Conditions: Autoimmune Disorder Rheumatoid Arthritis Systemic Lupus Erythematosus Primary Sjögren's Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and effectiveness of treatment with branebrutinib treatment in participants with active systemic Lupus Erythematosus (SLE) or Primary Sjögren's Syndrome (pSS), or branebrutinib treatment followed by open-label abatacept treatment in study participants with active Rheumatoid Arthritis (RA).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None

Interventions: intervention 1: branebrutinib intervention 2: abatacept intervention 3: branebrutinib placebo
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Assess the Efficacy and Safety of 
Branebrutinib Treatment in Subjects with Active Systemic Lupus Erythematosus or Primary Sjögren’s 
Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept Treatment in Subjects with 
Active Rheumatoid Arthritis 
 
PROTOCOL(S) IM014-029 
 
NCT Number: NCT04186871 
  
Document Date (Date in which document was last revised): December 01, 2021 


Page: 1 
Protocol Number: IM014029 
IND Number: 142401 
EX-US Non-IND 
EUDRACT Number: 2019-002205-22 
Date: 01-Jul-2019
Revised Date: 01-Dec-2021
Clinical Protocol IM014029 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Assess the Efficacy and 
Safety of Branebrutinib Treatment in Subjects with Active Systemic Lupus Erythematosus or 
Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept 
Treatment in Subjects with Active Rheumatoid Arthritis 
Protocol Amendment 04 
Study Director 
Medical Monitor 
 
 
Bristol Myers Squibb Company 
556 Morris Avenue, Building S5 
Summit, NJ 07901 
 
 
 
Telephone (office): 
 
Email: 
 
Medical Monitoring Support Center 
Telephone (office): 
 
Mobile: 
 
Fax:
 
Email: 
 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol Myers Squibb Company
3401 Princeton Pike 
Lawrenceville, NJ 08648 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure, or dissemination of this information is strictly prohibited unless expressly 
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Protocol Amendment No.: 04 
Date: 01-Dec-2021 
2 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization. 
© 2020 Bristol Myers Squibb Company 
 
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Clinical Protocol 
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Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
3 
DOCUMENT HISTORY 
Document 
Date of Issue 
Approver(s) 
Summary of Change 
Protocol 
Amendment 04 
01-Dec-2021 
 
 
 
 
 
Bristol Myers Squibb 
Changed timing for primary endpoint and other 
efficacy, safety, PK, and PD analysis for the RA 
sub-protocol; included patient-reported outcome 
assessments as Additional endpoints in all 3 
sub-protocols; updated unintentionally omitted 
changes in inclusion criteria in RA sub-protocol 
schema; added information from Administrative 
Letter 03, Administrative Letter 04 FR, and 
Administrative Letter 05; clarified PK and 
biomarker blood samples to be collected for 
abatacept and branebrutinib, respectively, at 
Week 24 in the RA sub-protocol
 
 
; corrected an 
inclusion criterion numbering error in the 
previous version of the RA sub-protocol; and 
removed unintentionally retained subject 
assessment of pain in Section 9.3.3 of the RA 
sub-protocol. 
Revised Protocol 
03 
30-Mar-2021 
 
 
 
 
 
Bristol Myers Squibb 
Removed Study Acknowledgment/Disclosure 
page; added number of subjects that have 
received at least 1 dose of branebrutinib; added 
section for study termination for unexpectedly 
unfavorable risk/benefit balance; added 
information/guidance related to SARS-CoV-2 
infection/COVID-19 pandemic, including 
vaccines (also included for influenza), titers, 
serology, exploratory endpoints, and exclusion 
criteria; changed the maximum age of the study 
population; clarified CS requirements (SLE 
sub-protocol only); excluded subjects with 
diagnosis of antiphospholipid syndrome from 
SLE sub-protocol; clarified LTBI prestudy 
treatment requirements; deleted all references to 
legally acceptable/ 
authorized representative or legal guardian; 
clarified all instances in which branebrutinib may 
be discontinued permanently or temporarily at the 
discretion of the investigator/Medical Monitor; 
added blood pressure hypertension exclusion 
criterion; added information/exclusion criterion 
related to ECGs; removed cerivastatin from 
excluded/restricted medication; referenced 
inclusion criteria sections in Appendix 4 for 
specific requirements for male and female 
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Date: 01-Dec-2021 
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Document 
Date of Issue 
Approver(s) 
Summary of Change 
contraception; added optional post-hoc 
measurements/analysis/PK sample collection 
timing for concentrations of chronic medications 
that could be sensitive to modulation of 
CYP2C8/P-gp; extended duration after 
completion of IP dosing in which live vaccines 
are prohibited (SLE and pSS sub-protocols); 
clarified permitted and restricted medication 
usage requirements (SLE and pSS sub-protocols); 
clarified at which study visits the study drug is to 
be administered/dispensed at the site; added 
optional salivary/parotid gland biopsy analysis as 
exploratory endpoint (pSS sub-protocol); deleted 
Week 4 postdose PK sample collection for 
branebrutinib (RA sub-protocol); clarified the 
scheduling of EOT and Safety FU visits/ 
assessments required at premature treatment 
and/or study termination; updated required 
washout periods prior to randomization for 
antimalarial drugs; increased time interval 
between RA diagnosis and screening for study 
eligibility; clarified use of first screening MRI 
results for rescreening (RA sub-protocol); 
provided general window for abatacept 
administration during the open-label part of RA 
sub-protocol; rearranged subheadings/streamlined 
assessments in SoA tables/Efficacy Assessments 
section in all 3 sub-protocols; updated language 
and/or figures in clinical efficacy appendices; 
removed Subject-reported Pain Assessment 
appendix for RA; and added Physician Global 
Assessment of Disease Activity appendix for RA. 
Revised Protocol 
02a 
Argentina-Specif
ic 
17-Sep-2020 
  
 
 
 
 
Bristol Myers Squibb 
Updated all sub-protocols in response to ANMAT 
review comments 
Revised Protocol 
02a France- 
Specific 
08-Sep-2020 
  
 
 
 
 
Bristol Myers Squibb 
Updated all sub-protocols in response to French 
CEC review comments 
Revised Protocol 
02b Germany- 
Specific 
20-Aug-2020 
  
 
Updated all sub-protocols in response to BfArM 
review comments 
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Date: 01-Dec-2021 
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Document 
Date of Issue 
Approver(s) 
Summary of Change 
 
Bristol Myers Squibb 
Revised Protocol 
02a Germany- 
Specific 
24-Jun-2020 
 
 
 
 
 
 
Bristol Myers Squibb 
Updated all sub-protocols in response to BfArM 
review comments 
Revised Protocol 
02a UK-Specific 
17-Feb-2020 
 
 
 
 
 
  
Bristol Myers Squibb 
Updated all sub-protocols in response to MHRA 
review comments 
Revised Protocol 
02 Global 
Global Protocol 
v2.0, Revised 
Protocol 2 
Global_Final 
Approved 
18-Dec-2019 
 
Bristol Myers Squibb 
 
 
 
Bristol Myers Squibb 
Updated RA sub-protocol to include omitted joint 
assessor instructions, 
Updated all sub-protocols to current BMS 
standards for reproductive status inclusion criteria 
Global 
Amendment 1 
Global Protocol 
v2.0, Revised 
Protocol 1 
Global_Final 
Approved 
07-Oct-2019 
 
Bristol Myers Squibb 
 
 
 
Bristol Myers Squibb 
Updated RA sub-protocol to exclude combination 
therapy of branebrutinib and abatacept, revised 
timing period for collection of nonserious AEs in 
all sub-protocols, 
updated and aligned branebrutinib PK sampling 
schedule in all sub-protocols to accommodate 
change in RA protocol design 
Original Protocol 
(Version 2.0, 
submitted to 
FDA) 
Original Protocol 
v2.0_Final 
Approved 
01-Jul-2019 
 
 
 
Bristol Myers Squibb 
 
 
 
Bristol Myers Squibb 
Minor editorial changes for consistency 
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Document 
Date of Issue 
Approver(s) 
Summary of Change 
Original Protocol 
(Version 1.0, not 
released) 
Original Protocol 
v1.0_Final 
Approved 
24-Jun-2019 
 
 
 
Bristol Myers Squibb 
 
 
 
