitor of BTK, compared 
with placebo in participants with RMS. 
BTK inhibition results in a decrease in B-cell activation and proliferation, which may 
explain its effects on the inflammatory pathways related to MS disease activity.  BTK 
inhibition also has direct effects on myeloid lineage cells.  As a result, there is a potential 
for BTK inhibition to affect microglia that are associated with the pathophysiology of MS 
disease progression independent of relapse.  Indeed, the role of BTK inhibition in MS 
has been established by the results from two Phase II randomized clinical trials, one 
study (NCT02975349) evaluated the safety and efficacy of evobrutinib in participants 
with RMS (Montalban et al. 2019) and one study (NCT03889639) evaluated SAR442168 
in participants with RMS (Clinicaltrials.gov 2020; Sanofi Virtual Scientific Meeting 2020).  
Given the similar mechanism of action, the results of these Phase II trials suggest that 
fenebrutinib will have a positive treatment effect on MS pathophysiology and thus 
support further study of this BTK inhibitor (fenebrutinib) in MS.  
Clinical safety data are available from Phase I and Phase II studies in several different 
indications including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and 
chronic spontaneous urticaria (CSU).  As of the writing of this protocol, more than 
1200 participants and healthy volunteers have received fenebrutinib in clinical trials.  

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
28/Protocol GN43271, Version 3 
Over 650 participants have received the 200 mg twice a day (BID) dosing regimen 
(either blinded or open-label) that has been characterized in clinical trials in RA, SLE, 
and CSU.  Across indications, 93 participants have received fenebrutinib at a dosage of 
200 mg BID for 24 to 48 weeks; 491 participants for 48 to 96 weeks; and 8 participants 
for 96 weeks or more.  The safety profile for the administration of fenebrutinib 200 mg 
BID is described in detail in the Fenebrutinib Investigator’s Brochure and has been 
consistent across all the indications studied. 
Refer to Appendix 3 for information on anticipated risks for fenebrutinib and risk 
mitigation measures, including guidelines for managing adverse events associated 
with fenebrutinib. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of fenebrutinib may be found in the Fenebrutinib 
Investigator’s Brochure. Considering the mechanism of action of fenebrutinib, the 
Phase II efficacy data in other BTK inhibitors, the safety profile for fenebrutinib, and the 
risk mitigation measures for the study, the benefit-risk ratio is expected to be acceptable 
to evaluate fenebrutinib in clinical trials for MS.  
COVID-19 Pandemic 
A risk-assessment was conducted to determine whether there is any impact of the 
coronavirus disease 2019 (COVID-19) pandemic on the benefit-risk assessment of the 
conduct of this study protocol including but not limited to the patient population under 
study and study treatment(s) being evaluated (EMA Guidance 2021).  Based on this 
assessment, the anticipated impact of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) is no different from any other acute infection.  The existing safety 
monitoring and management guidelines, as well as the risk minimization measures 
outlined in the clinical protocol are considered appropriate.  Concomitant administration 
of an approved non-live COVID-19 vaccine is permitted.  Examples of permitted 
vaccines include mRNA, inactivated virus, and replication-deficient viral vector vaccines. 
3. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of fenebrutinib 
compared with placebo in participants with RMS.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 4 and Table 5 . 
 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
29/Protocol GN43271, Version 3 
Table 4 
Primary and Secondary Objectives and Corresponding 
Estimands 
Primary Objective 
Estimand Definition 
 To evaluate the efficacy of fenebrutinib 
compared with placebo on the total number of 
new gadolinium-enhancing T1 MRI lesions   
 Population: all randomized patients 
 Endpoint:  Total number of new gadolinium-
enhancing T1 lesions observed on MRI scans of 
the brain at Weeks 4, 8, and 12 
 Treatment: 
 200 mg BID oral fenebrutinib 
 placebo 
 Intercurrent events and handling strategy:  
 Withdrawal from treatment: hypothetical 
strategy 
 Initiation of another MS therapy: not 
allowed while on study. In case of such 
intercurrent event: hypothetical strategy 
 Population level summary: rate ratio from 
Negative Binomial model  
Secondary Objectives 
Estimand Definition 
 To evaluate the effect of fenebrutinib on MRI 
lesions 
 Population: all randomized patients 
 Endpoint:   
(1). Total number of new or enlarging T2-
weighted lesions observed on brain MRI at 
Weeks 4, 8, and 12  
(2). Proportion of participants free from any 
new gadolinium-enhancing T1 lesions and 
new or enlarging T2-weighted lesions 
observed on brain MRI at Weeks 4, 8, and 12 
 Treatment: 
 200 mg BID oral fenebrutinib 
 placebo 
 Intercurrent events and handling strategy:  
 Withdrawal from treatment: hypothetical 
strategy (see Section 9.4.3) 
 Initiation of another MS therapy: not 
allowed while on study. In case of such 
intercurrent event: hypothetical strategy 
 Population level summary:  
 For Endpoint (1):  rate ratio from Negative 
Binomial model 
For Endpoint (2):  odds ratio from logistic 
regression model 
BID = twice a day; MRI = magnetic resonance imaging 
  

Fenebrutinib—F. Hoffmann-La Roche Ltd 
30/Protocol GN43271, Version 3 
Table 5 
Other Secondary and Exploratory Objectives and Endpoints 
Secondary Objectives 
Corresponding Endpoints 
To evaluate the safety of fenebrutinib
compared with placebo
• Incidence and severity of adverse events
• Change from baseline in vital signs
• Change from baseline in targeted clinical 
laboratory test results
• Proportion of participants with suicidal ideation 
or behavior, as assessed by Columbia-Suicide 
Severity Rating Scale (see $SSHQGL[ ) 
To characterize the fenebrutinib PK profile
Plasma concentration of fenebrutinib at specified
timepoints
Exploratory Objectives 
Corresponding Endpoints 
To evaluate the effect of fenebrutinib on MS
relapses
To evaluate fenebrutinib concentration in the
CSF
To evaluate changes in inflammatory markers
in the CSF
ARR
CSF concentration of fenebrutinib (CSF sample
is optional)
CSF IgG index and oligoclonal bands (CSF
sample is optional)
CSF NfL levels (CSF sample is optional)
To identify and/or evaluate biomarkers that
are predictive of response to fenebrutinib, are
early surrogates of efficacy, are associated
with susceptibility to developing adverse
events, can provide evidence of fenebrutinib
activity, or can increase the knowledge and
understanding of disease biology and drug
safety
Levels of and change in serum NfL and other
pharmacodynamic biomarkers related to disease
activity and/or mechanism of action of
fenebrutinib
ARR   annualized relapse rate; CSF  cerebrospinal fluid; CTCAE   Common Terminology Criteria 
for Adverse Events; MRI  magnetic resonance imaging; MS  multiple sclerosis; NfL  neurofilament 
light chain; PK   pharmacokinetic. 

 
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4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a Phase II, double-blind, placebo-controlled, randomized study with a primary 
efficacy objective of evaluating the effect of fenebrutinib on the total number of new 
Gd-enhancing T1 brain MRI lesions in participants with RMS.  The safety and 
pharmacokinetics of fenebrutinib will also be evaluated in the study.  
The study will enroll approximately 102 participants with RMS with recent disease 
activity and will consist of the following phases: 
 
Screening phase, of approximately 4 weeks  
 
Double-blind treatment (DBT) phase, where participants will be randomized in a 
2:1 ratio to either 200 mg BID oral fenebrutinib or placebo for 12 weeks.  
The primary efficacy endpoint is the total number of new gadolinium-enhancing T1 
(T1Gd) lesions on brain MRI measured at Weeks 4, 8, and 12.  The secondary 
efficacy outcomes are 1) the total number of new or enlarging T2 lesions on brain 
MRI measured at Weeks 4, 8, and 12, and 2) the proportion of participants free from 
any new Gd-enhancing T1 lesions and new or enlarging T2-weighted lesions 
observed on brain MRI at Weeks 4, 8, and 12.  Drug safety will be evaluated by 
measuring number and severity of adverse events, changes in vital signs, and 
changes in laboratory parameters.  The primary analysis will be performed when the 
last patient completes the Week 12 visit or withdraws. 
 
Optional open-label extension (OLE) phase will be available for eligible participants 
within the current protocol.  Participants may receive up to a maximum of 
192 weeks of open-label fenebrutinib in this protocol.  Participants will be moved to 
a program level OLE (separate protocol, protocol number TBD) as soon as it is 
available.  
 
A safety follow-up (SFU) phase is available to participants who discontinue study 
drug early from either the DBT or OLE phases, who complete the DBT phase 
without going to OLE, or who complete the OLE phase.  Participants will be followed 
in the SFU for approximately 4 weeks. 
 
Participants may enroll in an optional substudy in which cerebrospinal fluid (CSF) will 
be collected.  
Patient safety will be monitored by an independent Data Monitoring Committee (iDMC) 
throughout the DBT phase.  Further details regarding the iDMC review will be specified 
in a separate iDMC charter. 
4.2 
RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population 
The study will enroll participants with RMS.  Participants must have recent inflammatory 
MS activity to enroll, defined in the inclusion criteria as two clinical relapses in the last 

 
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2 years, or one clinical relapse in the last 12 months or at least one T1 Gd lesion on 
MRI in the 6 months prior to randomization.  This population will be informative for the 
objective of evaluating the efficacy of fenebrutinib in reducing the development of new 
T1 Gd MRI lesions. 
4.2.2 
Rationale for Control Group 
The control arm for the study will receive matching oral placebo.  A placebo comparator 
was chosen to enable a clear and efficient evaluation of the safety and efficacy profile of 
fenebrutinib monotherapy.  Given the availability of approved treatments for RMS, the 
period of placebo exposure should be as short as possible and should not present an 
inappropriate risk to participating participants.  The period of placebo exposure in the 
DBT phase will be limited to a maximum of 12 weeks.  A 2:1 randomization ratio will be 
used to limit the number of participants in the placebo arm.  Informed consent materials 
will clearly explain the existence of alternative approved treatments, and that by 
participating in the study participants are foregoing those treatments and may receive 
placebo for up to 12 weeks (Polman 2008). 
4.2.3 
Rationale for Blinding 
The study is double-blinded to reduce the risk of bias in adjudication of efficacy and 
safety endpoints.  The primary efficacy endpoint of number of new T1 Gd MRI lesions 
will be determined by an independent MRI rater who is blinded to treatment 
assignments.  Since the study is only 12 weeks, the investigators will be blinded to the 
MRI results for only a short period of time.  
4.2.4 
Rationale for Biomarker Sample Collection Schedule 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to fenebrutinib (i.e., predictive biomarkers), 
are early surrogates of efficacy, are associated with progression to a more severe 
disease state (i.e., prognostic biomarkers), are associated with acquired resistance to 
fenebrutinib, are associated with susceptibility to developing adverse events or can lead 
to improved adverse event monitoring or investigation (i.e., safety biomarkers), can 
provide evidence of fenebrutinib activity (i.e., pharmacodynamic biomarkers), or can 
increase the knowledge and understanding of disease biology and drug safety, on the 
basis of the following exploratory endpoints: 
 
Relationship between baseline biomarkers in blood (serum and/or plasma, RNA 
PAXgene) including, but not limited to neurofilament light chain, and efficacy, 
safety, PK, or other biomarker endpoints  
 
Relationship between baseline biomarkers in CSF (optional collection, CSF 
supernatant, and CSF cells which may include RNA sequencing) including, but not 
limited to neurofilament light chain, and efficacy, safety, PK, or other 
biomarker endpoints  

 
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 
Change from baseline to post-treatment sampling in blood (serum and/or plasma) 
including, but not limited to neurofilament light chain, and efficacy, safety, PK, or 
other biomarker endpoints  
 
Exploratory biomarker analysis results may be reported separately from the GN43271 
clinical study report (CSR). 
4.2.5 
Rationale for Endpoints 
The total number of new T1 Gd MRI lesions and number of new or enlarging T2 MRI 
lesions are the primary and secondary efficacy endpoints.  These endpoints are 
standard Phase II efficacy outcomes for RMS.  These imaging outcomes may be 
predictive of the ability of fenebrutinib to reduce the number of new clinical relapses, 
which is the endpoint that is used in Phase III studies to demonstrate efficacy.  
Annualized relapse rate (ARR) will be measured as an exploratory efficacy outcome in 
this study, though the study is not powered to identify a significant effect on 
this outcome.  
The study will utilize standard endpoints to evaluate PK and safety, including number 
and severity of treatment emergent adverse events, vital signs, ECGs, laboratory 
parameters, and suicidal ideation.  
Blood biomarkers will be measured as exploratory outcomes.  Serum neurofilament light 
chain is a blood biomarker of neuronal damage, for which increases are associated with 
inflammatory activity and with MS disability progression (Thebault et al. 2022).  Serum 
NfL will be measured to determine if fenebrutinib decreases a biomarker of neuronal 
injury relative to placebo-treated participants.  Serum may be used to assess antigen 
specific antibody responses. 
The rationale for CSF biomarkers is described in Section 4.2.8. 
4.2.6 
Rationale for Pharmacokinetic Sample Collection Schedule 
The sampling schedule is designed to assess plasma fenebrutinib concentrations in 
participants with MS that will enable the estimation of systemic fenebrutinib exposure 
parameters, which may be reported separately from the Clinical Study Report.  Sparse 
PK samples will be collected in all participants.  However, to better characterize 
fenebrutinib pharmacokinetics, more intensive PK samples may be collected in at least 
30 randomized participants (at least 20 participants receiving fenebrutinib) during the 
DBT phase. 
4.2.7 
Rationale for Stratification Factors 
Randomization will be stratified based on the presence or absence of T1 Gd lesions on 
the screening MRI.  The number of new MRI lesions may be higher after randomization 
in participants with an active MRI lesion at baseline relative to those without an active 
MRI lesion at baseline.  Stratification by this factor will ensure that the treatment arms 

 
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are balanced with respect to the proportion of participants with a T1 Gd lesion on MRI 
at baseline. 
4.2.8 
Rationale for the Optional Cerebrospinal Fluid Substudy 
Fenebrutinib reduces both B-cell and myeloid lineage-cell activation by binding to and 
blocking the function of BTK; effects on both these cell types may be important to the 
drug’s effect on participants with MS.  Persistent blood-brain barrier disruption and 
leakage have been reported in participants with MS.  It may be important to estimate 
fenebrutinib’s CNS exposure level in participants with MS in order to understand the 
drug’s potential to affect CNS compartmentalized inflammation.  Clinically, CSF drug 
levels have frequently been used to estimate drug exposure in the CNS.  The optional 
CSF substudy proposes to collect CSF from approximately 10 participants at two 
timepoints.  The fenebrutinib concentration may be measured in the CSF and compared 
to the serum concentration measured contemporaneously.  To evaluate fenebrutinib’s 
effect on antibody formation within the CNS, the CSF to serum IgG index may be 
measured, as will the number of unique CSF oligoclonal bands. 
4.3 
JUSTIFICATION FOR DOSE AND SCHEDULE 
A fenebrutinib dosage of 200 mg BID was selected for evaluation in this study based on 
the high level of target inhibition associated with this dosage, the Phase II clinical effect 
observed in RA, SLE, and CSU, as well as on the body of clinical safety data for these 
indications (see the Fenebrutinib Investigator’s Brochure). 
Target inhibition was assessed using a CD63 basophil assay in Phase I, single and 
multiple ascending dose studies in healthy participants in which a dose- and 
exposure-dependent relationship with BTK inhibition was observed (Herman et al. 2018). 
The fenebrutinib dosage of 200 mg BID is expected to achieve a high level of target 
engagement (more than 90% inhibition of BTK) in the majority of participants based on 
simulations using a PK/PD model constructed with data from the Phase I, 
ascending-dose studies (Herman et al. 2018).  Furthermore, a dosage of 200 mg BID is 
expected to maintain an extensive degree of target engagement over the entire dosing 
interval.  On the basis of the PK/PD relationship characterized in the Phase I studies, 
doses higher than 200 mg BID are unlikely to significantly improve target engagement.  
Data from other BTK inhibitors has demonstrated that BTK inhibition is associated with 
decreases in the number of new T1 Gd lesions in the CNS in participants with MS 
(Montalban et al. 2019; Sanofi Virtual Scientific Meeting 2020).  
The proposal to evaluate the 200 mg BID dosing regimen in this study is supported by 
the safety dataset in which the 200 mg BID dosing regimen has been characterized.  
The fenebrutinib safety profile is described in detail in the most recent version of the 
Fenebrutinib Investigator’s Brochure.  The existing clinical experience with fenebrutinib 
200 mg BID in other autoimmune diseases supports testing this dosage in an 
MS population. 

 
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4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed the 
last visit shown in the schedule of activities. 
The end of this study is defined as the date of the last visit of the last participant in the 
study shown in the schedule of activities for the last participant in the study globally or 
the date at which the last data point required for statistical analysis or safety follow-up is 
received from the last participant, whichever occurs later.  The end of the study, 
including OLE, is expected to occur approximately 4 years after the last participant 
is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
4.5 
DURATION OF PARTICIPATION 
The duration of participation for each individual is expected to be 12 weeks 
(approximately 3 months) plus 4 weeks of safety follow up, if applicable.  This will be 
followed by participation in an optional OLE period. 
5. 
STUDY POPULATION 
Approximately 102 participants with RMS will be enrolled in this study.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
 
Participants who are capable of giving signed informed consent and able to 
complete the study protocol 
 
Participants who are aged 18 to 55 years inclusive at the time of signing Informed 
Consent Form 
 
A diagnosis of RMS in accordance with the revised 2017 McDonald Criteria 
(Thompson et al. 2018) and one of the following: 
– 
At least two documented clinical relapses within the last 2 years or one 
documented clinical relapse within 12 months of screening (but not within the 
30 days prior to screening) 
– 
Documented evidence of the presence of at least one T1 Gd lesion on MRI in 
the 6 months prior to randomization (may include the screening MRI) 
Note:  RMS may include active secondary progressive MS as defined by 
Lublin 2014. 
 