Bristol Myers Squibb 
Not applicable 
 
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04 
The primary purpose of this Global Protocol Amendment is to change the timing for primary 
endpoint analysis in the rheumatoid arthritis (RA) sub-protocol to after all subjects have either 
completed Week 12 efficacy assessments or discontinued prior to Week 12, rather than waiting 
for all subjects to either complete Week 24 activities or discontinue prior to Week 24. 
Key additions and clarifications include: 
x Changing timing for primary endpoint and other efficacy, safety, PK, and PD analyses to after 
all subjects in the RA sub-protocol have completed Week 12 efficacy assessments or 
discontinued treatment/study prior to Week 12 
x Including patient-reported outcome assessments as Additional endpoints in all 3 sub-protocols, 
as appropriate 
x Updating unintentionally omitted changes in inclusion criteria in the RA sub-protocol schema 
to match protocol text 
x Clarifying pharmacokinetic (PK) and biomarker blood samples to be collected for abatacept 
and branebrutinib, respectively, at Week 24 in the RA sub-protocol 
x Adding information from Administrative Letter 03 (provided updated Appendix 7 figure for 
proper rendering in the published PDF version), Administrative Letter 04 France (clarified the 
days after randomization within which the initial magnetic resonance imaging screening may 
be used for rescreening, respectively), and Administrative Letter 05 (added unintentionally 
omitted biomarker blood samples to be collected for Bruton’s tyrosine kinase occupancy from 
Week 0 to Week 12 in the RA sub-protocol and aligned SARS-CoV-2 serology collection at 
Week 12 in Table 8 with that in Table 2 of the RA sub-protocol) 
x Correcting an inclusion criterion numbering error in the previous version of the RA 
sub-protocol 
x Removed unintentionally retained subject assessment of pain in Section 9.3.3 of the RA 
sub-protocol 
This protocol amendment will be implemented upon receiving all appropriate Agency and 
Institutional Review Board/Ethics Committee approvals. 
All changes applied to the body were applied to the synopsis, as necessary, and synopsis changes 
are not included in the list below. 
Only major additions and deletions are provided in this summary document, and all minor 
grammatical, formatting, rephrasing, stylistic changes, or clarifications, as well as reorganizational 
changes, are not included. 
The rationales for changes to this Protocol Amendment are provided in the summary of key 
changes table, as shown below: 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section 1.4.6.3: Master Protocol: 
Analysis and Reporting 
Section RA 9.4.4 Analysis and 
Reporting 
Changed timing for primary endpoint and 
other efficacy, safety, PK, and PD analysis to 
after all subjects in the RA sub-protocol have 
completed Week 12 efficacy assessments or 
discontinued treatment/study prior to 
Week 12, as opposed to waiting for all 
subjects to either complete Week 24 
activities or discontinue prior to Week 24. 
Results from the 12-week 
primary endpoint and other 
efficacy, safety, PK, and PD 
analysis is required for timely 
decision-making and planning 
of further branebrutinib 
development in RA. Performing 
this analysis prior to completion 
of the 12-week abatacept 
treatment period will not affect 
the scientific value of the study 
since (i) there are no data 
accruing for primary or 
secondary endpoints after 
Week 12, (ii) the abatacept 
treatment period from Week 12 
to Week 24 is open-label and 
only supports "additional" and 
"exploratory" endpoints, and 
(iii) no change in study conduct 
will accrue from the results of 
the rescheduled 12-week 
primary endpoint analysis. 
Section SLE 3: Objectives and 
Endpoints, SLE Table 3 
Section SLE 9.3.3: Additional 
Endpoints 
Section pSS 3: Objectives and 
Endpoints, pSS Table 3 
Section pSS 9.3.2: Additional 
Endpoints 
Section RA 3: Objectives and 
Endpoints, RA Table 4 
Section RA 9.3.3: Additional 
Endpoints 
To harmonize with text in Section 8 of each 
sub-protocol, patient-reported outcome 
(PRO) assessments were included as 
Additional endpoints in each sub-protocol 
objectives and endpoints table, as follows: 
SLE Sub-protocol 
Patient-Reported Outcomes Measurement 
Information System (PROMIS) Fatigue 6 a 
SLE Pain Numeric Rating Score (NRS) 
pSS Sub-protocol 
PROMIS Fatigue 6 a 
Physician Global Assessment and Subject 
Global Assessment 
NRS for Mouth and Eye Dryness 
RA Sub-protocol 
PROMIS Fatigue 6 a 
PRO assessments were already 
included in the protocol to 
assess critical aspects of 
patient-reported quality of life 
and the data collected; however, 
these assessments were 
unintentionally omitted from 
the list of endpoints in each 
sub-protocol in previous 
protocol amendments. This 
error in the tables is corrected 
in this amendment. No changes 
were made to the actual 
endpoints being assessed in the 
protocol. 
Section RA 1.2: Schema 
Updated the RA sub-protocol schema 
(Section RA 1.2) to accurately reflect 
Inclusion Criterion 3h in Section RA 5.1: 
diagnosis of RA < 4 years before screening 
The previous protocol 
amendment extended the time 
from diagnosis to screening 
from 2 years to 4 years. This 
was mistakenly not updated in 
the schema of Section RA 1.2, 
and is now corrected in this 
amendment. 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 
Section Number & Title 
Description of Change 
Brief Rationale 
Section RA 1.3: Schedule of 
Activities, RA Table 2 
 
 
Added due to unintentional 
omission of these blood sample 
collections in Revised 
Protocol 03 Global. 
Section RA 5.1, 3) Type of 
Subject and Target Disease 
Characteristics: RA Sub-protocol 
Changed repeated inclusion criterion 3)h) to 
3)i) in the RA sub-protocol. 
This corrects erroneous 
assignment of the same 
numbering "3)h)" to distinct 
inclusion criterion. 
Section RA 5.4.1: Rescreening 
and Retesting During Screening 
Period 
Section RA 8.1.2.3: RA Magnetic 
Resonance Imaging (MRI) 
Scoring System 
Revised from within 28 days of 
randomization to within 30 days of 
randomization for initial MRI performance 
date at Screening, should the subject require 
rescreening. 
To incorporate changes in the 
RA sub-protocol from 
Administrative Letter 04 
France. 
Section RA 8.4.5: Clinical Safety 
Laboratory Assessments, 
RA Table 8,Other Analyses 
Added SARS-CoV-2 serology collection at 
Week 12 in RA Table 8. 
To align SARS-CoV-2 serology 
collection at Week 12 in 
RA Table 8 with that in 
RA Table 2. 
Section RA 8.5.1: PK and 
Immunogenicity of Abatacept 
(Weeks 12 and Later), 
RA Table 10: PK and 
Immunogenicity Sampling 
Schedule for Abatacept 
Section RA 8.6: Biomarkers, 
RA Table 11: PD Sampling for 
Branebrutinib 
Clarified that the PK and biomarker blood 
samples to be collected for abatacept and 
branebrutinib, respectively, at Week 24 in the 
RA sub-protocol are not to be collected 
predose. 
Since abatacept and 
branebrutinib are not 
administered at Week 24 (last 
administration for both study 
treatments is at Week 20), these 
blood samples cannot be 
collected predose. Previously 
confusing language regarding 
“predose” has been deleted. 
Section RA 9.3.3: Additional 
Endpoints 
Removed subject assessment of pain in 
Section RA 9.3.3. 
This assessment was removed 
throughout Revised Protocol 03 
Global, but was unintentionally 
retained in Section RA 9.3.3, 
and is now removed in this 
amendment. 
Appendix 7: British Isles Lupus 
Assessment Group 
(BILAG)-2004 Index 
Updated appendix figure for proper rendering 
in the published PDF version. 
To incorporate changes from 
Administrative Letter 03. 
 
Please provide a copy to your Investigational Review Board/Ethics Committee, unless 
agreed otherwise with BMS. 
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Protocol Amendment No.: 04 
Date: 01-Dec-2021 
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MASTER TABLE OF CONTENTS 
CLINICAL PROTOCOL IM014029 ...............................................................................................1 
DOCUMENT HISTORY .................................................................................................................3 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04 ................................................7 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 ...................................8 
MASTER TABLE OF CONTENTS .............................................................................................10 
1 
STUDY IM014029 MASTER PROTOCOL ..............................................................13 
1.1 
Introduction: Role of Bruton’s Tyrosine Kinase in Normal Immune Function 
and Dysregulation in the Pathogenesis of Autoimmunity ..........................................13 
1.2 
Rationale for a Master Protocol for Three Immune-mediated Diseases with 
Shared Disease Mechanisms Including Dysregulation of BTK-Mediated 
Pathways: Systemic Lupus Erythematosus, Primary Sjögren’s Syndrome, and 
Rheumatoid Arthritis ..................................................................................................14 
1.2.1 
Rationale for Sub-protocols ........................................................................................15 
1.3 
Master Protocol: Overall Research Hypothesis ..........................................................17 
1.4 
Master Protocol Study Design ....................................................................................18 
FIGURE 1 MASTER PROTOCOL STUDY DESIGN ................................................................18 
1.4.1 
Master Protocol: Study Population ............................................................................18 
1.4.2 
Master Protocol: Study Treatment .............................................................................18 
1.4.3 
Master Protocol: Independent Data Monitoring Committee .....................................19 
1.4.4 
Master Protocol: Duration of Participation ...............................................................19 
1.4.5 
Master Protocol: Study Assessments ..........................................................................19 
1.4.6 
Master Protocol: Statistical Methods .........................................................................19 
1.4.7 
Master Protocol: Justification for Dose .....................................................................20 
1.5 
Master Protocol: Benefit/Risk Assessment ................................................................21 
1.5.1 
Branebrutinib ..............................................................................................................21 
1.5.2 
Open-label Therapy with Abatacept after Week 12 ....................................................24 
1.5.3 
Concomitant Medication Exclusions and Restrictions for All Sub-protocols ............25 
TABLE 1 CONCOMITANT MEDICATIONS REQUIRING EXCLUSIONS FROM 
STUDY OR RESTRICTIONS ...................................................................................25 
1.5.4 
Approach to SARS-CoV-2 ...........................................................................................28 
1.5.5 
Study Termination for Unexpectedly Unfavorable Risk/Benefit Balance ...................29 
SLE SUB-PROTOCOL .................................................................................................................31 
PSS SUB-PROTOCOL ................................................................................................................112 
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RA SUB-PROTOCOL .................................................................................................................193 
2 
REFERENCES .........................................................................................................282 
3 
APPENDICES ..........................................................................................................288 
APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS ................................................288 
APPENDIX 2 
STUDY GOVERNANCE CONSIDERATIONS ........................................294 
APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING .........................................................................301 
APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION .......................................................................305 
DEFINITIONS 
305 
METHODS OF CONTRACEPTION ..........................................................................................306 
COLLECTION OF PREGNANCY INFORMATION ................................................................308 
APPENDIX 5 
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING 
CLINICS CLASSIFICATION (SLICC) CRITERIA FOR SYSTEMIC 
LUPUS ERYTHEMATOSUS ..................................................................................309 
APPENDIX 6 
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING 
CLINICS/AMERICAN COLLEGE OF RHEUMATOLOGY DAMAGE 
INDEX (SDI) ............................................................................................................311 
APPENDIX 7 
BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG)-2004 
INDEX ......................................................................................................................312 
APPENDIX 8 
SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE ACTIVITY 
INDEX 2000 (SLEDAI-2K) .....................................................................................314 
APPENDIX 9 
CUTANEOUS LUPUS ERYTHEMATOSUS DISEASE AREA 
AND SEVERITY INDEX (CLASI) .........................................................................315 
APPENDIX 10 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(PGA) (SLE; VAS) ...................................................................................................317 
APPENDIX 11 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(SGA) (SLE; VAS) ...................................................................................................318 
APPENDIX 12 
PATIENT-REPORTED OUTCOMES MEASUREMENT 
INFORMATION SYSTEM-FATIGUE INSTRUMENT 
(PROMIS FATIGUE 6 A) (SLE; PSS; RA) .............................................................319 
APPENDIX 13 
EQ-5 D-5 L, EQ VAS (SLE; PSS, RA) .......................................................320 
APPENDIX 14 
SYSTEMIC LUPUS ERYTHMASTOSUS PAIN NUMERIC 
RATING SCORE (SLE, NRS) .................................................................................324 
APPENDIX 15 
EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) 
SJÖGREN’S SYNDROME DISEASE ACTIVITY INDEX (ESSDAI, PSS) .........325 
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APPENDIX 16 
DISEASE ACTIVITY SCORE 28 C-REACTIVE PROTEIN 
(DAS28-CRP) (PSS; RA) .........................................................................................331 
APPENDIX 17 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(PGA) (PSS) .............................................................................................................332 
APPENDIX 18 
EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) 
SJÖGREN’S SYNDROME PATIENT-REPORTED INDEX (ESSPRI) (PSS) ......333 
APPENDIX 19 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(SGA) (PSS;VAS) ....................................................................................................334 
APPENDIX 20 
SIMPLIFIED DISEASE ACTIVITY INDEX (SDAI) (RA) .......................335 
APPENDIX 21 
CLINICAL DISEASE ACTIVITY INDEX (CDAI) (RA) ..........................336 
APPENDIX 22 
AMERICAN COLLEGE OF RHEUMATOLOGY DISEASE 
ACTIVITY SCORE-28 ERYTHROCYTE SEDIMENTATION RATE 
(DAS28-ESR) (RA) ..................................................................................................337 
APPENDIX 23 
AMERICAN COLLEGE OF RHEUMATOLOGY HEALTH 
ASSESSMENT QUESTIONNAIRE DISABILITY INDEX (HAQ-DI) (RA) ........338 
APPENDIX 24 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(RA) (VAS) ..............................................................................................................342 
APPENDIX 25 
RHEUMATOID ARTHITIS MAGNETIC RESONANCE IMAGING 
SCORING SYSTEM (RAMRIS) .............................................................................343 
APPENDIX 26 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(RA) (VAS) ..............................................................................................................345 
APPENDIX 27 
ADME GENES ............................................................................................346 
 
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1 
STUDY IM014029 MASTER PROTOCOL 
1.1 
Introduction: Role of Bruton’s Tyrosine Kinase in Normal Immune 
Function and Dysregulation in the Pathogenesis of Autoimmunity 
Bruton’s tyrosine kinase (BTK) is a member of the Tec family of nonreceptor tyrosine kinases and 
is expressed in all hematopoietic cells, except T cells and terminally-differentiated plasma cells.1 
The underlying pathobiology of several immune-mediated diseases involves signaling pathways 
associated with BTK activation. 
In B cells, BTK plays an essential role in mediating the B cell receptor (BCR) responses to 
autoantigens and pro-inflammatory signaling.2 Regulation of BTK has also been shown to be 
important for B cell tolerance. Elevated expression of BTK has been associated with 
immune-mediated diseases in human and animal models, and BTK levels in B cells are correlated 
with autoantibody titers.3, 4 In addition to the formation of autoantibodies, BTK plays a critical 
role in autoimmunity through antibody-independent mechanisms, including the activation of 
pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6 and tumor necrosis factor 
71)ĮBTK also plays a role in signaling via the Fc gamma receptor (FcJR)IIa and FcJRIIIa 
receptors (low affinity activating receptors for immune complexes [ICs] containing 
immunoglobulin [Ig]G on myeloid and dendritic cells5, 6, 7) and low affinity activating receptors 
for immune complexes (ICs) containing immunoglobulin (Ig)G, which may play a critical role in 
the immunopathology of immune-mediated disorders. 
BTK inhibition is expected to inhibit antigen-dependent B cell signaling and function without 
depleting B cells,2 lead to decreases in IC-mediated production of pro-inflammatory cytokines, 
and reduce IC signaling to monocytic cells.8, 9, 10, 11 Many of the processes targeted by BTK 
inhibition are shared key pathogenic molecular mechanisms of immune-mediated diseases. 
BTK inhibitors (eg, ibrutinib, acalabrutinib) have already been approved for the treatment of 
hematological malignancies, including chronic lymphocytic leukemia and Waldenstrom’s 
macroglobulinemia. One BTK inhibitor, ibrutinib, has a number of off-target activities; other more 
selective BTK inhibitors are currently being developed for treatment of immune-mediated diseases 
in which a more favorable adverse event (AE) profile is sought. There have already been successful 
Phase 2 studies with BTK inhibitors in diseases where antibody production plays an important 
role, such as pemphigus. Studies with BTK inhibitors are ongoing in rheumatoid arthritis (RA), 
systemic lupus erythematosus (SLE), as well as in primary Sjögren’s syndrome (pSS). For 
example, evobrutinib (EMD Serono Research and Development, Inc.) is being evaluated in both 
SLE and RA (refer to ClinicalTrials.gov evobrutinib in SLE [Identifier: NCT02975336] and 
evobrutinib in RA [Identifier: NCT03233230] for study details), and tirabrutinib (Gilead Sciences) 
is being evaluated in pSS (refer to ClinicalTrials.gov tirabrutinib in pSS [Identifier: 
NCT03100942] for study details). 
Branebrutinib (BMS-986195) is an oral highly selective, irreversible covalent inhibitor of BTK. 
The effect of BTK inhibition on antigen-specific BCR-mediated B cell functions and 
IgG-FRQWDLQLQJ,&VLJQDOLQJWKURXJK)FȖUeceptors in monocytic cells may provide benefit in the 
treatment of multiple immune-mediated disorders, including those to be evaluated in the current 
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proposed Master Protocol, Study IM014029. In addition, BTK plays a role in receptor activation 
of nuclear factor kappa-B (RANK)-dependent osteoclastogenesis, as well as IgE-containing 
signaling through the BTK-GHSHQGHQW UHFHSWRU )F HSVLORQ UHFHSWRU )Fİ5, LQ PDVW FHOOV DQG
basophils. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of branebrutinib is 
provided in the Investigator’s Brochure (IB).12 Due to the potent and highly selective inactivation 
of BTK and optimized pharmacokinetics (PK) of branebrutinib, the efficacious dose in humans is 
SURMHFWHGWREH 10 mg/day; branebrutinib 9 mg has been selected as the dose that will be used in 
all 3 sub-protocols that will comprise this study. 
1.2 
Rationale for a Master Protocol for Three Immune-mediated Diseases 
with Shared Disease Mechanisms Including Dysregulation of 
BTK-Mediated Pathways: Systemic Lupus Erythematosus, Primary 
Sjögren’s Syndrome, and Rheumatoid Arthritis 
Traditional randomized clinical studies focus on a specific single disease type. However, the 
demarcations of named diseases are in most cases over a century old. This clinical study will use 
a 3-sub-protocol study design under a master protocol to evaluate the efficacy of branebrutinib on 
the basis of its potential shared mechanisms in 3 indications (SLE, pSS, and RA). Prospectively 
planned evaluation of primary endpoints will be carried out for each sub-protocol. Since each 
sub-protocol will enroll a small number of subjects to establish the proof of mechanism, the 
number of subjects treated will be minimized compared to a stand-alone study for each indication; 
however, composite safety data will be evaluated across all 3 sub-protocols, as well as within each 
sub-protocol. 
The choice of a master protocol design to evaluate the safety and efficacy of branebrutinib in 
3 separate disease states (SLE, pSS, and RA) is based primarily on several known overlapping 
features 
present 
in all 
3 immune-mediated/autoantibody-mediated 
diseases, 
including 
dysregulation of BTK pathways, and it is possible that BTK inhibition could confer clinical 
benefits across these diseases. In addition, because the experience and available study populations 
in rheumatology clinics commonly cover all 3 of these indications, the master protocol design is 
likely to facilitate clinical site readiness, recruitment efficiency, accuracy in investigator 
assessments, understanding of common treatments, and the administration of study treatment 
across the sites. It is further expected that these logistical benefits will require fewer overall sites 
to complete the study, thereby supporting greater consistency in the evaluation of disease states 
and in testing the safety and efficacy of study treatment. Moreover, analysis of the study using a 
master protocol design will allow for a comparison of safety and efficacy (where feasible) across 
indications, in addition to composite views of safety, which can also provide important data on the 
impact of some shared concomitant treatments across indications. The fact that all subjects will 
receive the same dose of branebrutinib will also provide safety data from a larger population and 
will allow better representation of minority demographic variables to contribute to the analysis of 
safety and biomarkers. 
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In all sub-protocols, a placebo (PBO) control is included to allow the assessment of effects of 
treatment, both desired and adverse, to be appropriately attributed to the treatment received. The 
PBO control will also provide a basis for comparison of safety assessments. 
In summary, the effect of BTK inhibition by branebrutinib on antigen-specific BCR-mediated B 
cell functions and IgG-FRQWDLQLQJ,&VLJQDOLQJWKURXJK)FȖUHFHSWRUVRQPRQRF\WLFFHOOVPD\
provide benefit in the treatment of the immune-mediated/autoantibody-mediated diseases SLE, 
pSS, and RA. Additional effects on signaling through the BTK-GHSHQGHQWUHFHSWRU)Fİ5,RQPDVW
cells and basophils, as well as RANK-dependent osteoclastogenesis, can also be evaluated. 
1.2.1 
Rationale for Sub-protocols 
 