Expanded Disability Status Scale (EDSS) at screening from 0 to 5.5 points 

 
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 
For women of childbearing potential: participants who agree to remain abstinent 
(refrain from heterosexual intercourse) or use contraception, and agreement to 
refrain from donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 28 days after the final dose 
of fenebrutinib.  
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  
Hormonal contraceptive methods must be supplemented by a barrier method. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
 
For men:  participants who agree to remain abstinent (refrain from heterosexual 
intercourse) or use a condom, and agree to refrain from donating sperm, as 
defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 28 
days after the final dose of fenebrutinib to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 

 
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5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
 
Disease duration of  10 years from the onset of symptoms and an EDSS score at 
screening  2.0 
 
Participants who are pregnant or breastfeeding, or intending to become pregnant 
during the study or within 28 days after the final dose of fenebrutinib 
Women of childbearing potential must have a negative serum pregnancy test 
result at screening. If a urine pregnancy test is positive at a subsequent visit, it 
must be confirmed by a serum pregnancy test, ideally from the 
central laboratory. 
 
Men intending to father a child during the study or within 28 days after final dose of 
study drug 
 
A diagnosis of primary progressive MS or non-active secondary progressive MS 
 
Any known or suspected active infection at screening or baseline (excluding 
onychomycosis), or any major episode of infection requiring hospitalization or 
treatment with IV anti-microbials within 8 weeks prior to or during screening or 
treatment with oral anti-microbials within 2 weeks prior to or during screening 
 
History of progressive multifocal leukoencephalopathy (PML) 
 
History of cancer, including hematologic malignancy and solid tumors, within 
10 years of screening 
Basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured and in situ carcinoma of the cervix treated with apparent success 
by curative therapy  1 year prior to screening is not exclusionary 
 
Presence of other neurological disorders that could interfere with the diagnosis of 
MS or with the assessments of efficacy or safety during the study, including, but not 
limited to, the following:  
– 
History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic 
attack, spontaneous intracranial hemorrhage, or traumatic intracranial 
hemorrhage) or ischemia of the spinal cord 
– 
History or known presence of CNS or spinal cord tumor (e.g., meningioma, 
glioma) 
– 
History or known presence of potential metabolic causes of myelopathy (e.g., 
untreated vitamin B12 deficiency) 
– 
History or known presence of infectious causes of myelopathy (e.g., syphilis, 
Lyme disease, HTLV-1, herpes zoster myelopathy) 
– 
History of genetically inherited progressive CNS degenerative disorder (e.g., 
hereditary paraparesis, mitochondrial myopathy, encephalopathy, lactic 
acidosis, and stroke-like episodes [MELAS] syndrome) 
– 
Neuromyelitis optica spectrum disorder 

 
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– 
History or known presence of systemic autoimmune disorders potentially 
causing progressive neurological disease (e.g., lupus, anti-phospholipid 
antibody syndrome, Sjögren syndrome, Behçet disease) 
– 
History or known presence of sarcoidosis 
– 
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
 
Evidence of clinically significant psychiatric, pulmonary, renal, hepatic (including 
Gilbert syndrome), metabolic, gastrointestinal (GI), or cardiovascular disease 
(including arrhythmias or QTc prolongation), or endocrine disease (including 
uncontrolled diabetes, non-gallstone pancreatitis, or chronic pancreatitis) that, in the 
investigator’s opinion, would preclude patient participation 
 
Presence of the New York Heart Association Class III and Class IV criteria for 
congestive heart failure 
 
Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect patient safety or interpretation of study results, including QT interval corrected 
through use of Fridericia’s formula (QTcF)  440 ms demonstrated by at least two 
ECGs  30 minutes apart 
 
Current treatment with medications that are well known to prolong the QT interval at 
doses that have a clinically meaningful effect on QT, as determined by 
the investigator 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome); 
structural heart disease; coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing, prior coronary artery bypass grafting, or 
coronary lesions  70% diameter stenosis that have not been or cannot be re-
vascularized); clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia); family history of sudden, unexplained death; or 
cardiac ion channel genetic mutations (e.g., congenital long QT syndrome) 
 
Participants undergoing dialysis or estimated glomerular filtration rate (eGFR) 
 60 mL/min/1.73 m2 (may be repeated if eGFR 4559 mL/min/1.73 m2) 
 
Any of the following laboratory results: 
– 
ALT or AST  2  upper limit of normal (ULN) 
– 
Total bilirubin greater than 1.5  ULN 
– 
Hemoglobin  9.5 g/dL (may be repeated if 99.4 g/dL) 
– 
White blood cell count  2000 cells/mm3 (L) 
– 
Platelet count  100  109/L (may be repeated if 80100  109/L) 
– 
Absolute neutrophil count  1500 cells/mm3 (L) 
– 
IgG  500 mg/dL 

 
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 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the 12-week 
double-blind study period 
 
History of alcohol or other drug abuse within 12 months prior to screening 
 
Positive screening tests for active, latent, or inadequately treated hepatitis B (as 
evidenced by either of the following): 
– 
Positive hepatitis B surface antigen (HBsAg) 
– 
Positive hepatitis B core antibody [total HBcAb] with detectable hepatitis B virus 
(HBV) DNA 
 
Positive screening tests for hepatitis C (positive hepatitis C antibodies) 
 
Evidence of active or latent or inadequately treated infection with tuberculosis (TB) 
as defined by the following: 
A positive QuantiFERON TB-Gold (QFT) test is found at screening. QFT 
testing should be performed through the central laboratory (see Table A2-1 for 
test requirements). 
An indeterminate QFT test should be repeated. 
A positive QFT test or two successive indeterminate QFT results should be 
considered a positive diagnostic TB test. 
An indeterminate QFT test followed by a negative QFT test should be 
considered a negative diagnostic TB test.   
 
Abnormalities in hepatic synthetic function tests (e.g., PT, INR, aPTT) judged by the 
investigator to be clinically significant 
 
History of hospitalization or transfusion for a GI bleed  
 
Known bleeding diathesis 
 
Any condition possibly affecting oral drug absorption 
 
History of or currently active primary or secondary (non−drug-related) 
immunodeficiency, including known history of HIV infection 
 
Inability to complete an MRI scan (contraindications for MRI scan, including but not 
restricted to, pacemaker, cochlear implants, intracranial vascular clips, surgery 
within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to 
the time of the intended MRI scan) or contraindication to Gd administration 
 
Any previous history of organ transplantation  
 
Any previous treatment with bone marrow transplantation or hematopoietic stem 
cell transplantation 
 
Adrenocorticotropic hormone or systemic corticosteroid therapy within 4 weeks prior 
to screening or during the screening period  
Inhaled and topical corticosteroids are allowed 

 
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 
Receiving an unstable dosing regimen of proton pump inhibitors (PPIs) or 
H2receptor antagonist (H2RAs) during the screening phase and/or no plan to remain 
at a stable dose for the duration of study treatment 
Participants must not initiate PPIs or H2RAs within 2 weeks prior to 
randomization. 
 
Treatment with IVIg or plasmapheresis within 12 weeks prior to randomization 
 
Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib  
 
Receipt of a live-attenuated vaccine within 6 weeks prior to randomization.  
Influenza vaccination is permitted if the inactivated vaccine formulation 
is administered. 
 
Need for systemic anticoagulation (oral or injectable) or anti-platelet agent other 
than nonsteroidal anti-inflammatory drugs, aspirin, and other salicylates (aspirin up 
to 162 mg QD is allowed) 
 
Previous treatment with fenebrutinib or another BTK inhibitor for any indication 
 
Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, 
within 7 days or 5 drug-elimination half-lives (whichever is longer) prior 
to randomization 
 
Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days 
or 5 drug-elimination half-lives (whichever is longer) prior to randomization 
 
Previous use of anti-CD20 therapies, unless the last infusion was more than 2 years 
prior to screening and B-cell count is normal at screening 
 
Previous use of fingolimod, siponimod, ozanimod, or ponesimod within 6 weeks 
of randomization 
 
Previous use of natalizumab within 6 months of randomization 
 
Previous treatment with azathioprine, mycophenolate mofetil, or methotrexate within 
12 weeks of randomization 
 
Previous use of teriflunomide, unless teriflunomide plasma concentrations are 
 0.02 mg/L at screening 
 
Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or 
cyclophosphamide 
 
Treatment with dimethyl fumarate or monomethyl fumarate within 4 weeks of 
randomization 
 
Treatment with any investigational agent within 5 half-lives of randomization  
 
Requirement for any prohibited concomitant medications 
 
Previous treatment with any other immunomodulatory or immunosuppressive 
medication not already listed above without appropriate washout as described in the 
applicable local label 
If the washout requirements are not described in the applicable local label, then 
the wash out period must be 5 times the half-life of the medication.  The PD 

 
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effects of the previous medication must also be considered when determining 
the required time for washout. 
Note: No washout is required for interferon or glatiramer acetate.  
Note: Participants screened for this study should not be withdrawn from 
therapies for the sole purpose of meeting eligibility for the trial.  Participants 
who discontinue their current therapy for non-medical reasons should 
specifically be informed of their treatment options before deciding to enter 
the study. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment: furanocoumarin derivatives, such as those found in 
grapefruit, Seville oranges, pomegranates, or star fruit juice or products. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
This study has no caffeine, alcohol, or tobacco restrictions. 
5.3.3 
Activity 
This study has no activity restrictions. 
5.3.4 
Contraception Requirements 
During the study, participants must use contraception or take other precautions as 
described in Section 5.1. 
5.4 
SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
qualify for one re-screening opportunity (for a total of two screenings per individual) at 
the investigator's discretion.  Individuals must re-sign the consent form prior to 
re-screening.  The investigator will maintain a record of reasons for screen failure. 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY 
Study treatment is defined as any investigational treatment, marketed product, placebo, 
or medical device intended to be administered to a study participant according to the 
study protocol. 
The investigational medicinal product (IMP) for this study is fenebrutinib (or 
fenebrutinib‑matching placebo).  Appendix 11 identifies all investigational medical 
products, and auxiliary medicinal products for this study. 
6.1 
STUDY TREATMENTS ADMINISTERED 
Table 6 provides a description of assigned study treatments for this study. 

 
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Table 6 
Study Treatment Description 
Use 
Fenebrutinib 
Placebo 
Experimental 
Placebo comparator 
Type of 
medicinal 
product 
IMP 
IMP 
Drug form 
Tablet 
Tablet 
Unit Dose 
Strength(s) 
100 mg 
Not applicable 
Dosage Level(s) 
200 mg BID 
2 tablets BID 
Formulation(s) 
Refer to pharmacy manual and 
Investigator's Brochure  
Not applicable 
Packaging 
Pill bottle 
Pill bottle 
Labeling 
Per local requirements 
Route of 
administration 
Oral 
Oral 
Source 
Sponsor 
Sponsor 
IMP  investigational medicinal product 
  
6.1.1 
Fenebrutinib and Placebo 
Participants will take two 100 mg tablets PO BID for a total dose of 400 mg of 
fenebrutinib (or placebo) every day.  Participants will self-administer two 100 mg tablets 
in the morning and two 100 mg tablets in the evening by mouth.  The tablet should be 
swallowed whole with some water, can be taken with or without food, and should be 
taken at the same time each day.  Participants should be instructed that a missed 
fenebrutinib (or matching placebo) dose should not be taken with the next scheduled 
dose.  Administration of fenebrutinib (or matching placebo) should be staggered with 
antacid use (i.e., study drug should be taken 2 hours before or 2 hours after antacid 
administration).  In addition, any antacids (e.g., bismuth subsalicylate, calcium 
carbonate, aluminum-magnesium hydroxide) should be recorded as 
concomitant medications. 
All participants will provide PK samples on Day 1 (baseline), on Day 29 (DBT Week 4), 
and at other visits as specified in Table 3.  At the baseline and DBT Week 4 visits, the 
fenebrutinib (or matching placebo) morning dose will be administered at the morning 
(mandatory) clinic visit while the patient is fasting.  The dates and times of the most 
recent prior meal, most recent antacid administration, last dose of oral study drug (prior 
to the clinic visit), and timing of oral study drug administration in the clinic should be 
recorded at each clinic visit with PK sampling. 

 
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6.2 
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel e.g., pharmacist) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each participant, and disposition or return of unused IMP, thus enabling reconciliation of 
all IMP received, and for ensuring that participants are provided with doses specified by 
the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the interactive 
voice or web-based response system (IxRS) to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  The investigator or designee must 
confirm that appropriate temperature conditions have been maintained during transit, by 
temperature monitoring, for all IMPs received and that any discrepancies have been 
reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff. 
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
The IMPs will either be disposed of at the study site according to the study site's 
institutional standard operating procedure or be returned to the Sponsor (if supplied by 
the Sponsor) with the appropriate documentation.  The site's method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the fenebrutinib Investigator's Brochure for 
information on IMP preparation, storage, handling, and accountability. 
6.3 
TREATMENT ASSIGNMENT AND BLINDING 
6.3.1 
Treatment Assignment 
This is a randomized, double-blind study.  Randomization will be employed to minimize 
bias in treatment assignment and to provide the basis for valid statistical inference.  After 
initial written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established for a participant, 
the study site will obtain the participant's identification number and treatment assignment 
from an IxRS.  Participants who discontinue treatment for any reason will not be 

 
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replaced, except for participants who withdraw before receiving any study treatment. 
Participants who enroll in this study and who have completed or prematurely 
discontinued from treatment as specified are not permitted to be re-randomized to this 
study under any circumstances.  
Participants will be randomly assigned to one of two treatment arms: fenebrutinib or 
placebo.  Randomization will occur in a 2:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified by presence or absence of T1 Gd lesions on the 
screening MRI. 
6.3.2 
Blinding 
To maintain the integrity of the trial results and to prevent potential unblinding of the 
assigned arm as a result of adverse events or changes in laboratory results, the 
following additional measures will be implemented until the time of the primary analysis:  
 
Blinded, central MRI assessments:  During the study, a blinded, central MRI reader 
will assess all MRI scans performed during the study.  Of note, screening scans will 
be used for the assessment of patient eligibility and therefore will not be blinded.  A 
local radiologist who is independent of the study team will review all scans at site for 
safety and report only significant nonMS-related findings to the treating investigator 
(or treating team). 
 
Blinding of laboratory parameters:  Immunoglobulins (IgG, IgM, IgA, and total Ig) will 
be blinded until the primary database lock for the primary analysis.  
 
Study drug treatment allocation will remain blinded until the primary database lock 
for the primary analysis. 
 
To facilitate analysis of the biological samples collected in this study, the treatment code 
will be released to the responsible analytical person when the samples have been 
received at the analytical site and are ready for assay.  The result of the analysis must 
not be released with individual identification of the patient until after the unblinding for 
the primary analysis.  
Study site personnel and participants will be blinded to treatment assignment until after 
the primary analysis.  The Sponsor and its agents will also be blinded to treatment 
assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a study.  These roles include the unblinding 
group responsible, clinical supply chain managers, sample handling staff, IxRS service 
provider, and iDMC members. 
The PK samples must be collected from participants assigned to the comparator arm to 
maintain the blinding of treatment assignment; however, PK assay results for these 
participants are generally not needed for the safe conduct or proper interpretation of this 
study.  Laboratories responsible for performing study drug PK assays will be unblinded 
to participants' treatment assignments to identify appropriate samples to be analyzed.  

 
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PK samples from participants assigned to the comparator arm will not be analyzed for 
study drug PK concentration except at baseline or by request (e.g., to evaluate a 
possible error in dosing). 
If study treatment unblinding is necessary for a medical emergency (e.g., in the case of a 
serious adverse event for which participant management might be affected by 
knowledge of treatment assignment), the investigator will be able to break the treatment 
code by contacting the IxRS.  The treatment code should not be broken except in 
emergency situations.  The investigator is not required to contact the Medical Monitor 
prior to breaking the treatment code.  However, the investigator should inform the 
Medical Monitor that the treatment code has been broken. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly prior 
to unblinding.  
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to participant unblinding, the investigator will 
be able to break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the investigator or Sponsor to be related to an a drug listed in 
Section 8.3.4.  The participant may continue to receive treatment, and the investigator, 
participant, and Sponsor personnel, with the exception of the Drug Safety representative 
and personnel who must have access to participant treatment assignments to fulfill their 
roles (as defined above), will remain blinded to treatment assignment. 
6.4 
STUDY TREATMENT COMPLIANCE 
When participants self-administer study treatment at home, compliance with study 
treatment will be assessed. 
At each clinic visit, participants will return all previously dispensed 70-mL bottles and all 
leftover fenebrutinib (or placebo) tablets.  The site will count the leftover study drug 
tablets and assess compliance during DBT and during the OLE.  Refer to the pharmacy 
manual for detailed instructions on drug storage and administration. 
Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration electronic Case Report Form (eCRF).  
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
potential associated adverse events, should be reported as described in Appendix 3. 
6.5 
DOSE MODIFICATION 
Modification of the fenebrutinib/placebo dose is not permitted. 