Rationale for the Sub-protocol in Systemic Lupus Erythematosus 
Systemic lupus erythematosus is a systemic immune-mediated disease characterized by the 
production of autoantibodies to components of the cell that results in a diverse array of clinical 
manifestations including musculoskeletal, cutaneous, renal, constitutional, hematologic, 
neurologic, cardiovascular, and other vital organ involvement. 
Current therapies for SLE are unsatisfactory. Patients with moderate to severe flares of SLE 
usually receive immunosuppressive drugs and corticosteroids (CSs), which must be used over 
many years, can only temporarily control SLE flares, and are associated with numerous toxicities. 
Adverse effects of CS use are serious and include increased risk of cardiovascular events, 
infections, osteoporosis, and many other morbidities. The goal in management of SLE is to achieve 
disease and symptom control while minimizing excessive immunosuppressive drug exposure and 
limiting CS exposure. Specific standard of care (SOC) treatments include antimalarials, 
immunosuppressants (especially azathioprine, mycophenolate, methotrexate [MTX], leflunomide, 
and tacrolimus), biologics including belimumab (approved in most countries), and other agents 
(generally prescribed off-label). The only Food and Drug Administration (FDA)-approved 
treatments for SLE are steroids, antimalarials, aspirin, and belimumab. Other SOC treatments were 
borrowed from other diseases and have not completed a scientifically rigorous approval process 
for patients with SLE. There remains an unmet need for novel, well-tolerated, orally administered 
therapies that can effectively modify the disease course and control symptoms, while minimizing 
CS and immunosuppressive drug exposure. In particular, treatment of this difficult disease will be 
improved when agents with clearly understood molecular targets are properly characterized with 
available technology to improve rationale for treatment selection and dosing. 
Systemic lupus erythematosus is associated with the presence of autoreactive ICs that induce 
pathobLRORJ\WKURXJKWKHDFWLRQRI)FȖUHFHSWRUVOther approaches to targeting B cells have been 
validated in lupus.13 Preclinical models suggest IgG-IC-GULYHQSDWKRELRORJ\E\DFWLYDWLQJ)FȖ
receptors, is key to perpetuating adaptive immunity, and may provide a promising approach to the 
treatment of patients with SLE.14, 15 Basophils, when stimulated by autoreactive IgE through the 
BTK-GHSHQGHQWUHFHSWRU)Fİ5,KDYHDOVREHHQLPSOLFDWHGLQOXSXVQHSKULWLV16 and could have 
some relevance to other manifestations of SLE. Therefore, BTK inhibition may target pathogenic 
mechanisms of SLE on several levels. 
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The SLE sub-protocol in this study will help determine if branebrutinib is biologically active and 
whether it can demonstrate efficacy in the treatment of SLE patients with active disease despite 
SOC. 
 
Rationale for the Sub-protocol in Primary Sjögren’s Syndrome 
Sjögren’s syndrome is a chronic, systemic immune-mediated disease characterized by 
lymphocytic infiltration of salivary and lacrimal glands, systemic manifestations including renal, 
pulmonary, and neurological complications, and an increased incidence of lymphoma.17 Damage 
to exocrine glands is slowly progressive, initially recognized as persistent dryness of the mouth 
and eyes due to functional impairment of the salivary and lacrimal glands. Over half of pSS 
subjects experience extraglandular symptoms, including overwhelming fatigue, arthralgias and 
myalgias, and Raynaud’s phenomenon. pSS is also recognized frequently in patients with RA and 
SLE, underscoring clinical relationships that could have shared pathophysiologic features. pSS 
itself is heterogeneous, and not all patients exhibit all of the same symptoms. 
In pSS, there is no currently approved treatment that targets the underlying immune pathology of 
the disease, indicating a clear unmet medical need in this patient population. 
B and T cells play key roles in the pathobiology of pSS.17 As evidenced by 
hypergammaglobulinemia, alterations in B cell subpopulations, ectopic germinal center-like 
structures in the affected glands, and increased risk of lymphoma, B cells are critical in driving the 
disease.17 B cells produce autoantibodies such as anti-Ro/Sjögren’s syndrome antigen A (SSA) 
and anti-La/Sjögren’s syndrome antigen B (SSB), that both drive the amplification of type I 
interferon (IFN) production. B cells are also prominent at sites of inflammation in the glands, 
producing pro-inflammatory cytokines.17 Within salivary glands, ectopic germinal center-like 
structures have been identified, which likely serve as primary sites for B cell/T cell interactions.18
Moreover, B-lymphocyte stimulator (BlyS), which drives B cell proliferation and survival, has 
been shown to be elevated both in the serum and salivary glands of patients with pSS.19, 20, 21
Recently, increased levels of BTK protein have been observed in circulating B cells of patients 
with pSS and appear to correlate with rheumatoid factor (RF) levels and parotid gland T cell
infiltration.4 Since BTK plays an essential role in the mediation of BCR response to autoantigen 
and pro-inflammatory signaling in B cells, BTK inhibition may address key pathogenic 
mechanisms of pSS.
 
Rationale for the Sub-protocol in Rheumatoid Arthritis 
Rheumatoid arthritis is a chronic disease affecting 0.5 to 1.0% of the population in which 
diarthrodial (synovial) joints become inflamed, usually with a bilateral symmetric pattern, and with 
a high incidence of damage and disability.22 RA is a systemic disease, and manifestations may 
include constitutional symptoms such as fatigue, fever and malaise, vasculitis, cardiovascular 
complications, ocular involvement, pulmonary interstitial disease, and widespread nodulosis. 
Patients with RA have a reduced life span which correlates with disease severity, and increased 
levels of cytokines such as TNF-Į,/-1 and IL-6, circulating ICs, RF, and anti-citrullinated protein 
antibodies (ACPAs).23
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Despite recent progress in RA therapy with a number of approved targeted biologics in the United 
States (US) and Europe,12 unmet medical needs remain.24 First, many agents approved for RA 
exhibit significant safety concerns, including risk of tuberculosis (TB) and other serious infections, 
malignancies, and gastrointestinal perforation. Second, many patients are only partial responders 
to current available therapies, and true remission is achieved by only a minority of patients (< 10% 
in many series). Third, current treatments have toxicities that lead to frequent drug discontinuation. 
In addition, the destructive process of RA cannot be halted in all patients, and new drugs that 
reduce osteoclast-mediated bone loss and inflammation may offer unique benefits to patients with 
RA.25 
ICs containing IgG play a critical role in the immunopathology of many immune-mediated 
disorders. In RA, ICs are present in the joints and act on synovial macrophages to drive the 
production of the cytokines, chemokines, and matrix metalloproteinases (MMPs) that are critical 
LQPHGLDWLQJGLVHDVHSDWKRORJ\([SUHVVLRQRI)FȖ5,,DDQG)FȖ5,,,DDUHLQFUHDVHGLQPRQRcytes 
and macrophages of patients with RA,26, 27, 28 DQGSURGXFHKLJKHUOHYHOVRI71)ĮDQGMMPs than 
healthy controls.26 
$FWLYDWLQJ)FȖ receptors are also important in the activation of monocyte-derived dendritic cells.29 
Genome-ZLGHDVVRFLDWLRQVWXGLHVKDYHVKRZQ)FȖ5,,,DWREHDVVRFLDWHGZLWK5$VXVFHSWLELOLW\30 
and murine models of RA such as the collagen-induced arthritis (CIA) model have demonstrated 
DUROHIRUDFWLYDWLQJ)FȖUHFHSWRUVLQGLVease pathogenesis.31, 32 BTK is highly expressed in myeloid 
OLQHDJHVDQGUHJXODWHVVLJQDOLQJSDWKZD\VOHDGLQJIURPWKHELQGLQJRI,&VWR)FȖ5,,,DDQG)FȖ5,,D
to expression of pro-inflammatory cytokines, chemokines, and cell adhesion molecules.5, 6, 7, 33, 34 
%7.DOVRPHGLDWHV)FȖ5, signaling in mast cells and basophils although the role of these pathways 
in RA is not well established. However, IgE ACPAs have been identified in patients with RA,10 
and the number of activated mast cells may be increased in synovial tissue and have been correlated 
with disease activity.8, 9, 11 Thus, inhibition of BTK could have therapeutic benefit on a variety of 
immunopathogenic features of RA. 
Lastly, BTK inhibition could potentially counter the bone damage in RA through its role in 
mediating RANK-dependent osteoclastogenesis.35, 36 
The RA sub-protocol of this study will help determine if branebrutinib is biologically active and 
effective in the treatment of RA (see Section RA 4.4). 
In addition, the safety and efficacy of switching from branebrutinib or PBO to abatacept (also 
named BMS-188667 and Orencia™; referred to hereafter as abatacept) will also be evaluated. 
1.3 
Master Protocol: Overall Research Hypothesis 
The processes targeted by BTK inhibition are shared pathogenic molecular mechanisms of 
multiple immune-mediated diseases. Treatment with branebrutinib (BMS-986195), an oral, highly 
selective, irreversible inhibitor of BTK, may provide clinical benefit in the treatment of the 
immune-mediated diseases SLE, pSS, and RA. 
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1.4 
Master Protocol Study Design 
This Master Protocol with 3 sub-protocols is a double-blind, placebo-controlled multicenter study 
to assess the effect of branebrutinib (BMS-986195) treatment in subjects with SLE 
(SLE sub-protocol), pSS (pSS sub-protocol), and RA (RA sub-protocol). In the RA sub-protocol, 
the safety and efficacy of switching from branebrutinib or PBO to abatacept, which will be 
administered at a dose of 125 mg subcutaneously (SC), once weekly (QW), will also be evaluated. 
Enrollment in each sub-protocol will be concurrent. 
Figure 1 
Master Protocol Study Design 
 
pSS = primary Sjögren’s syndrome; QD = once daily; R = randomization ratio; RA = rheumatoid arthritis; 
SLE = systemic lupus erythematosus 
1.4.1 
Master Protocol: Study Population 
x The study population will include male and female subjects aged 18 (or age of majority) to 
75 years inclusive at screening. Subjects must have active SLE, moderate to severe pSS, 
or moderate to severe adult-onset RA. 
x Approximately 185 subjects will be randomized in the study (60 subjects in the SLE 
sub-protocol, 45 subjects in the pSS sub-protocol, and 80 subjects in the RA sub-protocol).
x For the SLE and pSS sub-protocols, there will be a 24-week double-blind 
placebo-controlled treatment period in which subjects will receive branebrutinib 9 mg or 
placebo once daily (QD). For the RA sub-protocol, there will be a 12-week double-blind 
PBO-controlled treatment period in which subjects will receive branebrutinib 9 mg or 
branebrutinib PBO, followed by an additional 12 weeks of treatment with open-label 
abatacept (Section 1.4.2). 
1.4.2 
Master Protocol: Study Treatment 
Blinded treatment assignment will be conducted by randomization on Day 1 and managed by 
interactive response technology (IRT). Subjects will undergo screening evaluations to 
determine eligibility within 28 days prior to administration of study medication. After 
successfully meeting entry criteria and completing screening assessments, subjects in each 
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sub-protocol will be randomized in a blinded manner to branebrutinib or PBO treatment.
Separate randomization schedules will be developed for each sub-protocol. Details of blinding 
and treatment assignment are provided in Section 6.0 of each sub-protocol. Subjects will be 
randomized to branebrutinib or PBO as follows: 
o
SLE sub-protocol – 3:1 ratio of branebrutinib 9 mg to PBO QD
o
pSS sub-protocol – 2:1 ratio of branebrutinib 9 mg to PBO QD
o
RA sub-protocol – 3:1 ratio of branebrutinib 9 mg to PBO QD
x
Randomization in the SLE sub-protocol will be stratified by immunosuppressant use
(yes/no).
x
Randomization in the pSS sub-protocol will be stratified by hydroxychloroquine (HCQ)
use (yes/no).
x
No stratification will be imposed in the RA sub-protocol.
1.4.3 
Master Protocol: Independent Data Monitoring Committee 
Safety monitoring, including laboratory monitoring, will be ongoing throughout the study, for 
subjects in all treatment arms, along with the employment of an Independent Data Monitoring 
Committee (DMC). The DMC will conduct at regular, prespecified intervals and on an ad hoc
basis if warranted, safety review meetings throughout the study to ensure that the benefit and risks 
of study participation remain acceptable. Based on the DMC’s assessment, recommendations of 
protocol modifications or other actions may occur, including but not limited to sample size 
adjustment, study modification, or discontinuation of the study or one or more of the sub-studies. 
In addition, hold of enrollment, pending more detailed assessment may be requested. For details, 
please refer to Sections SLE 4.1.1, pSS 4.1.1, and RA 4.1.1. 
1.4.4 
Master Protocol: Duration of Participation 
x
The duration of participation in the SLE and pSS sub-protocols will be approximately
32 weeks divided into the following periods: screening (up to 4 weeks [28 days]), double-blind
PBO-controlled treatment for 24 weeks (Week 0 to Week 24) and follow-up (4 weeks).
x
The duration of participation in the RA sub-protocol will be approximately 32 weeks divided
into the following periods: screening (up to 4 weeks), double-blind PBO-controlled treatment
for 12 weeks (Week 0 to Week 12), open-label abatacept treatment for an additional 12 weeks
(all subjects; Week 12 to Week 24), and follow-up (4 weeks).
1.4.5 
Master Protocol: Study Assessments 
Efficacy and safety will be assessed throughout the study. Blood samples will be collected for PK 
and biomarker clinical laboratory assessments. 
1.4.6 
Master Protocol: Statistical Methods 
General Methodology 
Efficacy, safety, PK, and biomarker data will be combined and summarized across each 
sub-protocol for variables that are similar among the sub-protocols in addition to analyses provided 
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separately for each sub-protocol. Statistical methods will be similar to those specified in the 
sub-protocols. 
 
Master Protocol: Interim Analysis 
An interim analysis will be performed for future study planning at a time point after approximately 
50% of the RA subjects have either completed Week 12 efficacy assessments or have discontinued 
prior to Week 12. The objective of this interim analysis will be to help in early planning for further 
clinical development of the compound. The study will not be stopped on the basis of any efficacy 
findings in the interim analysis, and there is no plan to modify the study design based on the results 
of this interim analysis. The results of this interim analysis will be reviewed by an unblinded 
development team that is independent of the study team responsible for the conduct of the study. 
The study team responsible for managing the study, including the Medical Monitors, will remain 
blinded to treatment assignment and will not have access to any unblinded interim analysis results 
or data until the study is completed and there is a final database lock and unblinding. 
 