 
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6.6 
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY 
Participants may be eligible to receive fenebrutinib as part of an extension study within 
the current protocol, as described in Section 4.1.  In addition, participants will be moved 
to a program level OLE (separate protocol, protocol number TBD) as soon as it is 
available. The Roche Global Policy on Continued Access to Investigational Medicinal 
Product is available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
6.7 
TREATMENT OF OVERDOSE 
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose.  There is no known antidote for treating an overdose.  Cases of overdose, along 
with any associated adverse events, should be reported as described in Appendix 3. 
In the event of an overdose, the investigator should take the following steps: 
1. 
Contact the Medical Monitor immediately. 
2. 
Closely monitor the participant for any adverse event or serious adverse event and 
laboratory abnormalities until fenebrutinib can no longer be detected systemically 
(at least 5 days). 
3. 
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis). 
 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor on the basis of clinical evaluation of 
the participant. 
6.8 
CONCOMITANT THERAPY 
Previous treatment with anti-CD20 therapy (e.g., rituximab, ocrelizumab) should be 
reported up to 3 years prior to randomization and other MS disease modifying therapies 
(DMTs) should be reported up to 1 year prior to randomization.  Receipt of any prior 
SARS-CoV-2 vaccine should be recorded in the concomitant medications eCRF.  All 
other medications (e.g., prescription drugs, MS symptomatic therapies, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) and 
non-medicinal treatments (e.g., physiotherapy, occupational therapy) used by the patient 
within 3 months prior to initiation of study treatment will be recorded in the appropriate 
eCRF along with the following information: 
 
Reason for use 
 
Dates of administration, including start and end dates 
 
Dosage information, including dose and frequency 
 

 
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The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy. 
Paracetamol or acetaminophen, at doses of  2 grams/day is permitted for use any time 
during the study.  
6.8.1 
Permitted Therapy 
In general, investigators may manage a participant's care (including preexisting 
conditions) through use of supportive therapies, as clinically indicated and per local 
standard practice, with the exception of prohibited therapies defined in Section 6.8.3. 
and taking into account cautionary therapies defined in Section 6.8.2. 
6.8.1.1 
Oral Contraceptives and Hormone-Replacement Therapy 
Participants who use oral contraceptives or hormone-replacement therapy can continue 
their use.  All concomitant medications should be reported to the investigator and 
recorded on the appropriate eCRF.  Participants using hormone-replacement therapy 
will be encouraged to use the minimal dose required to control their symptoms.   
6.8.1.2 
Symptomatic Treatments of Multiple Sclerosis  
Participants requiring symptomatic treatment for MS (e.g., fampridine) and/or 
physiotherapy must be treated at a stable dose/regimen prior to the initiation of study 
drug and must have a plan to remain at a stable dose/regimen for the duration of the 
12-week randomized controlled period.  Concomitant treatments for symptoms related to 
MS should be kept constant throughout the randomized controlled period, but could be 
adapted according to patient’s needs. 
Participants must not start or modify their symptomatic treatment within 4 weeks of 
randomization.  Symptomatic treatment may be initiated during the trial at the discretion 
of the investigator and should be kept at a stable dose as much as possible. 
6.8.1.3 
Treatment of Relapses 
Participants who experience a relapse during the study may receive treatment with IV or 
oral corticosteroids, if judged to be clinically appropriate by the investigator.  The 
following standardized treatment regimen may be used as warranted, 1 g/day IV 
methylprednisolone or equivalent dosing or oral steroid for a maximum of 5 consecutive 
days.  At the discretion of the investigator, corticosteroids may be stopped abruptly or 
tapered over a maximum of 10 days.  Such participants should not discontinue the 
treatment period solely based on the occurrence of a relapse, unless the patient or 
investigator feels he or she has met the criteria for withdrawal. 
6.8.2 
Cautionary Therapy 
6.8.2.1 
Acid-Reducing Agents 
The solubility of fenebrutinib is pH-dependent, and absorption is negatively impacted by 
acid-reducing agents, such as PPIs and H2RAs, thereby decreasing systemic exposure.  

 
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Participants who use antacids (e.g., bismuth subsalicylate, calcium carbonate, 
aluminum-magnesium hydroxide) for symptomatic relief of heartburn should take 
fenebrutinib (or placebo) at least 2 hours before or 2 hours after antacid administration 
because gastric acid improves fenebrutinib absorption. 
Participants may be treated with PPIs or H2RAs at up to the maximum recommended 
dose in accordance with the local label.  The dose should remain stable for at least 
2 weeks prior to initiation of study treatment and throughout study treatment. 
Standalone doses of acid-reducing agents at visits requiring PK sampling is prohibited 
(see Table 3).  Any use of PPIs, H2RAs, and/or other antacids should be recorded as 
concomitant medications, including the date and time of last administration. 
6.8.2.2 
CYP3A- and Breast Cancer Resistance Protein-Mediated Drug 
Interactions 
The results of a clinical drug-drug interaction study (GP39616) suggest that fenebrutinib 
can be classified as a mild inhibitor of CYP3A at clinically relevant doses.  It is possible 
that fenebrutinib inhibition of CYP3A may alter the metabolism of CYP3A substrates and 
result in increased plasma concentrations of CYP3A substrates.  Therefore, medications 
that are sensitive CYP3A substrates should be used with caution.  
The use of hormone-replacement therapy or hormonal contraceptives containing the 
CYP3A substrate ethinylestradiol (with the concomitant use of a barrier method) is 
permitted; however, these agents should be used with caution, and participants should 
be counseled regarding the potential risks and benefit of these medications per the local 
prescribing information.  
In addition, the results of Study GP39616 indicate that fenebrutinib is a moderate 
inhibitor of the breast cancer resistance protein (BCRP; also known as ABCG2) 
transporter at clinically relevant doses.  There is a potential for increased plasma 
concentrations of drugs that are known to be substrates of the BCRP transporter.  
Plasma concentrations of the medications that are BCRP substrates may increase; 
therefore, such medications should be used with caution.  
The investigator may consult the Internet reference provided below to determine whether 
a certain medication interacts with CYP3A or BCRP.  The Internet reference is not 
necessarily comprehensive, and the investigator should consult local prescribing 
information for the concomitant medication when determining whether a concomitant 
medication can be safely administered with study treatment.  In addition, the investigator 
should contact the Medical Monitor (or delegate) if questions arise prior to concomitant 
administration with study treatment. 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginte
ractionslabeling/ucm093664.htm 

 
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6.8.2.3 
Statins 
Several lipid-lowering agents (statins) are metabolized by CYP3A (simvastatin, 
lovastatin, atorvastatin) and/or transported by BCRP (rosuvastatin, atorvastatin) and 
thus may be affected by drug-drug interaction with fenebrutinib.  Therefore, dose 
adjustments of these medications should be considered (Kellick et al. 2014) as follows: 
 
Simvastatin:  recommended maximum dose of 10 mg/day 
 
Lovastatin:  recommended maximum dose of 20 mg/day 
 
Rosuvastatin:  recommended maximum dose of 10 mg/day 
 
Atorvastatin:  recommended maximum dose of 20 mg/day 
 
The use of statins has been associated with myopathy, which can manifest as 
weakness, tenderness, or muscle pain with elevations of creatine kinase  10  ULN.  
In severe cases, myopathy can cause rhabdomyolysis with or without acute kidney injury 
secondary to myoglobinuria, and rare fatalities due to rhabdomyolysis have occurred.  
The risk of myopathy is increased by elevated plasma levels of statins.  Predisposing 
factors for myopathy include advanced age ( 65 years), female sex, uncontrolled 
hypothyroidism, renal impairment, or the use of concomitant medications that increase 
the plasma levels of the statin.   
6.8.2.4 
Herbal Therapies 
For the purposes of this study, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties. 
Vitamins, minerals, and purified food substances are allowed in amounts not known to 
be associated with adverse effects (e.g., hypervitaminosis).  Herbal therapies with 
pharmaceutical properties are allowed only if there is acceptable evidence of no CYP3A 
inhibition or induction (see Section 6.8.3 for a list of prohibited concomitant medications, 
including herbal products).  Herbal therapies with pharmaceutical properties must not be 
administered during the study, unless there are sufficient data available to ascertain 
there are no drug interactions with fenebrutinib.  Any questions can be directed to the 
Medical Monitor. 
6.8.3 
Prohibited Therapy 
The results of Study GP39616 suggest that fenebrutinib can be classified as a 
moderately sensitive substrate of CYP3A at clinically relevant doses.  There is a 
potential for a drug-drug interaction with any medication that strongly inhibits or induces 
this enzyme.  Therefore, medications in the following categories should be prohibited for 
7 days or 5 half-lives, whichever is longer, prior to the first dose of study drug and until 
the final dose of study drug. 
 
Strong CYP3A4 inhibitors  
 
Strong or moderate CYP3A inducers  
 

 
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The results of study (GP39616) suggest that fenebrutinib can be classified as a mild 
inhibitor of CYP3A at clinically relevant doses.  Fenebrutinib may increase plasma 
concentrations of the medications in the following category.  Therefore, the following 
medications should be prohibited during study treatment: 
 
CYP3A4 substrates with a narrow therapeutic window 
 
Table 7 summarizes a list of prohibited medications for the reasons listed above.  This 
list is not comprehensive, and the investigator should consult local prescribing 
information for the concomitant medication as well as the Internet reference provided 
below when determining whether a concomitant medication can be safely administered 
with study treatment.  In addition, the investigator should contact the Medical Monitor if 
questions arise regarding medications not listed. 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginte
ractionslabeling/ucm093664.htm 
 
Table 7 
List of Prohibited Medicines Due to CYP3A-Mediated Drug 
Interactions 
Class 
Examples of Drugs in this Class 
Strong CYP3A4 inhibitors 
Boceprevir, cobicistat, clarithromycin, danoprevir/ritonavir, 
elvitegravir/ritonavir, indinavir/ritonavir, itraconazole, 
idelalisib, ketoconazole, lopinavir/ritonavir, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, and nirmatrelvir/ritonavir. 
Strong CYP3A inducers 
Apalutamide, carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, and hyperforin (St. John's Wort) 
Moderate CYP3A inducers 
Bosentan, dexamethasone, efavirenz, etravirine, 
phenobarbital, primidone, phenobarbital, and rifabutin 
CYP3A4 substrate with a narrow 
therapeutic window 
Alfentanil, astemizole, cyclosporine, cisapride, 
dihydroergotamine, ergotamine, everolimus, fentanyl, 
pimozide, quinidine, sirolimus, terfenadine, and tacrolimus 
Note: This list is not comprehensive, and the investigator should consult local prescribing 
information for the concomitant medication as well as the Internet reference provided below 
when determining whether a concomitant medication can be safely administered with study 
treatment.  In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed. 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio
nslabeling/ucm093664.htm 
 
6.8.3.1 
Other Prohibited Therapies 
Use of the following concomitant therapies is prohibited as described below for 
participants in the DBT phase, OLE phase, and SFU phase:  
 
Investigational therapy (other than protocolmandated study treatment) 

 
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 
Any Bcell targeted therapy (e.g., rituximab, alemtuzumab, atacicept, belimumab, 
ublituximab, ofatumumab, or ocrelizumab) 
 
BTK inhibitors (other than fenebrutinib) 
 
Any other DMT for MS (including, but not limited to, cladribine, mitoxantrone, 
interferons, glatiramer acetate, dimethyl fumarate and other fumarates, and 
fingolimod and other sphingosine-1-phosphate receptor modulators) 
The Medical Monitor should be consulted if it is unclear if a medication is 
considered disease modifying. 
 
Systemic anticoagulation (oral or injectable) or antiplatelet agent other than 
nonsteroidal antiinflammatory drugs, aspirin, and other salicylates (aspirin up to 
162 mg four times a day (QID) is allowed) 
 
Use of “as needed” doses of acid-reducing agents (e.g., PPIs, H2RAs) at visits 
requiring PK sampling is prohibited (chronic dosing is acceptable) (see Table 3) 
 
High-dose biotin 
 
6.8.4 
Prohibited Food 
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment:  furanocoumarin derivatives, such as those found in 
grapefruit, Seville oranges, pomegranates, or star fruit juice or products. 
6.8.5 
Immunizations 
Participants will be excluded from study participation if they have been vaccinated with a 
live or live-attenuated vaccine (e.g., the intranasal live attenuated influenza vaccines, 
bacille Calmette Guérin, varicella) within 6 weeks of randomization.  In addition, 
immunization with a live or live-attenuated vaccine is prohibited for the duration of study 
participation, including the SFU phases. 
The effect of fenebrutinib upon the efficacy of vaccinations is unknown.  Vaccinations 
with vaccines other than live or live-attenuated vaccinations are permitted during the 
study period.  It is recommended that all vaccinations, other than live or live-attenuated 
vaccinations, should follow the local immunization schedule.  In addition, measurement 
of vaccine-induced response titers should be considered to determine if individuals can 
mount a protective immune response as the efficacy of the vaccination may be 
decreased.  Administration of a seasonal influenza vaccine, except for the intranasal 
live-attenuated influenza vaccine, is recommended but not required. 
Refer to Fenebrutinib Investigator’s Brochure and Appendix A6-1.4 for further details and 
precautions regarding vaccinations. 

 
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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
It may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment.  If study treatment is definitively discontinued, the 
participant should move to the Safety Follow-up Period.  Refer to the schedule of 
activities (see Section 1.3) for data to be collected at the time of discontinuation of study 
treatment (“Early Discontinuation Visit”) and the further follow-up evaluations that need 
to be completed in the Safety Follow-up Period. 
Participants must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
 
Demonstrate active hepatitis B infection 
 
PML 
 
First observation of AST or ALT elevation  8  ULN  
 
AST or ALT elevation  5  ULN persisting more than 2 weeks 
 
AST or ALT elevation  3  ULN in combination with any of the following: 
– 
Total bilirubin  2  ULN or clinical jaundice as defined by Hy’s Law 
– 
INR  1.5 
– 
Symptoms of hepatitis, such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness 
– 
Signs or symptoms of immune-related hepatotoxicity (fever, rash, or 
eosinophilia  5%) 
 
ALT or AST elevation between 35  ULN (inclusive) persisting for 4 weeks and in 
absence of alternative etiology 
 
Grade 3 neutropenia (ANC 5001000/mm³) persisting more than 1 month or 
reoccurring 
 
Grade 4 neutropenia (ANC  500/mm3) 
 
Grade 2 thrombocytopenia (platelet count 50,00075,000/mm³) persisting more than 
one month or reoccurring 
 
Grade 3 thrombocytopenia (platelet count 25,00050,000/mm3) or Grade 4 
thrombocytopenia ( 25,000/mm3) 
 
Malignancy (with the exception of non-serious local and resectable basal or 
squamous cell carcinoma of the skin) 

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•
Pregnancy
•
An episode of torsade de pointes or a new ECG finding of clinical concern or 
sustained (at least two ECG measurements > 30 minutes apart) QTcF that is
> 500 ms and/or > 60 ms longer than the baseline value (unless there is a clear 
alternative cause other than study drug) as described in ASSeQGL[   
Electrocardiogram assessment should be conducted as outlined in Section 8.2.3.
•
Requirement of chronic use of any prohibited medication as defined in
Section 6.8.3.  If any prohibited medication is considered to be medically necessary, the 
investigator should discuss with the Medical Monitor.  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Refer to the schedule of activities in Section 1.3 (see Table 1) for details on follow-up 
assessments to be performed for participants who permanently discontinue study 
treatment.  If a participant requests to be withdrawn from treatment or follow-up 
assessments, this request must be documented in the source documents and signed by 
the investigator. 
7.2 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM 
THE STUDY 
A participant may withdraw from the study at any time at his or her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a participant requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the schedule of activities (see Section 1.3).  Refer to 
the schedule of activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued both from the study treatment and from 
the study at that time. 
If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent.  Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) or local laws require 
destruction of the samples.  However, if samples have been tested prior to withdrawal, 
results from those tests will remain as part of the overall research data.  

 
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7.3 
PARTICIPANTS LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule.  If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic, and determine if there are ways to support participant 
participation.  
 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, three 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods).  These contact attempts should be 
documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up and will be withdrawn from the study.  
 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled individuals and for individuals who are not subsequently 
enrolled will be maintained at the study site. 
Study procedures and their timing are summarized in the schedule of activities (see 
Section 1.3).  Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a detailed record of 
all participants screened and to document eligibility or record reasons for screening 
failure, as applicable. 

 
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Medical history and baseline conditions, including clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), and 
reproductive status will be recorded at baseline.  Previous treatment with 
anti-CD20 therapy (e.g., rituximab, ocrelizumab) should be reported up to 3 years prior 
to randomization and other MS DMTs should be reported up to 1 year prior to 
randomization.  Receipt of any prior SARS-CoV-2 vaccine should be recorded in the 
concomitant medications eCRF.  All other medications (e.g., prescription drugs, MS 
symptomatic therapies, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) and non-medicinal treatments (e.g., physiotherapy, 
occupational therapy) used by the patient within 3 months prior to initiation of study 
treatment will be recorded in the appropriate eCRF.  Demographic data, including age, 
sex, and selfreported race/ethnicity, will also be recorded if allowed per local 
regulations.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should 
be recorded. 
Participants will be closely monitored for safety throughout the study.  Participants 
should be assessed for toxicity prior to each dose; treatment will be administered only if 
the clinical assessment and local laboratory test values are acceptable.  Urgent safety 
concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.  
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Magnetic Resonance Imaging 
Magnetic resonance imaging (MRI) is a useful tool for monitoring CNS lesions in MS.  
Different MRI derived parameters have been related to clinical activity and T1 weighted 
Gd-enhancing lesions or new and/or enlarging hyperintense T2 lesions have been 
related to relapses.  
Radiologic evaluation for the primary efficacy parameter will be performed using a 
standardized MRI protocol at screening, and at Weeks 4, 8, and 12.  Measurements 
from the screening MRI scan sequences will be used for the baseline MRI 
measurements; therefore, these sequences do not need to be repeated at the baseline 
visit.  In addition, mandatory MRI scans will be obtained in participants who withdraw 
from study treatment (at withdrawal visit) if one was not performed during the prior 
4 weeks.  While MRI scans are acquired in this study to support the primary and 
secondary endpoints, the set of images from each examination allows for the possibility 
of additional exploratory measurements.  
All MRI scans will be read by a centralized reading center for efficacy endpoints.  
The centralized reading center will be blinded to treatment assignment, and the reading 
will be performed in the absence of clinical information.  Further details on scanning 
acquisition sequences, methods, handling, and transmission of the scans, certification of 

 
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site MRI radiologist/technicians, and the procedures for the blinded analysis of the scans 
at the central reading center will be described in separate MRI acquisition procedures 
manuals and Imaging Review Charters. 
All MRI scans will also be reviewed locally by a radiologist for safety, and a MRI scan 
report containing only non-MS pathology will be provided to the treating investigator.  
During the DBT phase, only the local radiologist/technician at the investigational site who 
is assigned to this study may have access to the MRI scans, except at screening when 
the treating investigator may view the MRI scan.  To maintain the blind, the treating 
investigator must not review the MRI scans obtained after randomization unless a safety 
concern arises.  In the event that the treating investigator becomes aware of these MRI 
results, this should be documented in the eCRF, indicating the reason.  The treating 
investigator may have access to MRI scans performed during the OLE phase from their 
MRI facility.  
If participants receive corticosteroids for an MS relapse, every effort should be made to 
obtain an MRI scan prior to the first corticosteroid dose if the pre-corticosteroid scan is 
within 1 week of the scheduled visit.  In participants receiving corticosteroids for an 
MS relapse, there should be an interval of 3 weeks between the last dose of 
corticosteroids and the MRI scan. 
8.1.2 
Clinical Outcome Assessments 
Disability will be measured using the EDSS.  The EDSS is based on a standardized 
neurological examination, incorporating functional systems (visual, brainstem, pyramidal, 
cerebellar, sensory, bowel and bladder, and cerebral [or mental]) that are rated and then 
scored as a functional systems score (FSS), and ambulation, which is scored as 
ambulation score.  Each FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6 
and an ambulation score that is rated from 0 to 16.  These ratings are then used in 
conjunction with observations, as well as information, concerning ambulation and use of 
assistive devices to determine the total EDSS score.  The EDSS is a disability scale that 
ranges in 0.5-point steps from 0 (normal) to 10.0 (death) (Kurtzke 1983; Kappos 2011).  
All FSS, ambulation score, and total EDSS scores will be captured electronically.  
Note that the following items do not need to be scored for this study: sexual dysfunction 
and fatigue. 
8.1.3 
MS Relapse Assessment 
All new or worsening neurological events compatible with MS representing a clinical 
relapse will be reported in the appropriate eCRF.  The EDSS/FSS evaluation can be 
performed by the Principal Investigator or by a designated sub-investigator.  Whenever 
possible, the same rater should evaluate a patient throughout the study.  The EDSS 
should be performed within 7 days from the onset of the relapse.  If the change or 
intensification of existing neurological symptoms are more likely attributed to a transient 
systemic infection, then a referral to the examining investigator may not be warranted. 

 
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For this study, a protocol-defined relapse is defined as the occurrence of new or 
worsening neurological symptoms attributed to MS and immediately preceded by a 
relatively stable or improving neurological state of at least 30 days.  Symptoms must 
persist for  24 hours and should not be attributable to confounding clinical factors 
(e.g., fever, infection, injury, adverse reactions to concomitant medications).  The new or 
worsening neurological symptoms must be accompanied by objective neurological 
worsening consistent with an increase of at least one of the following: 
 
Half a step (0.5 point) on the EDSS 
 
Two points on one of the selected FSS listed below 
 
One point on two or more of the selected FSS listed below 
 
The change must affect the following selected FSS:  pyramidal, ambulation, cerebellar, 
brainstem, sensory, or visual.  Episodic spasms, sexual dysfunction, fatigue, mood 
change, or bladder or bowel urgency or incontinence will not suffice to establish a 
relapse.  Note that the following items need not be scored:  sexual dysfunction 
and fatigue. 
Derivation of protocol-defined relapses will be performed by the Sponsor.  Clinical 
relapses (i.e., regardless of whether or not they meet the criteria for a protocol-defined 
relapse) will be recorded in the eCRF. 
8.2 
SAFETY ASSESSMENTS 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the head, 
eyes, ears, nose, and throat and evaluation of the cardiovascular, dermatologic, 
musculoskeletal, respiratory, and gastrointestinal systems; genitourinary examinations 
may be performed if clinically indicated.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.  A neurological 
examination includes, but is not limited to, an assessment of mental status, level of 
consciousness, cranial nerve function, motor function, sensory function, reflexes, and 
coordination.  During an unscheduled visit, the neurological examination must be 
performed if the patient is experiencing neurological worsening between 
scheduled visits. 
8.2.2 
Vital Signs 
Vital signs will be measured in a seated position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.  
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the schedule of activities (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR interval, QRS interval, and QT interval.  QT interval corrected through use 
of Fridericia's formula (QTcF) can be calculated by the ECG machine or using standard 

 
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formulas.  Refer to Appendix 6 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the participant has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws).  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the preECG resting period and during 
ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all 
ECG reports.  Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site.  The following should be recorded on the appropriate 
eCRF:  heart rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and 
QTcF based on machine readings of the individual ECG tracings.  Any morphologic 
waveform changes or other ECG abnormalities must be documented on the eCRF.  If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory. 
If at a particular postdose timepoint the mean QTcF is  500 ms and/or  60 ms longer 
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted at the investigator's discretion.  If a PK sample is not scheduled for that 
timepoint, an PK sample should be obtained.  A decision on study drug discontinuation 
should be made, as described in  Appendix 6 (Section A62.4).  The investigator should 
also evaluate the participant for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
8.2.4 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
schedule of activities (see Section 1.3) for the timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the Adverse Event CRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  A laboratory test result must be reported as an adverse event if it 
meets any of the following criteria: 
 
Is accompanied by clinical symptoms 

 
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 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
ALT or AST  3  ULN unless attributed to a specific clinical diagnosis that is to be 
reported as the primary adverse event term (see Section 8.3.1 for more information 
on AE categories). 
 
Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks of the final dose of study treatment should be 
repeated until the values return to normal or baseline or are considered to be stable and 
no longer considered clinically significant by the investigator.  If such values do not 
return to normal or baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the schedule of activities. 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event or 
adverse event or dose modification), the results must be recorded on the eCRF.Samples 
collected for safety laboratory tests will be destroyed no later than the time of completion 
of the final Clinical Study Report. 
8.2.5 
Pregnancy Testing 
The schedule for pregnancy testing for enrolled female participants is outlined in 
Section 1.3 and will be conducted as outlined in Appendix 4.  
8.2.6 
Monitoring for Suicidal Ideation and Behavior 
Participants being treated with fenebrutinib should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in 
behavior, especially at the beginning and end of the course of treatment, or at the time of 
dose changes, either increases or decreases.  Consideration should be given to 
discontinuing the study medication in participants who experience signs of suicidal 
ideation or behavior, following a risk assessment.  
Screening assessment of suicidal ideation and behavior or treatment-emergent suicidal 
ideation and behavior will be monitored during Study GN43271 using the 
Columbia-Suicide Severity Rating Scale (C-SSRS). 

 
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8.3 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING 
The definitions of adverse event and serious adverse event can be found in Appendix 3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are 
considered related to the study treatment or study procedures, or caused the participant 
to discontinue the study treatment (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Event/Special Situations Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  All other 
medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the General Medical History and Baseline 
Conditions eCRF, not the Adverse Event eCRF. 
All adverse events will be reported from the start of treatment until 28 days after the final 
dose of study treatment at the timepoints specified in the schedule of activities (see 
Section 1.3). 
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation.  However, if the investigator learns of 
any serious adverse event, including a death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify 
the Sponsor. 

 
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8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about adverse event occurrences. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts.  All 
adverse events will be followed until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the participant is lost to follow-up (as 
defined in Section 7.3), or the participant withdraws consent.  Further information on 
follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the investigator to the Sponsor of a serious adverse event is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory authorities about the safety of a study treatment under clinical 
investigation.  The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards or 
Ethics Committees (IRBs/ECs), and investigators. 
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and Sponsor policy and forwarded to investigators 
as necessary. 
To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Fenebrutinib 
Fenebrutinib Investigator's Brochure  
  

 
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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
An investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 
events) from the Sponsor will review and then file it and will notify the IRB/EC, if 
appropriate according to local requirements. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 28 days after the final dose of fenebrutinib. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
28 days after the final dose of fenebrutinib. 
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Appendix 4.  The Sponsor or a designee may follow up by telephone, fax, email, and/or 
a monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
8.3.6 
Cardiovascular and Death Events 
Information on reporting deaths is provided in Appendix 3. 
8.3.7 
Anticipated Events Not Qualifying for Expedited Reporting 
Events not qualifying for expedited reporting will not be defined for this study.  
8.3.8 
Adverse Events of Special Interest 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after the investigator becomes aware 

 
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of the event; see Section A35 for reporting instructions).  Adverse events of special 
interest for this study are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
(  3  ULN) in combination with either an elevated total bilirubin ( 2  ULN) or 
clinical jaundice, as defined by Hy's Law (see Section A37.6) 
 
Cases of an elevated ALT and/or AST 35  ULN, INR  1.5, total 
bilirubin  2  ULN, and absence of clinical jaundice 
 
Cases of elevated ALT and/or AST 58  ULN, total bilirubin  2  ULN and absence 
of clinical jaundice 
 
Cases of elevated ALT and/or AST   8  ULN, total bilirubin  2  ULN and absence 
of clinical jaundice   
 
Suspected transmission of an infectious agent by a study treatment, as 
defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies only 
when a contamination of the study treatment is suspected. 
 
Laboratory results for adverse events of special interest pertaining to hepatic 
transaminase elevations should be closely monitored, as the AESI category should be 
upgraded to reflect the most severe liver enzyme results, where required.  
 
 
8.3.9 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study participants, access to Medical Monitors is available 
24 hours per day, 7 days per week.  An Emergency Medical Call Center will also be 
available 24 hours per day, 7 days per week.  The Emergency Medical Call Center will 
connect the investigator with an Emergency Medical Contact, provide medical translation 
service if necessary, and track all calls.  Contact information, including toll-free numbers 
for the Emergency Medical Call Center, will be distributed to investigators.  
8.4 
PHARMACOKINETICS 
Plasma samples of approximately 9 mL will be collected for measurement of plasma 
concentrations of fenebrutinib as specified in the schedule of activities (see Section 1.3).  
Optional additional intensive PK sample collection will be performed at the Day 1 and 
Day 29 visits for participants that consent to it.  The intensive PK sampling involves 
collection of blood samples according to the schedule shown in Table 3. 

 
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Instructions for the collection and handling of biological samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples will be used to evaluate the pharmacokinetics of fenebrutinib.  Samples 
collected for analyses of fenebrutinib plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on these plasma samples.  Participant 
confidentiality will be maintained.  
All PK samples will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed to allow for assay development and validation (if needed). 
Information on unblinding of personnel responsible for performing PK assays is provided 
in Section 6.3. 
8.5 
PHARMACODYNAMICS 
Refer to Section 8.7 for information on exploratory pharmacodynamic biomarkers. 
8.6 
GENETICS 
Refer to Section 8.10 for information on genetic biomarkers. 
8.7 
BIOMARKER ASSESSMENTS 
The following biomarker samples will be collected, as applicable, from participants at all 
sites: 
 
Serum and plasma samples for determination of fluid biomarkers of neuronal- and 
glial activity, B cell and myeloid cell biology, and the relationship between 
fenebrutinib exposure and selected pharmacodynamic biomarkers including but not 
limited to serum and/or plasma neurofilament light chain 
 
Flow cytometry: Analysis may include, but is not limited to, the determination of 
B-cell numbers (CD19+) and other lymphocyte subsets 
 
Blood samples for collection of RNA may be measured for exploratory biomarker 
analyses and may include but not be limited to neuronal- and glial activity, B cell and 
myeloid cell biology, and the relationship between fenebrutinib exposure to RNA gene 
expression.  Analyses may involve extraction of RNA for use of next-generation 
sequencing (NGS) of a comprehensive panel of genes.  NGS methods will not include 
whole genome sequencing (WGS) or whole exome sequencing (WES). 
Biomarker samples requiring separate consent are described in Section 8.10. 

 
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Screening blood samples, including those collected from individuals who do not enroll in 
the study, may be used for future research and/or development of disease-related tests 
or tools. 
Biomarker samples will be collected according to the schedule outlined in Section 1.3 
(see Table 1).  Biomarker samples will be sent to one or several central laboratories, 
academic laboratories or to the Sponsor or a designee.  Instructions for the collection 
and handling of biomarker samples, including sampling procedures, storage conditions, 
and shipment instructions, are provided in the laboratory manual.  
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.10) biomarker samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
8.8 
IMMUNOGENICITY ASSESSMENTS 
Immunogenicity assessments are not applicable for this study. 
8.9 
HEALTH ECONOMICS AND MEDICAL RESOURCE 
UTILIZATION 
Health economics and medical resource utilization assessments will not be performed in 
this study. 
8.10 
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT 
8.10.1 
Lumbar Punctures and CSF Substudy 
Consenting participants will undergo optional lumbar puncture for collection of CSF at 
the Baseline and Week 12 visits. 
The Informed Consent Form will contain a separate section that addresses optional 
lumbar punctures.  The investigator or authorized designee will explain to each 
participant the objectives, methods, and potential hazards of undergoing optional lumbar 
punctures.  Participants will be told that they are free to choose not to undergo optional 
lumbar punctures and may withdraw their consent at any time and for any reason.  A 
separate, specific signature will be required to document a participant's agreement to 
undergo optional lumbar punctures.  Participants who choose not to undergo optional 
lumbar punctures will not provide a separate signature.  The investigator should 
document whether or not the participant has given consent to undergo optional lumbar 

 
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punctures and (if applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF. 
Table 8 summarizes CSF substudy PK and biomarker collection during the double-blind 
treatment phase, according to the schedule outlined in Section 1.3 (see Table 1).  The 
baseline lumbar puncture can be performed at Day 1 prior to receiving the first dose of 
study drug, or it can be performed during the screening period prior to Day 1.  However, 
the baseline lumbar puncture should only be performed once other screening tests have 
been performed and it has been confirmed that the participant qualifies for the study.  
The lumbar puncture performed at the Week 12 visit should be performed between 1 to 
2 hours after the administration of study drug in clinic.  At the Week 12 lumbar puncture, 
a contemporaneous blood sample for PK measurement should be collected at the same 
time as the lumbar puncture is performed to enable comparison of CSF and plasma drug 
concentration.  If the Week 12 lumbar puncture is missed, it can be performed at a later 
visit, including an OLE visit.  
Inflammatory markers in the CSF will be measured as described in Section 4.2.8. 
Samples may be used for exploratory biomarker research as described in Section 8.7.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 8.7 for information on duration of sample storage 
and availability of data from biomarker analyses. 

 
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Table 8 
 Schedule of CSF Substudy Pharmacokinetic and Biomarker 
Samples for Double-Blind Treatment 
Visit 
Timepoint 
Sample Type 
Screening (Day 28 
to Day –1) or Day 1 
(Week 0) after 
patient has qualified 
for study 
NA 
Biomarkers (CSF, seruma) 
Day 85 (Week 12) 
1-2 hours after dosing 
PK (CSF, plasma), biomarkers (CSF, 
serum) 
CSF  cerebrospinal fluid; NA  not applicable; PPI  proton pump inhibitor; 
PK pharmacokinetic 
a Sample will come from the main study in order to avoid duplication.  This is not an additional 
sample to the main study 
Notes:   
 
Morning clinic visits are preferred for all visits but are required on Day 1.  Prior to each 
morning clinic visit, participants should be instructed not to take their morning dose and to 
bring their study medication with them to their clinic visit.  The dates and times of the last 
dose of oral study drug (prior to the clinic visit) and timing of oral study drug 
administration in the clinic should be recorded at each clinic visit.  Use of PPIs, 
H2-receptor antagonists, and/or other antacids (e.g., bismuth subsalicylate, calcium 
carbonate, aluminum-magnesium hydroxide) should be recorded as concomitant 
medications, including the date and time of last administration at each clinic visit. 
 
Single-dose acid-reducing agents are not permitted on the day of an in-clinic visit with 
PK assessments. 
 
At Week 12, PK CSF and plasma samples should be taken contemporaneously when 
feasible. 
 
8.10.2 
Samples for Research Biosample Repository 
8.10.2.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for participants in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 

 
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 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
8.10.3 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 8.10.6) 
will not be applicable at that site. 
8.10.4 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to fenebrutinib, diseases, or 
drug safety: 
 
Plasma samples collected as indicated in the schedule of activities 
 
Serum samples collected as indicated in the schedule of activities 
 
RNA samples collected as indicated in the schedule of activities 
 
DNA sample collected as indicated in the schedule of activities 
 
Leftover blood, serum, plasma, cerebrospinal fluid, and any derivatives thereof (e.g., 
DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  The WGS 
and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which participants are more likely to respond to a drug 
or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
All RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 

 
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IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
8.10.5 
Confidentiality 
All RBR samples and associated data will be labeled with a unique participant 
identification number. 
Participant medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
8.10.6 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to choose not to provide optional RBR samples and may 
withdraw their consent at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a participant's agreement to 
provide optional RBR samples.  Participants who choose not to provide optional RBR 
samples will not provide a separate signature.  The investigator should document 
whether or not the participant has given consent to provide optional RBR samples and (if 
applicable) the date(s) of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 

 
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8.10.7 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If a 
patient wishes to withdraw consent to the testing of his or her RBR samples during the 
study, the investigator must inform the Medical Monitor in writing of the patient’s wishes 
through use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the Sample Informed Consent/Withdrawal eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and patient number 
to the following email address: 
global.rcr-withdrawal@roche.com  
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
8.10.8 
Monitoring and Oversight 
All RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to an individual's participation in the RBR for the purposes of 
verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
9. 
STATISTICAL CONSIDERATIONS 
The primary analysis will be performed after the last patient completes the Week 12 visit 
or withdraws.  The analysis will be performed by the Sponsor.  Significance testing of the 
primary and secondary endpoints will account for multiplicity and control family-wise 
type I error.  All hypothesis tests will be 2-sided unless otherwise specified.  
9.1 
STATISTICAL HYPOTHESES 
The primary purpose of this study is estimation and hypothesis testing regarding the 
effect of fenebrutinib on the primary endpoint of total number of new T1 Gd lesions 
relative to placebo.  Point and interval estimates of the true underlying lesion rate ratio 
will be presented along with the p-value.  