Master Protocol: Analysis and Reporting 
After all subjects in the RA sub-protocol have completed Week 12 efficacy assessments or 
discontinued treatment/study prior to Week 12, an analysis of efficacy, safety, PK, and PD will be 
performed using data up to Week 12. The objective of this analysis will be to support early 
planning decisions on clinical development of the compound. After all subjects in a sub-protocol 
have finished the respective sub-protocol and the data have been locked for the sub-protocol, final 
analyses for that sub-protocol will be performed. Details of these analyses will be described in the 
statistical analysis plan (SAP). 
The study team responsible for managing the study, including Medical Monitors, will remain 
blinded to treatment assignment and the results of safety analysis until full database lock and 
treatment unblinding has occurred. The data will be reported only after completion of all 3 
sub-protocols. 
1.4.7 
Master Protocol: Justification for Dose 
The selection of the branebrutinib dose and regimen to be assessed in this Master Protocol study 
was based on findings in the first-in-human (FIH) and nonclinical studies. 
In the multiple ascending dose (MAD) panels (Part B) of the FIH study (Study IM014001), healthy 
subjects received branebrutinib solution once daily QD for 14 days at 4 dose levels (0.3, 1, 3, and 
10 mg; n = 6 subjects per dose).37 Increases in maximum observed plasma concentration (Cmax) 
and area under the plasma concentration-time curve (AUC) from the start to the end of the dosing 
period (AUC[TAU]) were approximately dose proportional within the dose levels tested. The 
mean half-life (T-HALF) was shorter than 2 hours across the dose range tested, indicating that 
branebrutinib was rapidly eliminated from the body. Consequently, as expected, accumulation at 
steady-state after multiple daily dosing was negligible. 
Safety results were similar between branebrutinib 3 mg and 10 mg solution doses in 
Study IM014001. The drug was well-tolerated at both dose levels and most AEs observed were 
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similar in subjects receiving PBO and active treatment. The most common AEs included headache 
and upper respiratory tract infection. Based on the AUC in rats and dogs at the 
no-adverse-effect-level (NOAEL) after chronic daily administration (rat, 6 months; dog, 
9 months), the safety multiple in humans after multiple doses of 10 mg is > 500×.12 In the current 
study, the dose level of branebrutinib will be 9 mg; consistent with a good safety margin for 
humans participating in the study. 
The dose for branebrutinib was selected based on the totality of data from multiple biomarkers 
obtained through post-hoc analysis from Study IM014001. The biomarkers evaluated were BTK 
occupancy by branebrutinib, inhibition of ex vivo stimulated cluster of differentiation (CD)69 
expression, and plasma C-X-C motif chemokine ligand 13 (CXCL13) levels. The maximum 
RFFXSDQF\UHDFKHGDWEUDQHEUXWLQLEGRVHVRI mg and above (100%; maximum occupancy 
DWGRVHV mg); however, the time to reach maximum occupancy was faster and maintained for 
a longer duration at 3 mg and 10 mg doses (solution formulation). The variability of the effect was 
lower for the higher dose of 10 mg. A similar result was obtained for CD69 inhibition, while the 
largest median inhibition in CD69 expression was observed at the branebrutinib 10 mg dose. The 
highest inhibition of plasma levels of CXCL13 was also obtained at the 10 mg dose level. 
Considering the higher variability and expression of BTK in patients with immune-mediated 
disorders,4 the higher dose is expected to sustain more stable inhibition of BTK for optimal chronic 
treatment of a larger proportion of patients. 
The comparison of exposure between the branebrutinib 10 mg solution formulation from 
Study IM014001 and the branebrutinib 9 mg capsule formulation (3 × 3 mg) from Day 1 Cycle 2 
in Study IM014023 demonstrated comparable exposure for Cmax and AUC(TAU) with only slight 
delay in time to maximum concentration (Tmax) for capsule formulation. Thus, the use of 3 × 3 mg 
capsules of branebrutinib is expected to be equivalent to the 10 mg solution formulation in terms 
of exposure, safety, and pharmacodynamic (PD) effects. 
The exposure for the 9 mg dose level is also much lower than the safety limit for exposure 
identified in preclinical studies. As previously mentioned, based on the AUC in rats at the NOAEL, 
the safety multiple in humans after multiple doses of 10 mg is > 500×. 
In summary, the dose to evaluate PD response with optimal safety and best potential to detect an 
efficacy signal was chosen to be 9 mg branebrutinib administered as 3 × 3 mg capsules. 
All RA subjects will receive open-label treatment with abatacept SC 125 mg administered QW in 
a prefilled syringe. This dose and regimen is approved for the treatment of patients with active RA 
and has demonstrated efficacy in Study IM101174 while maintaining steady-state trough 
concentration (Cminss) of 10 μg/mL and above, the exposure associated with near-maximal 
efficacy response in RA, in patients across all body weights.38 
1.5 
Master Protocol: Benefit/Risk Assessment 
1.5.1 
Branebrutinib 
At this early stage in the development of branebrutinib for the treatment of immune-mediated 
disorders, assessments of benefit and risk rely on nonclinical data and data from ongoing and 
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completed Phase 1 studies in healthy volunteer subjects. As of the date of this protocol amendment, 
143 subjects in the Phase 1 studies have received at least 1 dose of branebrutinib. The proposed 
9 mg QD dosing regimen reflects implementation of appropriate safety margins (> 500× based on 
the AUC in rats and dogs at the NOAEL [20 mg/kg/day and 15 mg/kg/day in rats and dogs, 
respectively]) and is within the range of doses tested in the FIH study (Study IM01400137). 
The effects of BTK inhibition by branebrutinib have been documented in pharmacology studies, 
and the potential for benefit in RA and SLE have been demonstrated by nonclinical studies using 
mouse models of RA and SLE. Branebrutinib demonstrated robust in vivo efficacy in CIA and 
collagen antibody-induced arthritis murine models of RA, protecting against clinically evident 
disease, histological joint damage, and bone mineral density loss. In both models, maximal 
efficacy was observed with t 95% inactivation of BTK in vivo. Similarly, potent efficacy was 
observed in a mouse model (New Zealand Black and New Zealand White) of lupus-induced 
nephritis (see branebrutinib IB Section 4.1.1.212 for further details). 
Findings in nonclinical toxicology studies were consistent with expectations based on the 
pharmacology of branebrutinib and included on-target PD effects such as decreases in B cells, 
suppression of keyhole limpet hemocyanin-specific IgM and IgG responses, and dose-related 
germinal center lymphoid depletion of minimal to moderate severity in the gut-associated 
lymphatic tissue. 
Branebrutinib-related pancreatic toxicity was identified in oral Sprague-Dawley (SD) rat toxicity 
studies with up to 6 months of exposure.39, 40, 41 Findings related to branebrutinib were noted at all 
doses, and were generally islet-centric (see the branebrutinib IB12 for further details). These 
pancreatic lesions are similar to those observed with other BTK inhibitors and represent an 
exacerbation of an age-related pancreatic finding specific to rats.42, 43, 44, 45 As such, these findings 
were considered nonadverse. The FDA has acknowledged that pancreatic lesions observed in rats 
treated with BTK inhibitors are unlikely to have relevance to the safety assessment for human 
subjects treated with this drug class. 
With the exception of an unrelated serious adverse event (SAE) that was consistent with the 
subject’s medical history, AEs in the FIH study (Study IM01400137) were mild to moderate, 
reversible, and consistent with expectations based on nonclinical experience. 
Based upon nonclinical toxicology findings and the mechanism of action of the compound 
(immunosuppression), BMS has implemented additional assessments and risk mitigation 
approaches (including careful consideration of appropriate exclusion criteria and monitoring of 
subjects during and after dosing) in combination with conventional safety monitoring. In Parts A, 
B, C, and D of the FIH study,37 there were no dose-related elevations of amylase, lipase, or fasting 
glucose; no decreases in white blood cells (WBCs) or Ig levels; and no clinically significant 
infections; however, this protocol continues to stipulate exclusion criteria (eg, assessment for latent 
TB infection [LTBI] and chronic viral infections) and clinical and laboratory monitoring to reduce 
the risk of infection. 
Because of the slow return of BTK activity following the discontinuation of branebrutinib dosing 
(based on post-hoc analyses following Study IM014001; BTK occupancy was found to be between 
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IM014029  
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10% and 30% with a steep downward trend following treatment with 10 mg branebrutinib for 
2 weeks), the duration of postdose follow-up of 4 weeks was chosen to account for the time needed 
to recover BTK activity. 
To minimize risk to participating subjects, this protocol has inclusion and exclusion criteria 
appropriate to the populations and proposed treatments, as well as frequent study visits for safety 
assessments. Blinded safety data will be reviewed on an ongoing basis by the BMS Medical 
Monitor and pharmacovigilance group to look for emerging safety trends or issues, and an 
independent external DMC will be in place for the duration of the study. 
In order to provide active study treatment to subjects who may be receiving PBO treatment for a 
maximum of 24 weeks, subjects in the SLE and pSS sub-protocols will also receive 
protocol-defined SOC therapy for their primary disease. Although successful CS tapering for those 
taking  10 mg/day will be encouraged as appropriate, inability to taper or a requirement to 
increase the CS dose to protect a subject’s safety or well-being will not be prohibited by the 
protocol. All subjects in the RA sub-protocol who may be receiving PBO treatment for a maximum 
of 12 weeks from Week 0 to Week 12 will also receive protocol-defined SOC therapy for their 
RA; all subjects will receive open-label abatacept from Week 12 to Week 24. 
The risk for drug-drug interactions (DDIs) with branebrutinib has previously been assessed. The 
potential for clinically relevant DDIs of branebrutinib with substrates of a number of enzymes and 
transporters (cytochrome P450 [CYP]1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and organic 
anion transporting polypeptide OATP1B1 and 1B3) is likely to be minimal based on the low 
projected therapeutic concentration (Cmax < 0.20 μM) and high serum protein binding.46 Based 
on the results of Study IM014013 and in vitro studies, branebrutinib may affect the PK of drugs 
that are sensitive substrates of CYP2C8 and P-glycoprotein (P-gp) as a weak inhibitor. Therefore, 
until more knowledge is gained, drugs that are sensitive substrates of CYP2C8 and P-gp may be 
restricted or excluded based on their therapeutic window and metabolism. 
In vivo studies to evaluate the developmental and reproductive effects of branebrutinib have shown 
developmental toxicity in rabbits (at an exposure multiple of 53u relative to the dose of 9 mg 
proposed for this study) that were associated with maternal mortality (IB Section 4.3.512). At the 
NOAEL of 40 mg/kg/day, the safety margin was 16u compared to the human AUC at 10 mg MAD. 
Branebrutinib was not associated with maternal or developmental toxicity in pregnant rats at 
exposure multiples up to 437u (versus human AUC at 10 mg MAD). Based on the exposure safety 
multiple, there is minimal risk to women of childbearing potential (WOCBP). However, to ensure 