 
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9.2 
SAMPLE SIZE DETERMINATION 
A sample size of 102 was chosen to ensure at least 90% power to detect a 60% 
reduction in total number of new T1 Gd lesions.  This assumes that the placebo arm 
has 0.7 new lesion per post-baseline scan and assuming 3% dropout by the end of 
study.  Approximately 68 will be randomized to receive fenebrutinib and 34 randomized 
to receive placebo.   
9.3 
ANALYSIS SETS 
All patients 
Efficacy and biomarker endpoints will be analyzed on all randomized patients.  
Efficacy and biomarker analyses will use all randomized patients grouped by treatment 
as assigned by randomization. 
Safety Population 
The Safety Population will include all participants who received any study drug.  Patient 
who received an incorrect medication rather than the one they were randomized will be 
summarized in the group according to the treatment actually received. 
All safety outcome measures will be analyzed using the Safety Population. 
PK Population 
The PK analysis population will consist of participants with sufficient data to enable 
estimation of key parameters, with participants grouped according to treatment received. 
9.4 
STATISTICAL ANALYSES 
The Statistical Analysis Plan (SAP) will be finalized prior to unblinding and database lock 
for the primary analysis, and it will include a more technical and detailed description of 
the statistical analyses described in this section.  This section is a summary of the 
planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints. 
9.4.1 
General Considerations 
Unless otherwise specified, all baseline and efficacy analyses will be performed on all 
randomized patients.  Participants will be analyzed according to the treatment assigned 
at randomization by IxRS.  
All safety analysis will be based on the safety evaluable population, unless otherwise 
specified.  Participants will be analyzed according to the treatment they actually 
received. 
9.4.2 
Primary Endpoint(s) 
The primary endpoint is the total number of new T1 Gd lesions observed on MRI scans 
of the brain at Weeks 4, 8, and 12.  The total number of new T1 Gd−enhanced lesions is 

 
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the sum of the individual number of new T1 Gd−enhanced lesions at Weeks 4, 8, 
and 12. 
The primary estimand follows a hypothetical strategy and estimates the treatment effect 
of fenebrutinib versus placebo had the patient not experienced an intercurrent event on 
the basis of the following attributes: 
 
Population: all randomized participants. 
 
Variable: total number of new T1 Gd lesions as described in Section 8.1.1 
 
Intercurrent events: 
Withdrawal from treatment: Data after participants withdrawn from treatment will 
be censored, following a hypothetical strategy. 
Initiation of another MS therapy: Initiation of another MS therapy is not allowed 
while on study. In case of such intercurrent event, patient will be considered as 
censored after initiation of another MS therapy, following a hypothetical 
strategy. 
 
Population-level-summary estimator: The total number of new T1 Gd lesions of 
primary analysis will be compared between the fenebrutinib and placebo using the 
negative binomial model, adjusting for stratification factor(s) (Section 6.3.1).  In case 
of early discontinuations, different number of scans among participants may be 
observed.  Log-transformed number of scans will be included in the negative 
binomial model as an “offset” variable to account for different number of scans.  The 
rate ratio and its two-sided 95% confidence intervals will be presented along with 
the p-value.  
 
Handling of missing data: 
Withdrawal from study: no imputation will be conducted for missing data. The 
negative binomial model with including number of scans as an “offset” variable 
accounts for different number of scans. 
 
If the model fails to converge due to high number of zero T1 Gd lesion counts, a logistic 
regression model will be performed on the status of new T1 Gd lesion post-baseline 
(present or not) adjusted for the same stratification factor(s).  The odds ratio and its 
two-sided 95% confidence intervals will be presented along with the p-value.  A 
hypothetical strategy will be used: 
 
Data after participants withdrawn from treatment will be censored.  
 
For the intercurrent event of withdrawal from treatment: 
Those withdrawn because of lack of efficacy or death and having no T1 Gd 
lesions are considered as having T1 lesions 
Otherwise, no imputation will be conducted. 
 

 
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Number of new T1 Gd lesions and proportion of participants with new T1 Gd+ lesions 
at each scheduled visit will be summarized by treatment groups.  Sensitivity analyses 
may also be performed for the primary endpoint and documented in the SAP. 
9.4.3 
Secondary Endpoints 
The estimands for the secondary endpoint of total number of new or enlarging 
T2 lesions, as defined in Section 3 (Table 3), will follow the same hypothetical strategy 
and have the same attributes as for the primary endpoint.  Number of new or enlarging 
T2 lesions and proportion of participants with new or enlarging T2 lesions at each 
scheduled visit will also be summarized by treatment groups. 
The secondary endpoint of proportion of participants free from any new 
gadolinium-enhancing T1 lesions and new or enlarging T2-weighted lesions observed on 
brain MRI at Weeks 4, 8, and 12 will use a logistic regression model similar as described 
for the primary endpoint.  A hypothetical strategy will also be used: 
 
Data after participants withdrawn from treatment will be censored.  
 
For the intercurrent event of withdrawal from treatment: 
Those withdrawn because of lack of efficacy or death and having no T1 
Gd lesions or new or enlarging T2 lesions are considered as not free from 
lesions. 
Otherwise, no imputation will be conducted. 
 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to the 
most current version of NCI CTCAE.  All adverse events, serious adverse events, 
adverse events leading to death, adverse events of special interest, and adverse events 
leading to study treatment discontinuation that occur on or after the first dose of 
study treatment (i.e., treatmentemergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, and severity grade.  For events of varying 
severity, the highest grade will be used in the summaries.  Deaths and cause of death 
will be summarized. 
Relevant laboratory and vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature) will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs will be summarized.  
Proportion of participants with suicidal ideation or behavior, as assessed by 
Columbia-Suicide Severity Rating Scale, will be summarized. 

 
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9.4.4 
Exploratory Endpoints 
Analyses on exploratory efficacy endpoints will be performed as data allows and further 
details will be described in the SAP. 
9.4.5 
Other Safety Analyses 
In addition to the analyses as specified for the secondary safety endpoint, study 
treatment exposure (such as treatment duration, total dose received and treatment 
interruptions) will be summarized with descriptive statistics. 
The ECG data will be displayed by time.  Changes in ECGs will be summarized.  
9.4.6 
Other Analyses 
9.4.6.1 
Summaries of Conduct of Study 
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study treatment discontinuation will also 
be tabulated.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm. 
9.4.6.2 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, T1 Gd lesions, etc.) will 
be summarized by treatment arm.  Baseline data are the last data obtained prior to 
initiation of study treatment.  Descriptive statistics (mean, standard deviation, median, 
and range) will be presented for continuous variables and counts and percentages will 
be presented for categorical variables. 
9.4.6.3 
Pharmacokinetic Analyses 
The PK analysis will include tabulation of plasma concentration data and summarization 
of plasma concentrations by visit, with participants grouped according to treatment 
received.  Descriptive summary statistics may include the arithmetic mean, median, 
range, standard deviation, and coefficient of variation, as appropriate.  
Interpatient variability will be evaluated, and potential sources of variability may be 
assessed.  Relationships between PK and PD, efficacy, and safety endpoints may be 
explored. 
Additional PK analyses will be conducted as appropriate and as specified in the SAP.  
The exploratory PK analyses may be reported separately. 
9.5 
INTERIM ANALYSIS 
There is no plan to conduct interim analysis. 
9.6 
INDEPENDENT DATA MONITORING COMMITTEE 
Refer to Section 4.1 for information on the iDMC for this study. 

 
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10. 
REFERENCES 
Clinicaltrials.gov. Dose-finding study for SAR442168 in relapsing multiple sclerosis 
[resource on the Internet]. 2020 [updated: January 2020; cited June, 2020]. 
Available from: https://clinicaltrials.gov/ct2/show/NCT03889639. 
Council for International Organizations of Medical Sciences. Drug-Induced Liver 
Injury (DILI): Current Status and Future Directions for Drug Development and 
the Post-Market Setting, A Consensus by a CIOMS Working Group; 
https://cioms.ch/publications/product/drug-induced-liver-injury/. Published 
August 2020. Accessed August 2021 
[EMA] European Medicines Agency. Guidance on the management of clinical trials 
during the COVID-19 (coronavirus) pandemic; Version 4 04/02/2021. 
GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of 
multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of 
Disease Study 2016. Lancet Neurol 2019;18:26985. 
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing 
multiple sclerosis. N Engl J Med. 2017:376;221-234. 
Herman AE, Chinn LW, Kotwal SG, et al. Safety, pharmacokinetics, and 
pharmacodynamics in healthy volunteers treated with GDC-0853, a selective 
reversible Bruton’s tyrosine kinase inhibitor. Clin Pharmacol Ther 
2018;103:102028. 
Howell OW, Rundle JL, Garg A et al. Activated microglia mediate axoglial disruption that 
contributes to axonal injury in multiple sclerosis. J Neuropatholol Exp Neurol. 
2010;69:1017-1033.  
Kappos L. Standardised neurological examination and assessment of Kurtzke's 
functional systems and expanded disability status scale. Slightly modified from J.F. 
Kurtzke, Neurol 1983:33,144452. Neurology, University Hospital Basel, 
Switzerland: Neurostatus Scoring Definitions, 2011. 
Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: 
recommendations for patient selection and monitoring. Lancet Neurol 
2007;6:43141. 
Kellick KA, Bottorff M, Toth PP, on behalf of The National Lipid Association's Safety 
Task Force. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol 
2014;8(3 Suppl):S3046. 
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurol 1983;33:144452. 
Lassmann H. Pathogenic mechanisms associated with different clinical courses of 
multiple sclerosis. Front Immunol 2019;9:3116.  

 
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76/Protocol GN43271, Version 3 
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple 
sclerosis: the 2013 revisions Neurology 2014;83:27886. 
Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an Oral BTK 
Inhibitor in Multiple Sclerosis. N Engl J Med 2019;380:240617. 
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary 
progressive multiple sclerosis. N Engl J Med 2017; 376:209-220. 
Polman CH, Reingold SC, Barkhof F, et al. Ethics of placebo-controlled clinical trials in 
multiple sclerosis: a reassessment. Neurology 2008;70:1134-40. 
Thebault S, Bose G, Booth R, et al. Serum neurofilament light in MS: the first true 
blood-based biomarker? Mult Scler 2022;28:14917.  
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 
revisions of the McDonald criteria. Lancet Neurol 2018;17:16273. 
U.S. Food and Drug Administration. Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation FDA Guidance 2009; 
https://www.fda.gov/media/116737/download. Published July 2009. Accessed 
August 2021 
Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United 
States: a population-based estimate using health claims data. Neurology 
2019;92:e102940. 
 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
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A11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
 
Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice 
 
Applicable laws and regulations 
 
The protocol, Informed Consent Form, Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board or 
Ethics Committee (IRB/EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated. 
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
 
Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures 
 
Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 CFR (U.S. sites only), the ICH Guideline for Good Clinical 
Practice, the IRB/EC, Regulation (E.U.) No. 536/2014 (E.U. sites only), and all other 
applicable local regulations 
 
A12. 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 4.4). 

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A13.  
INFORMED CONSENT PROCESS 
The investigator or authorized designee will explain the nature of the study to the patient 
or his or her legally authorized representative and answer all questions regarding the 
study. 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50 (U.S. sites only), the ICH Guideline for Good 
Clinical Practice, and the IRB/EC. 
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
Informed Consent Form. 
If the Informed Consent Form is revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or the patient's legally authorized representative must re-consent by 
signing the most current version of the Informed Consent Form or the addendum, in 
accordance with applicable laws and IRB/EC policy. 
A copy of each Informed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. 
Participants who are re-screened are required to sign a new Informed Consent Form. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period.  A 
separate signature will be required to document a patient's agreement to allow any 
remaining specimens to be used for exploratory research.  Participants who decline to 
participate in this optional research will not provide this separate signature. 
A14. 
DATA PROTECTION 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will 
be implemented. 

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Participants will be assigned a unique identifier by the Sponsor.  Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; the patient's 
name or any information that would make the patient identifiable will not be transferred. 
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the Informed Consent Form. 
Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities. 
A15. 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 35 sites globally will participate to enroll approximately 102 participants.  
Enrollment and randomization will occur through an interactive voice or web-based 
response system.  
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and pharmacokinetic analyses), as specified 
in Section 8 and Appendix 2.  Accredited local laboratories will be used for routine 
monitoring; local laboratory ranges will be collected. When discussed with the Sponsor 
or its CRO, local laboratory tests can be used instead of central laboratory tests in 
certain situations (e.g., urgent safety evaluations, lack of an adequate collection kit at the 
site). 
An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
An IRF will collect, store, and potentially review imaging data. 
A16. 
DISSEMINATION OF CLINICAL STUDY DATA 
Study data, which may include imaging data, may be submitted to government or other 
health research databases or shared with researchers, government agencies, 
companies, or other groups that are not participating in this study.  These data may be 
combined with or linked to other data and used for research purposes, to advance 
science and public health, or for analysis, development, and commercialization of 
products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and/or other summaries of clinical study results may be available in heath authority 
databases for public access as required by local regulation, and will be provided upon 

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request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Roche policy on study data publication. 
A17. 
DATA QUALITY ASSURANCE 
All patient data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site 
monitoring), are provided prior to study initiation, in the various functional 
monitoring plans (including, but not limited to, Quality Tolerance Limit Management Plan 
and Trial Monitoring Plan). 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
Study monitors will perform ongoing monitoring activities as specified in the Trial 
Monitoring Plan to confirm that data entered into the CRF by authorized site personnel 
are accurate, complete, and verifiable from source documents; that the safety and rights 
of participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, the ICH Guideline 
for Good Clinical Practice, and all applicable regulatory requirements. 

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Records and documents pertaining to the conduct of this study, including signed 
Informed Consent Forms, must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period.  No records may be destroyed during the retention period without the written 
approval of the Sponsor.  No records may be transferred to another location or party 
without written notification to the Sponsor. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
A18. 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the Case Report Form (CRF) or entered in the electronic Case Report 
Form (eCRF) that are transcribed from source documents must be consistent with the 
source documents, or the discrepancies must be explained.  The investigator may need 
to request previous medical records or transfer records, depending on the study.  Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in the Trial Monitoring Plan. 
A19. 
STUDY AND SITE CLOSURE 
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following: 
 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for Good Clinical Practice 
 
Inadequate recruitment of participants by the investigator 
 
Discontinuation of further study treatment development 
 

Appendix 1:  Regulatory, Ethical, and Study Oversight Considerations 
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83/Protocol GN43271, Version 3 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The Investigator shall promptly 
inform the participants and should ensure appropriate patient therapy and/or follow-up. 
A110. 
PUBLICATION POLICY 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
A111. 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
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Appendix 2  
Clinical Safety Laboratory Tests 
The tests detailed in Table A2-1 will be performed by the central laboratory, with the 
exception of the urine pregnancy test which will be performed at the site. 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for study treatment administration and/or response evaluation.  
If a local sample is required, it is important that a sample for central analysis be obtained 
at the same time.  Additionally, if the local laboratory results are used to make either a 
study treatment decision or a response evaluation, the results must be entered on the 
electronic Case Report Form. 
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations. 

Appendix 2:  Clinical Safety Laboratory Tests 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
85/Protocol GN43271, Version 3 
Table A2-1 Protocol-Required Safety Laboratory Assessments 
Central Laboratory Tests 
 Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential 
count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and other cells). 
 Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if considered 
standard of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, 
AST, urate, and LDH, amylase, lipase, and GGT. 
 Coagulation:  INR, aPTT, and PT 
 HIV serology:  HIV-1 antibody/HIV-1/2 antibody/HIV-2 antibody 
 HBV serology:  HBsAg, HBsAb, and total HBcAb for all individuals; HBV DNA for individuals 
with negative HBsAg and HBsAb tests and a positive total HBcAb test  
Individuals with a positive quantitative HBV DNA at screening (must be  500 IU/mL per 
the eligibility criteria) will undergo additional HBV DNA tests as outlined in the schedule 
of activities (see Section 1.3). 
 HCV serology:  HCV antibody for all individuals; HCV RNA for individuals with a positive HCV 
antibody test 
 Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
 Quantitative immunoglobulins:  IgA, IgG, and IgM 
 Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at screening.  Urine 
pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
 Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, and blood) and 
microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, and 
bacteria) 
 Tuberculosis test: QuantiFERON®-TB Gold 
Note: This test should be performed at the central laboratory; however, in the event of 
extenuating circumstances and with Sponsor approval, an appropriately accredited local 
laboratory may be used, and Roche will collect the results. 
Local Laboratory Tests 
 Urine pregnancy tests will be performed at screening and specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; 
HCV  hepatitis C virus. 
  
Investigators must document their review of each laboratory safety report.  
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel {until the study has been unblinded}.

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
87/Protocol GN43271, Version 3 
A31. 
DEFINITION OF ADVERSE EVENT 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a patient or clinical study 
patient temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment. 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
Events Meeting the Adverse Event Definition 
The following events meet the definition of adverse event: 
 
Any clinically relevant, abnormal laboratory test results (hematology, clinical 
chemistry, or urinalysis), or other safety assessments (e.g., ECG, radiological 
scans, vital sign measurements), including those that worsen from baseline.  Refer 
to Section 8.2.4 for reporting requirements of abnormal laboratory results as 
adverse events.  
 
Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
 
New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study 
 
Signs, symptoms, or clinical sequelae of a suspected drugdrug interaction 
 
Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication 
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or 
self-harming intent.  Such overdoses should be reported regardless of 
sequelae. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as an adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
88/Protocol GN43271, Version 3 
Events NOT Meeting the Definition of Adverse Event 
The following events do not meet the definition of adverse event: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the patient’s condition 
 
The disease or disorder being studied or expected progression, including MS 
relapses, signs, or symptoms of the disease or disorder being studied, unless more 
severe than expected for the patient’s condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy) 
The condition that leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen 
 
A32. 
DEFINITION OF SERIOUS ADVERSE EVENT 
If an event is not an adverse event per the definition in Section A31, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose: 
 
Results in death 
 
Is life threatening 
The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event.  It does not refer 
to an event that hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
89/Protocol GN43271, Version 3 
 
Results in persistent disability or incapacity 
The term "disability" means a substantial disruption of a person’s ability to 
conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly or birth defect 
 
Other situations: 
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development 
of drug dependency or drug abuse. 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]; 
see Section A33.2); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the electronic Case Report Form (eCRF). 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event) (see Section A35 for reporting instructions). 
A33. 
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS 
A33.1 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
RECORDING 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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90/Protocol GN43271, Version 3 
The investigator will then record all relevant adverse event or serious adverse event 
information on the eCRF. 
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event. 
A33.2 
ASSESSMENT OF SEVERITY 
The investigator will assess the severity of each adverse event reported during the study 
through use of the NCI CTCAE (v5.0) grading scale.  The investigator will use the 
grading scale in Table 1 for assessing the severity of adverse events that are not 
specifically listed in the NCI CTCAE. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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91/Protocol GN43271, Version 3 
Table A3-1 Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Examples of instrumental activities of daily living include preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by participants who 
are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section A35 for reporting instructions), per the definition of serious 
adverse event in Section A32. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section A35 for 
reporting instructions), per the definition of serious adverse event in Section A32. 
  
A33.3 
ASSESSMENT OF CAUSALITY 
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event. 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure and/or prescribing 
information (for marketed products) in his or her assessment. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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92/Protocol GN43271, Version 3 
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality. 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor. 
The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
A33.4 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
A33.4.1 
Investigator Follow-Up 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals. 
If a patient dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the Sponsor with a copy of any post-mortem findings, 
including histopathology.  
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated serious adverse event data to the Sponsor 
within 24 hours of receipt of the information.  New or updated information should be 
recorded on the originally completed Adverse Event eCRF.  For serious adverse events 
and adverse events of special interest, the investigator must report new significant 
follow-up information to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the information).  New significant information includes the 
following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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93/Protocol GN43271, Version 3 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
During the adverse event reporting period (defined in Section 8.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient's 
medical record to facilitate source data verification. 
A33.4.2 
Sponsor Follow-Up 
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
A34. 
REPORTING OF SERIOUS ADVERSE EVENTS 
A34.1 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA AN ELECTRONIC COLLECTION TOOL 
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A35. 
If the electronic system is unavailable, the site will use the paper Clinical trial Adverse 
Event/Special Situations Form, as described in Section A35, to report the event within 
24 hours. 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
After the study is completed at a given site, the electronic data collection tool will be 
taken off line to prevent the entry of new data or changes to existing data. 
If a site receives a report of a new serious adverse event from a study patient or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken off line, the site can report this information 
on a paper Clinical trial Adverse Event/Special Situations Form, as described in 
Section A35. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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94/Protocol GN43271, Version 3 
A34.2 
SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR 
VIA PAPER CRF 
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical trial Adverse Event/Special Situations Form, as 
described in Section A35. 
A35. 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A35.1 
EVENTS THAT OCCUR PRIOR TO STUDY TREATMENT 
INITIATION 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., biopsy, 
discontinuation of medications) should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators. 
A35.2 
EVENTS THAT OCCUR AFTER STUDY TREATMENT 
INITIATION 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported 4 weeks after the final dose of study treatment.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after the investigator becomes aware of the event) on the Adverse Event eCRF and 
submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
the investigator becomes aware of the event), either by faxing or by scanning and 
emailing the form, using the fax number or email address provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  
Instructions for reporting serious adverse events that occur more than 4 weeks after the 
final dose of study treatment are provided in Section A36. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
95/Protocol GN43271, Version 3 
A36. 
REPORTING ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
4 week after the final dose of study treatment), if the event is believed to be related to 
prior exposure to study treatment.  These events should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Special Situations Form, 
using the fax number or email address provided to investigators. 
A37. 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the patient's medical records to the Medical Monitor in lieu of completion 
of the eCRF.  Investigators should use correct medical terminology and concepts when 
recording adverse events on the Adverse Event eCRF.  Avoid colloquialisms and 
abbreviations.  Only one adverse event term should be recorded in the event field of the 
Adverse Event eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
A37.1 DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
96/Protocol GN43271, Version 3 
A37.2 
ADVERSE EVENTS THAT ARE SECONDARY TO OTHER 
EVENTS 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
A37.3 
PERSISTENT OF RECURRENT ADVERSE EVENTS 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware that the event became 
serious; see Section A35 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from "non-serious" to "serious," providing the date 
that the event became serious, and completing all data fields related to serious 
adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
97/Protocol GN43271, Version 3 
A37.4 
ABNORMAL LABORATORY VALUES 
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  
A laboratory value abnormality that is not associated with the underlying disease must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
ALT or AST  3  upper limit of normal (ULN) unless this is attributed to a specific 
clinical diagnosis that is to be reported as the primary adverse event term  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event (except for ALT/AST  3  ULN, 
which must always be reported as an adverse event in this protocol). 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A37.4 for 
details on recording persistent adverse events). 
A37.5 
ABNORMAL VITAL SIGN VALUES 
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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98/Protocol GN43271, Version 3 
A vital sign abnormality that is not associated with the underlying disease must be 
reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dose modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., hypertension) should be recorded 
on the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section A37.4 for 
details on recording persistent adverse events). 
A37.6 
ABNORMAL LIVER ENZYMES AND FUNCTION TESTS 
 
An elevated ALT and/or AST ( 3  ULN) must be reported as an adverse event in this 
protocol (refer to table A6-1). 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
( 3  ULN) in combination with either an elevated total bilirubin ( 2  ULN) or 
clinical jaundice, as defined by Hy's Law (refer to Table A6-1).   
 
Cases of elevated ALT and/or AST 35  ULN, INR  1.5, total bilirubin  2  ULN, 
and absence of clinical jaundice 
 
Cases of elevated ALT and/or AST 58  ULN, total bilirubin  2  ULN and absence 
of clinical jaundice  
 
Cases of ALT or AST  8  ULN, total bilirubin  2  ULN and absence of 
clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section A37.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A35). 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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99/Protocol GN43271, Version 3 
Abnormal liver enzymes will warrant close observation and ruling out of alternative 
causes (refer to Table A6-1 and Appendix 7). 
 
A37.7 
DEATHS 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 8.3.1), regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section A35). 
This includes death attributed to an MS relapse.  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of multiple sclerosis, "multiple sclerosis 
progression" should be recorded on the Adverse Event eCRF. Deaths that occur after 
the adverse event reporting period should be reported as described in Section A36. 
A37.8 
PREEXISTING MEDICAL CONDITIONS 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
A37.9 
LACK OF EFFICACY OR WORSENING OF MULTIPLE 
SCLEROSIS 
Medical occurrences or symptoms of deterioration that are anticipated as part of  the 
expected pattern of progression of the underlying disease, or other MS-related 
symptoms should not be recorded as adverse events.  Clinical MS relapses will be 
recorded on a dedicated eCRF.  However, deterioration that is judged by the investigator 
to have unexpectedly worsened in severity or frequency or changed in nature at any 
time during the study should be recorded as an adverse event.  If there is any 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
100/Protocol GN43271, Version 3 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.  When recording an unanticipated worsening of MS on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors.  Occasional isolated symptoms that according to the 
investigator are caused by MS, but do not constitute a full MS relapse, should be 
reported as an adverse event, with the causality "Disease under study" (see Section A3
5). 
A37.10 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section A32), except as 
outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Planned hospitalization required by the protocol unless prolonged  
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The patient was hospitalized for an elective procedure that was planned prior to 
the study, was scheduled during the study despite the fact that the condition 
had not worsened, or was scheduled during the study when treatment became 
necessary because of the expected normal progression of the condition.  Such 
events should still be recorded as medical procedures in the On Study 
Surgeries and Procedures eCRF.  
The patient has not experienced an adverse event 
 
Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with high dose corticosteroids 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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101/Protocol GN43271, Version 3 
A37.11 
CASES OF OVERDOSE , MEDICATION ERROR, DRUG ABUSE, 
OR DRUG MISUSE 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations") are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self administered by the patient, drug misuse could 
involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event; see Section A35).  For fenebrutinibmatching 
placebo, adverse events associated with special situations should be recorded as 
described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
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102/Protocol GN43271, Version 3 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with fenebrutinib and matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter fenebrutinib and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter fenebrutinib and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter fenebrutinib and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter fenebrutinib and "intercepted medication error" 
as the event term.  Check the "Medication error" box.  Enter a description of the 
error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter fenebrutinib and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter fenebrutinib and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the fenebrutinib and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter fenebrutinib and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter fenebrutinib and 
"patient supplied drug to third party" as the event term.  Check the "Drug 
misuse" box. 
 

Appendix 3:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
103/Protocol GN43271, Version 3 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
 

Appendix 4:  Collection of Pregnancy Information 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
105/Protocol GN43271, Version 3 
A41. 
PREGNANCIES IN FEMALE PARTICIPANTS 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 4 weeks after the final dose of fenebrutinib.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after the investigator becomes aware 
of the pregnancy), either by faxing or by scanning and emailing the form, using the fax 
number or email address provided to investigators.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study treatment and 
counsel the participant, discussing the risks of the pregnancy and the possible effects on 
the fetus.  Monitoring of the participant should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital anomaly 
or birth defect in the child) should be reported on the Adverse Event eCRF.  In addition, 
the investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A42. 
PREGNANCIES IN FEMALE PARTNERS OF MALE 
PARTICIPANTS 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if a female partner becomes pregnant during the study or within 
4 weeks after the final dose of fenebrutinib.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
participant exposed to study treatment.  When permitted by the site, the pregnant 
partner would need to sign an Authorization for the Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available.   

Appendix 4:  Collection of Pregnancy Information 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
106/Protocol GN43271, Version 3 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male participant or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A43. 
ABORTIONS 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event; see Section A35). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after the investigator becomes aware of the event; see 
Section A35).  A therapeutic or elective abortion performed for reasons other than an 
underlying maternal or embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
A44. 
ABNORMAL PREGNANCY OUTCOMES 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment or the female partner of a male participant exposed to study treatment 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event; see Section A35).

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
107/Protocol GN43271, Version 3 
Appendix 5  
Genetics:  Use and Analysis of DNA 
Genetic biomarker assessments will not be performed in this study.   

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
108/Protocol GN43271, Version 3 
Appendix 6  
Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib is not approved, and clinical development is ongoing.  The safety plan for 
participants in this study is based on clinical experience with fenebrutinib in completed 
and ongoing studies.  The anticipated important safety risks for fenebrutinib are outlined 
below.  Please refer to the Fenebrutinib Investigator's Brochure for a complete summary 
of safety information.  
Several measures will be taken to ensure the safety of study participants.  Eligibility 
criteria have been designed to exclude individuals at higher risk for toxicities.  
Participants will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for treatment interruption or discontinuation, are 
provided below. 
A61. 
RISKS ASSOCIATED WITH FENEBRUTINIB 
A61.1 
HEPATIC TRANSAMINASE ELEVATIONS 
In clinical Phase 2 studies to date, participants treated with fenebrutinib have been found 
to be at an increased risk of transaminase elevations than participants on placebo.   
Between 1% and 10% of participants in the fenebrutinib 200 mg BID treatment arms of 
blinded randomized studies and OLEs experienced Grade 2 or higher transaminase 
elevations (ALT/AST of 3-5  ULN or higher), compared with fewer than 1% of 
participants in the placebo arms across studies. 
Participants enrolled in clinical trials with fenebrutinib will be monitored for the risk of 
hepatotoxicity with regular measurement of transaminases as outlined in the schedules 
of activities (see Table 1).  They should receive appropriate supportive care as clinically 
indicated, with hepatotoxicity managed in accordance with the study protocols and site 
institutional guidelines.  Cases of potential drug-induced liver injury that include the 
categories below must be reported to Sponsor as an adverse event of special interest 
within 24 hours of awareness (see Section 8.3.8). 
 
Cases of elevated ALT or AST (3   ULN) in combination with either an elevated 
total bilirubin (  2  ULN) or clinical jaundice, as defined by Hy's Law (see 
A3 7.6) 
 
Cases of an elevated ALT and/or AST  35  ULN, INR  1.5, total 
bilirubin  2  ULN, and absence of clinical jaundice 
 
Cases of elevated ALT and/or AST  5-8 x ULN, total bilirubin    2 x ULN and 
absence of clinical jaundice 
 
Cases of elevated ALT and/or AST  > 8 x ULN, total bilirubin    2 x ULN and 
absence of clinical jaundice   
 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
109/Protocol GN43271, Version 3 
Guidelines for management of study treatment in the event hepatic transaminase 
elevation/hepatotoxicity is observed in participants are provided in Table A61 and 
Appendix 7. 
A61.2 
INFECTIONS 
Fenebrutinib is a reversible antagonist of BTK signaling in immune cells (B cells, myeloid 
cells, but not T cells) that may lead to immunomodulatory effects and an increased risk 
of infection in healthy participants.  Infections, including pneumonia and fatal influenza 
infections, have occurred in adult participants with B-cell malignancies treated with 
fenebrutinib.  Serious infections, including a case of tuberculosis (TB), have been 
reported in blinded, open-label, and completed studies of fenebrutinib in autoimmune 
indications.  As a safety precaution, the study protocol contains exclusion criteria for 
infections (including chronic infections such as hepatitis B) and potential infection risk 
and guidelines for study treatment management in the event of infection. 
All participants in the study should be monitored for fever and potential infectious 
complications, including opportunistic infections and TB, and should be evaluated 
promptly.  Physicians or a health care provider should give participants advice to prevent 
potential transmission of and exposure to endemic infections according to local or 
Centers for Disease Control and Prevention guidelines.  Participants should be advised 
to seek immediate medical attention if they develop signs and symptoms suggestive of 
an infection.  All infections occurring during the study, including, but not limited to, 
respiratory infections, cutaneous infections, urinary tract infections, systemic viral 
infections, and episodes of suspicious or febrile diarrhea, should be evaluated using 
serology or polymerase chain reaction, if available, and cultured, if feasible, and any 
identified organisms noted in the eCRF. 
Guidelines for management of study treatment in the event that infections are observed 
in participants are provided in Table A6-1.  
A61.3 
HEPATOTOXICITY 
Based on the clinical data, transaminase elevations are considered a risk associated 
with fenebrutinib (see Section A6-1.1).  Hepatotoxicity is a potential risk as it is unknown 
whether more severe drug-induced liver injury can be caused by fenebrutinib. 
Guidelines for management of study treatment in the event of hepatic transaminase 
elevations/hepatotoxicity is observed in participants are provided in Table A6-1 and 
Appendix 7, and refer to the Fenebrutinib Investigator’s Brochure for further details. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
110/Protocol GN43271, Version 3 
A61.4 EFFECT ON VACCINATIONS 
The effect of fenebrutinib upon the efficacy of vaccinations is unknown.  It is 
recommended that appropriate vaccinations for per local guidelines be up to date before 
study participation.  Refer to Section 5.2 for the exclusion criteria and Section 6.8.5 for 
vaccination requirements.  In addition, immunization with a live or live-attenuated 
vaccine is prohibited for the duration of study participation, including during the safety 
follow-up (SFU). 
A61.5 BLEEDING 
The effect of BTK inhibition as a potential risk factor for bleeding is unknown.  Bleeding 
was not observed in nonclinical studies with fenebrutinib.  Bleeding events, including 
Grade  3 GI bleeding, have been reported in participants with hematological cancer 
treated with fenebrutinib, and Grade  2 bleeding has been reported in participants 
enrolled in blinded studies for autoimmune diseases. 
See Section 5.1 and Section 5.2 for inclusion and exclusion criteria regarding bleeding 
risk.  Participants should be advised to seek immediate medical attention if they develop 
signs and symptoms suggestive of clinically significant bleeding. 
Guidelines for management of study treatment in the event that bleeding is observed in 
participants are provided in Table A6-1.  Refer to the Fenebrutinib Investigator’s 
Brochure for further details. 
A61.6 
CYTOPENIAS 
Cytopenias have been observed in the ongoing Phase I study of fenebrutinib in oncology 
participants (Study GO29089) and in the completed Phase II studies of fenebrutinib in 
participants with rheumatoid arthritis (RA) (Studies GA29350 and GA30067) and 
systemic lupus erythematosus (SLE) (Studies GA30044 and GA30066).  The cytopenias 
have been monitorable and clinically manageable, although some participants with SLE, 
enrolled in studies with fenebrutinib, have had protocol-mandated discontinuations 
because of cytopenias.  Participants should be monitored regularly with hematology 
laboratory evaluations, as outlined in the schedules of activities (see Section 1.3), and 
should receive appropriate supportive care as clinically indicated.  Participants should be 
advised to seek immediate medical attention if they develop signs and symptoms 
suggestive of cytopenias (e.g., persistent fever, bruising, bleeding, pallor).  Cytopenias 
should be managed according to local clinical guidelines. 
Guidelines for managing study treatment in the event that cytopenia is observed are 
provided in Table A6-1.  Refer to the Fenebrutinib Investigator’s Brochure for further 
details. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
111/Protocol GN43271, Version 3 
A61.7 
GASTROINTESTINAL EFFECTS 
Reversible body weight gain and food consumption changes have been observed in 
animals.  Mild diarrhea, nausea, and abdominal pain have been reported in participants 
with B-cell malignancies; however, the events have resolved and have not led to study 
treatment discontinuation.  Healthy participants in the multiple-ascending dose 
Study GA29347 reported events of mild self-limited nausea.  Across studies with 
immune indications receiving blinded or open-label treatment, approximately 5% of 
enrolled participants have reported nausea, vomiting, diarrhea, or other GI symptoms; 
these events occurred with similar frequencies in the fenebrutinib and placebo arms. 
Throughout the study, participants will be monitored for GI adverse events.  
Symptomatic treatment according to the investigator’s clinical judgment should be 
provided.  Refer to the Fenebrutinib Investigator’s Brochure for further details. 
A61.8 
CARDIOVASCULAR EFFECTS 
Fenebrutinib is considered to have a low potential to cause QT interval prolongation or to 
directly affect other cardiovascular parameters in humans at therapeutic exposures. 
Analysis of ECG data from the single-and multiple-ascending dose studies in healthy 
participants did not demonstrate any significant increase in either QRS interval or 
QTcF intervals.  However, cardiac safety will be evaluated in all participants at baseline 
and throughout this study, with routine monitoring of vital signs (including heart rate and 
blood pressure), routine safety ECGs, and collection of adverse events, until ECG 
effects can be ruled out (see Section 8.3.6 and Section 8.2.3). 
For management of participants with sustained QTcF prolongation (QTcF that is 
 500 ms or  60 ms longer than the baseline value), see Section 8.3.6 and 
Section A6-2.4.  The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, concomitant medications known 
to prolong the QT interval, severe bradycardia).  Refer to the Fenebrutinib Investigator’s 
Brochure for further details. 
A61.9 
VASCULAR INFLAMMATION 
Vascular inflammation (vasculitis) was observed in dogs administered fenebrutinib in the 
4-week toxicity study, and these changes were not completely reversed by the end of 
the 4-week recovery period; however, these changes were not observed in the 9-month 
toxicity study.  The translatability of these findings to humans is unknown; however, 
Beagle dogs are susceptible to spontaneous development of polyarteritis syndrome 
(Snyder et al. 1995) and may be more sensitive to any drug-induced effects.  All 
participants enrolled in the study will be monitored for adverse events suggestive of 
vasculitis as part of routine monitoring.  Creatinine, complete blood count, and urinalysis 