safety, the study will require WOCBP to use highly effective contraception, and pregnant women 
will not be enrolled in this study. It is not known whether branebrutinib passes into human milk. 
Therefore, breastfeeding women will also not be enrolled in this study. The DDI study with oral 
contraceptives (Study IM014023) demonstrated lack of PK interaction,47 which ensures efficacy 
of hormonal contraception co-administered with branebrutinib. 
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1.5.2 
Open-label Therapy with Abatacept after Week 12 
Only the RA sub-protocol includes open-label treatment with abatacept starting at Week 12. 
Abatacept, a soluble fusion protein that consists of the extracellular domain of human CTLA-4 
linked to the modified Fc (hinge, constant region heavy chain [CH]2, and CH3 domains) portion of 
human IgG1, is a selective co-stimulation modulator that inhibits T cell activation by binding to 
cluster of differentiation (CD)80 and CD86 molecules on antigen-presenting cells, thereby 
inhibiting interaction with CD28. 
Abatacept is a biologic compound approved for the treatment of patients with active RA (see the 
abatacept IB48 for properties and mechanisms of action of abatacept). 
In clinical studies, abatacept demonstrated clear, consistent, and medically important benefit in the 
treatment of signs and symptoms of RA, improving physical function, reducing the progression of 
structural damage, and improving the quality of life in subjects with moderate to severe RA who 
were MTX-naïve, or were inadequate responders to MTX or anti-TNF therapies.49 
With over 27,754 patient-years of abatacept exposure, clinical studies of abatacept provide 
extensive experience characterizing the safety and efficacy/effectiveness of abatacept.49 Review 
of safety data from the ongoing long-term extensions of the clinical studies reveals a consistent 
safety profile for abatacept over time. However, there are inherent limitations to the assessment of 
infrequent AEs in clinical programs. Abatacept was first approved in 2005. Since that time, there 
have been an estimated 648,974 patient-years of exposure to abatacept in the marketplace. 
Postmarketing reports have not altered the favorable benefit-risk profile for abatacept and its safety 
profile remains generally similar to that established during the clinical studies. There remains 
limited information in patients with hepatic and renal impairment, combination therapy including 
other biologics, and use in elderly subjects. 
Based on the clinical study experience in adults, the identified risks associated with the use of 
abatacept include infections (some of which may be serious or fatal), infusion-related reactions 
(IV only), and systemic injection reactions (SC only).49 The main potential risks include the 
development of malignancies and immune-mediated disorders, but an increased risk of these types 
of events has not been observed. The rate of immunogenicity has generally been low, and there 
has not been an apparent effect on safety, efficacy, or PK. 
With regard to the developmental and reproductive effects of abatacept, the study treatment has 
been shown to have no effects on male or female fertility in rats, no teratogenic effects in rats and 
rabbits at doses up to 200 mg/kg daily (29-fold higher than the human 10 mg/kg dose based on 
AUC in rats and rabbits), and no adverse effects in offspring of rats treated with abatacept during 
early gestation and throughout the lactation period at doses up to 45 mg/kg (threefold higher than 
the human 10 mg/kg dose based on AUC).50 Alterations in immune function in female rats 
consisting of increase in the T cell-dependent antibody response and inflammation of the thyroid 
in female have been observed, but only at a dose of 200 mg/kg (11-fold higher than the human 
10 mg/kg dose based on AUC). Evidence of thyroiditis has also been observed in adult rats treated 
with abatacept, but thyroiditis has not been observed in mice, monkeys, or humans treated with 
abatacept, and is not considered to be clinically relevant. Abatacept has also been shown to cross 
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the placenta in rats and rabbits. Because animal reproduction studies are not always predictive of 
human response, and because there are no adequate and well-controlled studies of abatacept use 
in pregnant women, pregnant and breastfeeding women will not be enrolled in this study, and 
WOCBP will be required to use protocol-specified highly effective contraceptive methods 
(APPENDIX 4). 
Detailed information about the known and expected benefits and risks and reasonably anticipated 
AEs of branebrutinib and abatacept are provided in the branebrutinib IB12 and the abatacept IB48, 
respectively. 
In summary, nonclinical data, clinical experience with branebrutinib in healthy subjects, ongoing 
clinical studies with other BTK inhibitors in RA, pSS, and SLE, and clinical experience with 
abatacept in RA, taken together with the design and study treatment doses selected for the current 
Phase 2a study indicate an overall favorable benefit/risk assessment for investigating branebrutinib 
in subjects with SLE, pSS, or RA, and treatment of branebrutinib followed by abatacept in subjects 
with RA. 
1.5.3 
Concomitant Medication Exclusions and Restrictions for All Sub-
protocols 
For concomitant medications exclusions and restrictions that apply to the SLE, pSS, and RA 
sub-protocols, see Table 1. This table lists concomitant medications that, if taken, may result in 
exclusions from the study or concomitant medication restrictions on use, irrespective of indication. 
Based on vitro and in vivo studies, properties of branebrutinib exhibit weak inhibitory potential 
toward P-gp transporter and CYP2C8 enzyme. The drugs that may be administered in combination 
with branebrutinib for the specified and other possible underlying conditions were evaluated to 
determine their sensitivity for potential interactions. The evaluation was based on the metabolism 
of the concomitant medications, prescribing dose range and therapeutic window, and known 
information on interactions with P-gp and CYP2C8 inhibitors. 
The strategy was to limit the upper dose so that possible weak interaction through P-gp and 
CYP2C8 (< 50% increase in bioavailability) would not result in exposure greater than the safe 
exposure established in patients. 
Table 1 
Concomitant Medications Requiring Exclusions from Study or Restrictions 
Drug 
Pathway 
Typical Dose Range 
Recommendations 
Exclusions 
pioglitazone 
CYP2C8 
15 mg or 30 mg QD 
Exclude subjects on this 
medication 
repaglinide 
CYP2C8 
0.5 mg to 1 to 2 mg with each meal 
preprandially 
Exclude subjects on this 
medication 
tolvaptan 
P-gp 
45+15 mg, 60+30 mg, or 90+30 mg 
BID 
Exclude subjects with autosomal 
dominant polycystic kidney 
disease or on tolvaptan 
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Table 1 
Concomitant Medications Requiring Exclusions from Study or Restrictions 
Drug 
Pathway 
Typical Dose Range 
Recommendations 
Restrictions 
ambrisentan 
P-gp 
5 to 10 mg QD 
Dose up to 5 mg can be used 
amitriptyline 
P-gp 
25 mg TID to 150 mg QD 
Allowed dose up to 100 mg (SLE, 
RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
aripiprazole 
P-gp 
10 to 15 mg/day 
Allowed dose up to 10 mg QD 
cevimeline 
P-gp 
30 mg TID 
Allowed; monitor for 
hyperhidrosis as adverse effect of 
increased exposure 
citalopram 
P-gp 
40 to 60 mg/day 
Allowed dose up to 40 mg QD 
clonazepam 
P-gp 
1.5 mg/day TID; 8 to 10 mg/day TID 
up to 20 mg/day 
Allowed dose up to 10 mg/day 
colchicine 
P-gp 
0.6 mg, prophylaxis – 1 tablet QD or 
BID, flares – 2 tablets 
Dose up to 0.6 mg QD can be used 
dabigatran etexilate 
P-gp 
110, 150, 220 mg BID 
Dose up to 150 mg can be used 
desipramine 
P-gp 
100, 200, 300 mg/day 
Allowed dose up to 200 mg/day 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
desvenlafaxine 
P-gp 
50, 100, 200 mg/day 
Allowed dose up to 100 mg QD 
digoxin 
P-gp 
Injection 125 to 500 mcg, weight 
based; tablets 0.0625 mg, 0.125 mg, 
and 0.25 mg – 8 to 12 mcg/kg, 
loading 500 to 750 mcg, additional 
125 to 375 mcg 
For acute use only; exclude at 
baseline; limit highest dose and 
monitor trough concentrations; 
stop treatment with branebrutinib 
during treatment with digoxin and 
for 3 days afterwards 
doxepin 
P-gp 
75 to 150 mg/day 
Allowed dose up to 150 mg QD 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
escitalopram 
P-gp 
10 to 20 mg/day 
Allowed dose up to 10 mg/day 
fexofenadine 
P-gp 
60 and 120 mg; starting dose 60 mg 
QD, then 60 mg BID or 120 mg QD 
Dose up to 60 mg QD can be used 
hydroxychloroquine 
P-gp 
Strength 200 mg; 6.5 mg (salt 
form)/kg ideal (lean) body weight; 
200 to 400 mg daily 
Limit to maintenance dose 400 mg, 
no loading dose; measure PK at 
any time during the screening visit. 
The time at which the sample was 
taken will be recorded and the time 
the HCQ was self-administered 
will be recorded by the subject. 
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Table 1 
Concomitant Medications Requiring Exclusions from Study or Restrictions 
Drug 
Pathway 
Typical Dose Range 
Recommendations 
HCQ concentration not to exceed 
ȝJP/DWVFUHHQLQJ 
imipramine 
P-gp 
100, 200, 250 to 300 mg/day 
Allowed dose up to 100 mg/day 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
minocycline  
P-gp 
100 mg or 200 mg initially, followed 
by 100 mg BID or 50 mg Q6h 
Dose up to 100 mg BID can be 
used 
mycophenolate 
mofetil 
P-gp 
1 to 1.5 g BID 
Allowed in SLE, limit highest dose 
to 2 g/day (in subjects of African 
ancestry, 3 g/day is acceptable). 
nortriptyline 
P-gp 
25 mg TID or QID, 100 to 
150 mg/day 
Allowed dose up to 100 mg/day 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
olanzapine 
P-gp 
5 to 20 mg/day 
Allowed dose up to 10 mg/day 
paroxetine 
P-gp 
10 to 60 mg/day 
Allowed dose up to 40 mg/day 
piroxicam 
P-gp 
20 mg, or 10 mg BID Then 10 to 
20 mg QD 
Dose up to 10 mg QD can be used 
posaconazole 
P-gp 
Loading 300 to 400 mg BID, then 
300 mg QD 
Dose up to 300 mg QD can be 
used as maintenance dose, for 
acute infections stop using 
branebrutinib until dosing with 
posaconazole is discontinued 
quetiapine 
P-gp 
50 to 800 mg/day 
Allowed dose up to 600 mg/day 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
ranolazine 
P-gp 
500 mg to 1000 mg BID 
Dose up to 500 mg BID can be 
used 
rivaroxaban 
P-gp 
10 and 20 mg QD 
Dose up to 10 mg QD can be used 
rosiglitazone 
CYP2C8 
2, 4, 8 mg 
Dose up to 4 mg can be used, 
monitor glucose closely 
torasemide 
CYP2C8 
2.5 mg to 20 mg 
Dose up to 10 mg can be used 
trimipramine 
P-gp 
75 mg/day BID or TID to 150 
mg/day in 25-mg increments 
Allowed dose up to 150 mg/day 
(SLE, RA) 
Exclude in pSS if taken within 4 
weeks of randomization 
venlafaxine 
P-gp 
75 to 225 mg/day 
Allowed dose up to 150 mg QD 
vilazodone 
P-gp 
10 to 40 mg/day 
Allowed dose up to 20 mg/day 
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BID = twice daily; CYP = cytochrome P450; ECG = electrocardiogram; P-gp = P-glycoprotein; 
PK = pharmacokinetic; Q6h = every 6 hours; QD = once daily; SLE = systemic lupus erythematosus; TID = 3 times 
daily. 
1.5.4 
Approach to SARS-CoV-2 
Since initiation of this study, a global pandemic of coronavirus disease 2019 (COVID-19) caused 
by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has supervened. 51 Critical 
illness and mortality occur more frequently with COVID-19 than with infections by common 
respiratory viruses - with increased risk in the aged and those with certain comorbidities. 52, 53 The 
impact of rheumatologic diseases and their treatments on COVID-19-associated risk remains, at 
the time of this authoring, unclear. 
The Sponsor is evaluating the risk-benefit profile of this study on an ongoing basis, and in 
particular, regarding (i) the risk-benefit profile of branebrutinib in the context of the COVID-19 
pandemic, and (ii) vaccination against SARS-CoV-2. 
 