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Fenebrutinib—F. Hoffmann-La Roche Ltd 
112/Protocol GN43271, Version 3 
are monitored in participants as outlined in schedules of activities (see Section 1.3).  
Refer to the Fenebrutinib Investigator’s Brochure for further details. 
A61.10 
MALIGNANCY 
The effect of BTK inhibition on the development of malignancies is not known; however, 
malignancies have been identified as a potential concern for immunomodulatory agents.  
Malignancies have been reported in participants with X-linked agammaglobulinemia 
(XLA), including lymphoreticular malignancies, gastric and colorectal adenocarcinoma, 
and squamous cell carcinoma of the lung.  No hyperplastic or neoplastic changes have 
been observed in nonclinical toxicology studies of fenebrutinib up to 4 weeks duration.  
Malignancies have been observed in participants enrolled in clinical trials of fenebrutinib 
in immune indications (RA and SLE).  Based on the limited clinical experience to date 
(short studies that cannot adequately characterize the risk of malignancy, no obvious 
pattern of malignancies was observed), it is not possible to determine if fenebrutinib may 
have played a role in the development of any of the malignancies. 
Participants with a history of cancer, including hematologic malignancy and solid tumors, 
within 10 years of screening will be excluded from the study.  Basal or squamous cell 
carcinoma of the skin that has been excised and is considered cured and in situ 
carcinoma of the cervix treated with apparent success by curative therapy more than 
1 year prior to screening are not exclusionary. 
Participants should follow local, age-appropriate cancer screening recommendations. 
Guidelines for management of participants who develop malignancies are provided in 
Table A6-1.  Refer to the Fenebrutinib Investigator’s Brochure for further details.  
A61.11 
EMBRYO-FETAL TOXICITY 
Based on data from animal models, fenebrutinib is currently classified as a suspected 
teratogen.  Fetal malformations, including domed heads, considered the result of dilated 
ventricles in the brain, and multiple malformations (gastroschisis and cardiovascular 
malformations) in one animal were seen in rabbits in the Segment II studies.  In rats, 
cleft palate and fetal skeletal variations consisting of changes in the numbers of 
ossification sites (increased thoracic vertebrae; reduced lumbar vertebrae) contributed to 
an increased number of ribs that were seen in the Segment II studies.  Maternal toxicity, 
consisting of body weight changes (i.e., reduced gain or loss) and reduced food 
consumption was observed in rabbit does and rat dams.  Seven pregnancies have 
occurred in women enrolled in clinical trials of fenebrutinib.  There have been no reports 
to date of fetal malformations.  Fenebrutinib should not be administered to pregnant 
women or to women trying to become pregnant (see Section 5.1 and Section 4.1 for 
details).  See Section 5.2 and Section 4.1 for details for women who are pregnant, 
nursing (breastfeeding), or intending to become pregnant.  All participants must adhere 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
113/Protocol GN43271, Version 3 
to the protocol contraception guidelines. For pregnancy testing requirements and 
contraceptive guidelines, see Section 5.1 and Section 4.1.  
See Section 5.3.4 for male contraception requirements.  
Refer to the Fenebrutinib Investigator’s Brochure for further details.  
A62. 
MANAGEMENT OF PARTICIPANTS WHO EXPERIENCE 
ADVERSE EVENTS 
A62.1 
DOSE MODIFICATIONS 
Dose modifications are not allowed. 
A62.2 
TREATMENT INTERRUPTION 
Fenebrutinib may be withheld in participants who experience toxicity considered to be 
related to study drug.  If fenebrutinib has been withheld for  28 days because of toxicity, 
the participant should be discontinued from fenebrutinib, unless resumption of treatment 
is approved by the investigator following consultation with the Medical Monitor.  
Fenebrutinib may be withheld for reasons other than toxicity (e.g., surgical procedures) 
at the investigator’s discretion following consultation with the Medical Monitor.  The 
investigator may consult  the Medical Monitor to determine the acceptable length of 
treatment interruption. 
A62.3 
MANAGEMENT GUIDELINES 
All participants in the study should be monitored for fever and potential infectious 
complications, including opportunistic infections and tuberculosis, and should be 
evaluated promptly.  Participants should be advised to seek immediate medical attention 
if they develop signs and symptoms suggestive of an infection. 
Participants will be asked to promptly report to the investigator any episode of jaundice, 
dark urine, or severe abdominal symptoms. 
Participants will be asked to promptly report to the investigator any bleeding events.  
Guidelines for management of specific adverse events provided in the subsections 
below are for guidance purposes only and are not intended to supersede the medical 
opinion of the treating investigator. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
114/Protocol GN43271, Version 3 
Table A6-1 Guidelines for Management of Participants Who Experience 
Adverse Events 
Event 
Action to Be Taken 
Infection a 
Serious Infection 
 Withhold study drug during antimicrobial//antiviral treatment.   
 Study drug may resume following full clinical resolution and 
re-assessment of benefit-risk for the treated patient. 
Bleeding events 
Grade 1 or 2 
 Maintain study drug dosing. 
Grade  3 
 For Grade  3 bleeding events, withhold study drug and initiate 
emergency therapy according to institutional guidelines.   
Study drug may be resumed after the event resolves. 
Neutropenia b 
Grade 1 
(ANC  LLN1500/mm3) or 
2 (ANC  15001000/mm/mm3) 
 Maintain study drug dosing. 
Grade 3: 
ANC  1000500/mm3 
 For the first event, hold study drug and recheck CBC in 7 days.   
 If neutrophil count has recovered to Grade 1 ( 1500/mm3) or has 
returned to the normal range, study drug can be resumed.   
 Discontinue study drug if event persists more than one month or 
event reoccurs.  
Grade 4: ANC  500 mm3 
 Discontinue study drug. 
Thrombocytopeniac 
Grade 1: PLT 
 LLN75,000/mm3 
 In the absence of bleeding event(s), maintain study drug dosing. 
Grade 2: 
PLT  75,00050,000/mm3 
 For the first event, hold study drug and recheck CBC in 7 days. 
  If platelet count has recovered to Grade 1 or has returned to the 
normal range, study drug can be resumed.   
 Discontinue study drug if event persists more than one month or 
event reoccurs. 
Grade  3: PLT  50,000/mm3 
 Discontinue study drug. 
Malignancy 
Any malignancy 
 Discontinue study drug with the exception of non-serious local 
and resectable basal or squamous cell carcinoma of the skin. 
 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
115/Protocol GN43271, Version 3 
Table A6-1 Guidelines for Management of Participants Who Experience 
Adverse Events (cont.) 
Event 
Action to Be Taken 
Liver function test elevation 
AST or ALT  3.05.0  ULN 
 Repeat testing of ALT, AST, ALP, total and direct bilirubin, GGT, 
CPK, LDH, complete blood count with differential, coagulation 
tests, and the “LFT unscheduled” lab kit within 4872 hours; 
inquire about symptoms, co-medications, co-morbidities, and 
alternative causes (refer to Appendix 7).  The medical monitor 
will provide guidance on additional lab testing that may be 
required. 
 If ALT or AST  3  ULN is confirmed on repeat testing, continue 
close observation (repeat testing of ALT, AST, ALP, and total 
bilirubin) every 4872 hours until transaminases stabilize, then 
weekly until AST and ALT  3  ULN.  Maintain study drug 
dosing.  
 If study drug was stopped, re-challenge is allowed.  
 Permanently discontinue study drug if AST or ALT  3.0  ULN 
persists for 4 weeks in absence of alternative etiology or if close 
observation is not possible. 
 Record as an adverse event.  
AST or ALT  5.08.0  ULN 
 Repeat testing of ALT, AST, ALP, total and direct bilirubin, GGT, 
CPK, LDH, complete blood count with differential, coagulation 
tests, and the “LFT unscheduled” lab kit within 4872 hours; 
inquire about symptoms, co-medications, co-morbidities, and 
alternative causes (refer to Appendix 7).  The medical monitor 
will provide guidance on additional lab testing that may be 
required. 
 Continue close observation (repeat testing of ALT, AST, ALP, and 
total bilirubin) every 4872 hours until transaminases stabilize, 
then weekly until AST and ALT  3  ULN.   
 Discontinue study drug if AST or ALT  5  ULN persist more than 
2 weeks or if close observation is not possible.  
 Re-challenge is not permitted.   
 Report as an adverse event of special interest within 24 hours. 

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
116/Protocol GN43271, Version 3 
Table A6-1 Guidelines for Management of Participants Who Experience 
Adverse Events (cont.) 
AST or ALT  8.0  ULN 
 Permanently discontinue study drug.   
 Repeat testing of ALT, AST, ALP, total and direct bilirubin, GGT, 
CPK, LDH, complete blood count with differential, coagulation tests 
and the “LFT unscheduled” lab kit within 4872 hours; inquire 
about symptoms, co-medications, co-morbidities, and alternative 
causes (refer to Appendix 7).  The medical monitor will provide 
guidance on additional lab testing that may be required. 
 Continue close observation (repeat testing of ALT, AST, ALP, and 
total bilirubin) every 4872 hours until transaminases stabilize, then 
weekly until AST and ALT  3  ULN.  
 Report as an adverse event of special interest within 24 hours.  
AST or ALT  3  ULN in 
combination with fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, or 
eosinophilia ( 5%) 
 Permanently discontinue study drug.   
 Repeat testing of ALT, AST, ALP, total and direct bilirubin, GGT, 
CPK, LDH, complete blood count with differential, coagulation 
tests, and the “LFT unscheduled” lab kit within 4872 hours; 
inquire about symptoms, co-medications, co-morbidities, and 
alternative causes (refer to Appendix 7).  The medical monitor will 
provide guidance on additional lab testing that may be required. 
 Continue close observation (repeat testing of ALT, AST, ALP, and 
total bilirubin) every 4872 hours until transaminases stabilize, then 
weekly until AST and ALT  3  ULN.  
 Record as an adverse event or an adverse event of special interest 
as appropriate.  

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
117/Protocol GN43271, Version 3 
Table A6-1 Guidelines for Management of Participants Who Experience 
Adverse Events (cont.) 
AST or ALT  3  ULN in 
combination with a total 
bilirubin  2  ULN or 
INR  1.5, or clinical jaundice 
 Permanently discontinue study drug.   
 Rapid evaluation, including repeat testing of ALT, AST, ALP, total 
and direct bilirubin, GGT, CPK, LDH, complete blood count with 
differential,coagulation tests, and the “LFT unscheduled” lab kit 
within 48-72 hours; inquire about symptoms, co-medications, co-
morbidities, and work-up for alternative etiologies, and hepatology 
or subspecialist consultation is required (refer to Appendix 7).  
The medical monitor will provide guidance on additional lab testing 
that may be required. 
 Continue close observation (repeat testing of ALT, AST, ALP, 
and total bilirubin) every 48-72 hours until transaminases 
stabilize, then weekly until AST and ALT  < 3 ´ ULN.  
 Report as an adverse event of special interest within 24 hours, 
(see Section 8.3.8).  
ALT and/or AST  3-
5  ULN, INR > 1.5, total 
bilirubin    2 ´ ULN, and 
absence of clinical jaundice 
 Permanently discontinue study drug.   
 Rapid evaluation, including repeat testing of ALT, AST, ALP, 
total and direct bilirubin, GGT, CPK, LDH, complete blood count 
with differential,coagulation tests, and the “LFT unscheduled” 
lab kit within 48-72 hours; inquire about symptoms, co-
medications, co-morbidities, and work-up for alternative 
etiologies, and hepatology or subspecialist consultation is 
required (refer to Appendix 7).  The medical monitor will provide 
guidance on additional lab testing that may be required. 
 Continue close observation (repeat testing of ALT, AST, ALP, 
and total bilirubin) every 48-72 hours until transaminases 
stabilize, then weekly until AST and ALT  < 3 ´ ULN.  
 Report as an adverse event of special interest within 24 hours, 
(see Section 8.3.8). 
LFT  liver function test; LLN  lower limit of normal; PLT   platelet count; ULN  upper limit of 
normal  
a Appropriate laboratory investigations, including but not limited to cultures, should be performed to 
establish the etiology of any serious infection. 
b Patients withdrawn from the study because of a reduced neutrophil count must be followed 
closely for signs of infection, with treatment as deemed appropriate by the investigator, and must 
have a repeat WBC count with differential performed weekly until the ANC is above 
1000 cells/mm3 (1.0  109/L).  If the ANC does not return to above 1000 cells/mm3 (1.0  109/L) 
within 2 months (or sooner if deemed necessary by the investigator), a hematology referral is 
recommended. 
c Patients withdrawn from the study because of a reduced platelet count must have a repeat 
platelet count checked weekly until the count is above 100,000 cells/mm3 (100  109/L).  
Additional management and treatment should be as deemed appropriate by the investigator.  If 
the platelets do not return to above 100,000 cells/mm3 (100  109/L) within 2 months (or sooner if 
deemed necessary by the investigator), a hematology referral is recommended. 
  

Appendix 6:  Safety Plan:  Management of Identified and Potential Risks 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
118/Protocol GN43271, Version 3 
A62.4 MANAGEMENT OF INCREASES IN QT INTERVAL 
Study drug should be discontinued in participants who develop any of the following, 
unless there is a clear alternative cause for the changes: 
 
Sustained (at least two ECG measurements  30 minutes apart) QT interval 
corrected through use of Fridericia's formula (QTcF) that is  500 ms and/or  60 ms 
longer than the baseline value 
 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  In 
such a situation, saving all available ECG data is highly suggested. 
Management of participants with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such participants. 
 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
119/Protocol GN43271, Version 3 
Appendix 7  
Guidance for Recording Information in eCRFs for Participants with Abnormal Liver Enzyme and Function Tests 
For any patient with ALT/AST  > 3 ´ ULN, please ask the questions below and record the relevant information in the appropriate eCRF.   
Liver Related Signs and Symptoms 
1).  Does the subject have any of the following liver-related signs and symptoms?: 
If “Yes” to Question 1:, if ALT/AST >5 x ULN, 
please report each symptom on the DILI Signs and 
Symptoms eCRF. 
If ALT/AST > 3 and   5 ´ ULN, please report each 
sign and symptom in the additional case details of 
the Abnormal Liver Enzyme Adverse Event eCRF 
(unless a specific diagnosis has been established 
that accounts for the symptom, in which case the 
specific diagnosis should be recorded). 
 
a) Fever  
b) Nausea 
c) Vomiting  
d) Abdominal pain  
e) Abdominal tenderness  
f) Joint pain/ arthralgia  
g) Joint swelling  
h) Rash  
i) Urticaria  
j) Mucosal inflammation or ulceration  
k) Asterixis  
l) Confusion/ disorientation  
m) Coma  
n) Jaundice  
o) Ascites  
p) Peripheral oedema  
q) Palmar erythema  
r) Fatigue  
s) Lymphadenopathy  
t) Dark urine  
u) Other liver-related signs or symptoms  

Appendix 7: Guidance for Recording Information in eCRFs for Patients with Abnormal Liver Enzyme and 
Function Tests cont. 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
120/Protocol GN43271, Version 3 
Medical history: Liver-Related Diseases 
2. Does the subject have a history of any of the following? 
If “Yes” to question 2:   
please report each liver-related disease on the 
Medical History/Baseline conditions eCRF as per 
protocol  Section 8.2.1 
a)  Hepatitis A 
b)  Hepatitis B 
c)  Hepatitis C 
d) Hepatitis D 
e)  Hepatitis E 
f) Autoimmune hepatitis  
g) Haemochromatosis 
h) Non-alcoholic fatty liver disease (NAFLD) 
i) Non-alcoholic steatohepatitis (NASH) 
j) Gallbladder disease  
   (e.g., gallbladder stones, cholecystitis, bile duct stones) 
k) Alcohol-related liver disease  
   (e.g., alcohol related cirrhosis, alcohol related hepatitis, steatosis) 
l) Drug-induced liver injury (DILI)   
   (Specify suspected drugs) 
m) Jaundice or hyperbilirubinaemia 
n) HIV infection 
o) Tuberculosis 
p) Congestive heart failure 
q) Right heart failure 
r) Hepatic metastasis 
s) Diabetes 
t) Inflammatory bowel disease  
   (Crohn's disease or ulcerative colitis) 
u) Hypotension 

Appendix 7: Guidance for Recording Information in eCRFs for Patients with Abnormal Liver Enzyme and 
Function Tests cont. 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
121/Protocol GN43271, Version 3 
v) Systemic infection or sepsis 
w) Seizures 
x) Recent drop in blood pressure or shock 
y) Herpes infection 
z) Uncontrolled diabetes mellitus 

Appendix 7: Guidance for Recording Information in eCRFs for Patients with Abnormal Liver Enzyme and 
Function Tests cont. 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
122/Protocol GN43271, Version 3 
 
Risk Factors for Conditions Associated with Liver Disease 
Has any of the following occurred within 1 week before the hepatic event? 
 
3. Did the subject engage in vigorous physical exercise? 
If ”Yes”’ for Question 3, please record in the “Additional Case Details” 
field of the hepatic adverse event that was reported. 
4. Has the subject taken acetaminophen (paracetamol)?  
If ”Yes” for Questions 4-6: 
please report on the Concomitant Medications eCRF (as per protocol 
Section 6.8). 
5. Have any other new medications or supplements been taken? 
6. Did the subject eat wild mushrooms? 
Has any of the following occurred within 3 months before the hepatic event? 
 
7. Has the subject gained or lost weight considered to be clinically significant? 
If ”Yes” for Question 7:  
please report on an Adverse Event eCRF (unless a diagnosis of liver injury 
has been established). 
8. Has the subject consumed alcohol? 
If ”Yes” for Question 8: 
please complete the Alcohol Use History eCRF. 
 
Please use chart when providing units in the Alcohol Use History eCRF 
9. Has the subject been exposed to an environmental or industrial toxin or a 
chemical agent? 
If ”Yes” for Question 9, please record in the “Additional Case Details” 
field of the hepatic adverse event that was reported. 
10. Has the subject received parenteral nutrition? 
If ”Yes” for questions 10, please report on the On Study Surgery and 
Procedure eCRF 

Appendix 7: Guidance for Recording Information in eCRFs for Patients with Abnormal Liver Enzyme and 
Function Tests cont. 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
123/Protocol GN43271, Version 3 
11. Has the subject used recreational drugs or injection drugs? 
a) Methamphetamines 
b) Cocaine 
c) Ecstasy 
d) Ketamine 
e) Narcotics 
f) Other, specify 
If “Yes” for Question 11, please report on the Concomitant Medications 
eCRF. 
 
12. Has the subject had a blood transfusion?  
If “Yes” for Question 12, please record on the On Study Surgery and 
procedures eCRF. 
 
Please add any other risk factors to the Additional Case Details and Event Narrative field in the Adverse Event eCRF reporting elevated liver enzymes. 
 
 
Hepatic Imaging Studies 
13.  Were imaging studies performed? 
 
Magnetic resonance imaging (MRI)/ magnetic resonance 
cholangiopancreatography  (MRCP)  
 
Abdominal ultrasound  
 
CT scan  
 
ERCP (Endoscopic retrograde cholangiopancreatography)  
If “Yes” for Question 13, please report in the On Study Surgery and 
Procedures eCRF and see Question 14 below 
14.  Were any abnormalities noted on an imaging study? 
If “Yes” to Question 14, please report on an Adverse Event eCRF (unless 
a specific diagnosis has been established that accounts for the imaging 
finding, in which case the specific diagnosis should be recorded) 
  
Liver biopsy 
15. Was a liver biopsy performed? 
If “Yes” for Question 15, please report in the On Study Surgery and 
Procedures eCRF and see Question 16 below 
16. Were any abnormalities noted on the liver biopsy? 
If “Yes” for Question 16, Please report on an Adverse Event eCRF (unless a 
specific diagnosis has been established that accounts for the imaging finding, 
in which case the specific diagnosis should be recorded). 
 
Family History 
17. Do any of the subject's first-degree relatives have a-1 antitrypsin deficiency, 
hereditary haemochromatosis, or autoimmune liver disease? 
If Yes for Question 17, please record in the “Additional Case Details” 
field of the hepatic adverse event that was reported. 
 

Appendix 7: Guidance for Recording Information in eCRFs for Patients with Abnormal Liver Enzyme and 
Function Tests cont. 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
124/Protocol GN43271, Version 3 
Local Laboratory Tests 
Hepatic tests should be monitored during the event (as per Table 1 of the Safety Monitoring Plan (see Appendix 6) until resolution or return to baseline 
levels, regardless of whether the study drug is continued or not. 
18. Were local laboratory tests 
performed? 
If “Yes” for Question 18,  please provide results of laboratory tests with reference ranges on the adverse event 
eCRF when applicable. 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
125/Protocol GN43271, Version 3 
Appendix 8 
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy 
ACTION STEPS IF PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY IS SUSPECTED 
Participants with suspected progressive multifocal leukoencephalopathy (PML), defined 
as a new or worsening neurological symptom that necessitates magnetic resonance 
imaging (MRI) and/or lumbar puncture and cerebrospinal fluid (CSF) analyses to rule 
out PML, should be withheld from study treatment until PML is ruled out by complet e 
serial clinical evaluations and appropriate diagnostic testing.  The Medical Monitor 
should be contacted by email and should be immediately contacted by telephone. 
If the clinical presentation is suggestive of PML, further investigations should include 
brain MRI evaluation as soon as possible.  If MRI evaluation reveals lesions suspicious 
for PML (see Figure A8-1), a lumbar puncture with evaluation of the CSF for the 
detection of JC virus (JCV) DNA using a validated sensitive assay should be 
undertaken.  A diagnosis of PML can potentially be made by evaluating clinical and MRI 
findings plus the identification of JCV in the CSF (see Table A8-1). 
There is no known treatment or cure for PML.  Treatment considerations are discussed 
in the medical literature (Calabrese et al. 2007) 
MRI ASSESSMENT 
Although there are no pathognomonic findings that differentiate PML from multiple 
sclerosis (MS), a brain MRI scan that includes fluid-attenuated inversion recovery 
(FLAIR) and T2-weighted and T1-weighted sequences, with and without gadolinium 
(Gd), should be performed to assess participants with neurological changes suggestive 
of PML (see Figure A8-1). 
Comparison with a baseline scan may assist with interpretation of the findings on the 
newly acquired MRI scan (see Table A8-2) for differences in lesion characteristics that 
may help differentiate between PML and MS). 
CSF ASSESSMENT 
The detection of JCV DNA in the CSF of a patient with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML. 
If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, 
a repeat lumbar puncture should be performed. 
If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may 
be considered to establish a definitive diagnosis. 

Appendix 8: Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
127/Protocol GN43271, Version 3 
Table A8-1 Clinical Signs and Symptoms Typical of MS and PML 
Onset 
MS 
PML 
Acute 
Subacute 
Evolution 
 
Over hours to days 
 
Normally stabilized 
 
Resolve 
spontaneously even 
without therapy 
 
Over weeks 
 
Progressive 
Clinical 
presentation 
 
Diplopia 
 
Paresthesia 
 
Paraparesis 
 
Optic neuritis 
 
Myelopathy 
 
Cortical symptoms/signs 
 
Behavioral and neuropsychological 
alteration 
 
Retrochiasmal visual defects 
 
Hemiparesis 
 
Cerebellar symptoms/signs (e.g., gait 
abnormalities, limb incoordination)  
MS  multiple sclerosis; PML  progressive multifocal leukoencephalopathy. 
Source:  Adapted from Kappos et al. 2007. 
 
Table A8-2 MRI Lesion Characteristics Typical of PML and MS 
Feature 
MS (relapse) 
PML 
Location of new 
lesions 
Mostly focal; affect entire brain 
and spinal cord, in white and 
possibly gray matter 
Diffuse lesions, mainly subcortical and 
rarely periventricular, located almost 
exclusively in white matter, although 
occasional extension to gray matter has 
been seen; posterior fossa frequently 
involved (cerebellum) 
Borders 
Sharp edges; mostly round or 
finger-like in shape (especially 
periventricular lesions), 
confluent with other lesions; 
U-fibers may be involved 
Ill-defined edges; irregular in shape; 
confined to white matter; sparing gray 
matter; pushing against the cerebral cortex; 
U-fibers destroyed 
Mode of extension Initially focal; lesions enlarge 
within days or weeks and later 
decrease in size within months 
Lesions are diffuse and asymmetric, 
extending homogeneously; no confluence 
with other lesions; confined to white-matter 
tracks, sparing the cortex; continuous 
progression 
Mass effect 
Acute lesions show some mass 
effect 
No mass effect even in large lesions (but 
lesion slightly abuts cerebral cortex) 
 

Appendix 8: Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
128/Protocol GN43271, Version 3 
Table A8-2 MRI Lesion Characteristics Typical of PML and MS - (cont.) 
Feature 
MS (relapse) 
PML 
On T2-weighted 
sequence 
 
Acute lesions: 
hyperintense center, 
isointense ring, discrete 
hyperintensity outside the 
ring structure 
 
Subacute and chronic 
lesions: hyperintense with 
no ring structure 
Diffuse hyperintensity, slightly increased 
intensity of newly involved areas compared 
with old areas, little irregular signal intensity 
of lesions 
On T1-weighted 
sequence 
Acute lesions: densely 
hypointense (large lesions) or 
isointense (small lesions); 
increasing signal intensity over 
time in 80%; decreasing signal 
intensity (axonal loss) in about 
20%  
Slightly hypointense at onset, with signal 
intensity decreasing over time and along 
the affected area; no reversion of signal 
intensity 
On FLAIR 
sequence 
Hyperintense, sharply 
delineated 
Hyperintensity more obvious; true extension 
of abnormality more clearly visible than in 
T2-weighted images 
With enhancement 
 
Acute lesions: dense 
homogeneous 
enhancement, sharp 
edges 
 
Subacute lesions: ring 
enhancement 
 
Chronic lesions: no 
enhancement 
Enhancement is possible, particularly in 
natalizumab-associated PML (Maas et al. 
2016); in participants with HIV, some 
peripheral enhancement is possible, 
especially under therapy 
Atrophy 
Focal atrophy possible due to 
focal white-matter 
degeneration; no progression 
No focal atrophy 
FLAIR  fluid-attenuated inversion recovery; MS  multiple sclerosis; PML  progressive multifocal 
leukoencephalopathy. 
Source:  Adapted from Yousry TA et al. 2006. 
 

Appendix 8: Guidance for Diagnosis of Progressive Multifocal Leukoencephalopathy 
 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
129/Protocol GN43271, Version 3 
REFERENCES: 
Berger JR, Aksamith A, Clifford DB. PML diagnostic criteria: consensus statement from 
the AAN Neuroinfectious Disease Section. Neurology 2013:80;143038. 
Calabrese LH, Molloy ES, Huang D, et al. Progressive multifocal leukoencephalopathy in 
rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis 
Rheum 2007;56:211628. 
Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: 
recommendations for patient selection and monitoring. Lancet Neurol 
2007;6:43141. 
Maas RP, Muller-Hansma AH, Esselink RA, et al. Drug-associated progressive 
multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid 
analysis of 326 cases. J Neurol 2016;263:200421. 
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of participants treated with 
natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 
2006:354;92433.

 
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Appendix 9 
Columbia-Suicide Severity Rating Scale 
Baseline/Screening Version and Since Last Visit Version 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study. 
 

Appendix 9:  Columbia-Suicide Severity Rating Scale Baseline/Screening Version and 
Since Last Visit Version  
  
Fenebrutinib—F. Hoffmann-La Roche Ltd 
131/Protocol GN43271, Version 3 

Appendix 9:  Columbia-Suicide Severity Rating Scale Baseline/Screening Version and 
Since Last Visit Version  
  
Fenebrutinib—F. Hoffmann-La Roche Ltd 
132/Protocol GN43271, Version 3 

Appendix 9:  Columbia-Suicide Severity Rating Scale Baseline/Screening Version and 
Since Last Visit Version  
  
Fenebrutinib—F. Hoffmann-La Roche Ltd 
133/Protocol GN43271, Version 3 

Appendix 9:  Columbia-Suicide Severity Rating Scale Baseline/Screening Version and 
Since Last Visit Version  
  
Fenebrutinib—F. Hoffmann-La Roche Ltd 
134/Protocol GN43271, Version 3 

Appendix 9:  Columbia-Suicide Severity Rating Scale Baseline/Screening Version and 
Since Last Visit Version  
  
Fenebrutinib—F. Hoffmann-La Roche Ltd 
135/Protocol GN43271, Version 3 

 
Fenebrutinib—F. Hoffmann-La Roche Ltd 
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Appendix 10 
Telephone Interviews 
The purpose of the semi-structured interview is to identify and collect information on any 
changes in the participant’s health status that may warrant an unscheduled visit (e.g., 
new or worsening neurological symptoms, suspected unplanned pregnancy).  The 
telephone interview will be conducted by treating team personnel familiar with the 
participant(s) (see Table 2). 
The questions below will be asked and the participant’s answers during the telephone 
interview will be recorded: 
1. 
Since your last visit or telephone interview, have you had any new or worsening 
neurological symptoms (such as sudden changes in your thinking, alterations in 
your thinking, alterations in your behavior, visual disturbance, extremity weakness, 
limb coordination problems or gait abnormalities) that have persisted over more than 
one day? 
2. 
Since your last visit or telephone interview, have you had any new or worsening 
medical problems? 
3. 
How do you feel overall? Have you lost your appetite, are you nauseous, fatigued, 
have changes in your sleep patterns? 
4. 
Since your last visit or telephone interview, have you had any infections or signs 
suggestive of infection, such as fever, headache, sore throat, cough, altered 
digestive transit, and/or burning sensation while urinating? 
5. 
For female participants, since your last visit or telephone interview, have you had a 
positive urine pregnancy test? 
6. 
Since your last visit or telephone interview, have you taken any new medicines 
(including medicines to treat multiple sclerosis, steroid medicines, or medicines that 
reduce the acid in your stomach)? 
 
If the participant answered YES to any question, discuss and review the participant’s 
answer(s) with the treating investigator.  If warranted, the participant should return for 
an unscheduled visit.  If an unplanned pregnancy is suspected, an unscheduled visit to 
confirm the pregnancy is required. 
All relevant information should be recorded in the appropriate electronic Case 
Report Form. 

 
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Appendix 11  
Investigational Medicinal Product and Non-Investigational Medicinal 
Product Designations (for Use in European Economic Area and 
United Kingdom) 
Table 1 Investigational, Authorized Auxiliary, and Unauthorized Auxiliary 
Medicinal Product Designations for European Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing 
Authorization Status 
in EEA  
Used within 
Marketing 
Authorization 
Fenebrutinib 
IMP (test product)  
Not Authorized 
Not applicable 
Placebo 
IMP (Placebo)  
Not Authorized 
Not applicable 
EEA = European Economic Area; IMP = investigational medicinal product; AxMP = 
authorised auxillary medicinal product. 
  
Table 2 Investigational and Non-Investigational Medicinal Product 
Designations for European Economic Area /and/ United Kingdom 
Product Name 
IMP/NIMP Designation 
Marketing 
Authorization Status 
in U.K.  
Used within 
Marketing 
Authorization 
Fenebrutinib 
IMP (test product)  
Not Authorized 
Not applicable 
Placebo 
IMP (Placebo)  
Not Authorized 
Not applicable 
EEA = European Economic Area; IMP = investigational medicinal product; NIMP = non-
investigational medicinal.  
 

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Appendix 12 
Protocol Amendment History 
A rationale for the current amendment precedes the Table of Contents. 
PROTOCOL AMENDMENT, VERSION 2:  13 JULY 2021 
Protocol GN43271 has been amended to provide additional guidance on safety 
reporting, and eligibility criteria.  Substantive changes to the protocol, along with a 
rationale for each change, are summarized below. 
 
The following changes have been added to clarify the reporting procedures for 
cases of transaminase increases: 
– 
Text has been added to specify that all laboratory reports of ALT or AST  3  
upper limit of normal (ULN) are to be reported as adverse events 
(Sections 8.2.4, A31, A37.4, A37.6, and Table A61).  
– 
Text has been added to specify that all laboratory reports of ALT or AST  5  
ULN are to be reported as Adverse Events of Special Interest (Sections 8.3.8, 
A37.6, A61.1, and Table A61). 
– 
The Schedule of Activities has been updated to include elevated ALT or AST  
3  ULN as a clinically appropriate reason for an unscheduled visit to be 
performed.  
 
The pharmacokinetic and biomarker samples and collection timepoints have been 
updated in the Schedule of Activities and Pharmacokinetic and Biomarker Samples 
for Open-Label Extension Phase (Section 1.3, Tables 2 and 3).  
 
Details regarding the administration of Coronavirus disease 2019 vaccines were 
added to provide clarity (Section 2.3).  
 
The exclusion criterion regarding a white blood cell count of  4000 cells/mm3 (L) 
was changed to  2000 cells/mm3 (L) as a more appropriate critically low value 
(Section 5.2).  
 
QFT test only screening procedure for patients with a history of Bacille 
Calmette-Guérin vaccination was removed from the exclusion criterion for patients 
with active or latent or inadequately treated infection with tuberculosis (Section 5.2) 
because QFT is the only testing option for all patients. 
 
The eligibility requirement on disease-modifying therapy washout periods prior to 
study entry was amended to unify across different drug labels/countries and account 
for the long term pharmacodynamic effect of selected treatments (Section 5.2).   
– 
Exclusion criterion was revised to reduce previous use of fingolimod, 
siponimod, ozanimod, or ponesimod from 8 to 6 weeks prior to randomization 
(Section 5.2).   
– 
Exclusion criterion was revised to remove previous use of natalizumab for more 
than 1 year prior to randomization (Section 5.2). 

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139/Protocol GN43271, Version 3 
 
Text regarding screen failure and re-screening has been revised to clarify that 
medical monitor permission is required to re-screen a patient more than once 
(Section 5.4).  
 
Text has been updated to clarify the regulatory requirements for substantial 
amendments  and to align with the current Roche process (Section A11). 
 
Text has been updated to clarify platelet count ranges for adverse event 
management of thrombocytopenia (Appendix 6, Table A61).   
 
The EUDRACT number was corrected to update a mistake in the first request in the 
title page. 

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Appendix 13 
Abbreviations 
Abbreviation or Term 
Definition 
ATP 
adenosine triphosphate 
BCRP 
breast cancer resistance protein 
BTK 
Brutons tyrosine kinase 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CTR 
Clinical Trial Regulation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSU 
chronic spontaneous urticaria 
D/C 
discontinuation 
DBT 
double blind trial 
DMT 
disease modifying therapies 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDSS 
expanded disability status scale 
FSS 
functional systems score 
Gd 
gadolinium 
H2RA 
H2 receptor agonist 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IxRS 
interactive voice or web-based response 
system 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 

Fenebrutinib—F. Hoffmann-La Roche Ltd 
141/Protocol GN43271, Version 3 
Abbreviation or Term 
Definition 
NfL 
neurofilament light chain 
NGS 
next-generation sequencing 
OLE 
open label extension 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PPI 
proton pump inhibitor 
PPMS 
primary progressive MS 
QTcF 
QT interval corrected through use of 
Fridericia's formula 
RA 
rheumatoid arthritis 
RBR 
Research Biosample Repository 
RMS 
relapsing MS 
RRMS 
relapsing remitting MS 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome 
coronavirus 2 
SFU 
safety follow up 
SLE 
systemic lupus erythematosus 
SPMS 
secondary progressive MS 
T1Gd 
T1-weighted gadolinium-enhancing 
TB 
tuberculosis 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 

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