Risk/Benefit Profile of Branebrutinib in the Context of the COVID-19 
Pandemic
Risk from SARS-CoV-2 is intimately linked with the immune response following exposure. The 
immune system must control viral replication and cytopathology54, while avoiding the exaggerated 
inflammation associated with severe COVID-19. 55 It is reasonable to hypothesize that BTK 
function may influence both these aspects of the response to SARS-CoV-2. BTK is central to 
activation, proliferation, and survival responses downstream of the B cell antigen receptor and 
other receptors on B cells and key myeloid cell types. Details of BTK signaling are summarized 
in Section 1.1 of this protocol, Section 2 of the IB, and references therein. Notably, however, 
signaling through BTK depends both on the latter’s kinase activity, and on its “scaffolding” 
activity (ie, physical association with other proteins). 2, 56, 57 
Insights into the effect of deficiency in both BTK activities can be gained by observing COVID-19 
outcomes in patients with X-linked agammaglobulinemia (XLA), a genetic immunodeficiency 
characterized by profound reductions in B cell counts and serum immunoglobulins caused by null 
mutations in BTK. XLA patients demonstrate high susceptibility to bacterial and some viral 
infections that is largely ameliorated by administration of intravenous immunoglobulin and 
prophylactic antibiotics. 58 Published cases of COVID-19 in XLA patients reveal disease courses 
ranging from mild disease 59 to nonlethal pneumonia. 60, 61, 62 While these reports are anecdotal, 
they do demonstrate that lifelong deficiency of BTK kinase and scaffolding activities does not 
preclude recovery from COVID-19. Moreover, susceptibility to COVID-19 in rheumatology 
patients treated with branebrutinib is plausibly lower than that of XLA patients because the former 
have: (i) intact BTK protein despite inhibition of kinase activity, (ii) fully-developed adaptive 
immunity with a lifetime of intact pretreatment BTK function, and (iii) normal B cell counts. 
A published description of 5 COVID-19 cases in Waldenstrom’s macroglobulinemia patients 
chronically treated with full-dose ibrutinib demonstrated a mild infection course without need for 
hospitalization; a sixth patient chronically treated with low-dose ibrutinib had a more severe course 
but showed improvement temporally linked with increased dosage. 63 A cohort of 19 severely 
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affected COVID-19 patients without prior indication for BTK inhibitor therapy, who were treated 
acutely and experimentally with acalabrutinib, demonstrated reduced inflammatory measures, and 
outcomes no worse than expected given their disease severity. 64 Thus, publicly disclosed 
COVID-19 experiences in patients with XLA or receiving BTK inhibitors do not indicate increased 
risk of adverse COVID-19 outcomes associated with pharmacologic BTK inhibition. Furthermore, 
professional rheumatology organizations have not advocated prophylactic withdrawal of any class 
of rheumatologic treatment -- including immunosuppressants and Janus kinase (JAK) inhibitors. 
65, 66 Indeed, elevated disease activity in RA and SLE is associated with greater susceptibility to 
serious infections in general 67, 68, while treatment with biologic or targeted DMARDs may be 
associated with reduced risk of COVID-19-associated hospitalization. 69 
Branebrutinib offers the potential for better disease control with acceptable safety, as discussed in 
Sections 1.1 and 1.5.3 of this protocol and in the IB. This, together with the currently available 
insight regarding BTK and COVID-19, supports the continued clinical evaluation of branebrutinib 
despite the pandemic. Individual investigators and each potential subject together should decide 
the appropriateness of study participation depending on the medical particulars of each subject, 
and the local COVID-19 situation. Because the understanding of COVID-19 risk and disease 
mechanisms is rapidly evolving, the Sponsor will monitor for emerging knowledge that might 
affect the risk-benefit profile of this study. 
 
Vaccination Against SARS-CoV-2 
Vaccines against SARS-CoV-2 are emerging rapidly on an emergency basis, though the degree of 
protection in patients with rheumatologic diseases with or without disease-modifying treatment 
remains unclear. Experience with influenza vaccination may be informative however, which 
strongly supports the protective effect of inactivated influenza vaccination in rheumatology 
patients taking DMARDs, such as methotrexate, anti-TNF agents, and others 70. Furthermore, a 
small study indicates that hematology patients who are not heavily pretreated and are receiving 
ibrutinib can still mount clinically significant anti-influenza titers following vaccination with 
high-dose inactivated influenza vaccine. 71 This experience forms the basis for emerging 
professional rheumatologist guidance supporting SARS-CoV-2 vaccination for rheumatology 
patients receiving DMARDs. 72, 73, 74 As with general COVID-19 risk assessment, the management 
of SARS-CoV-2 vaccination in rheumatology patients is also rapidly evolving and is a focus of 
ongoing monitoring by the Sponsor. 
Vaccination prior to enrollment in this study is encouraged; however, this may be difficult due to 
inconsistent vaccine availability and variable patient perception of the vaccines. Thus, this 
amended protocol permits vaccination, during study treatment, against SARS-CoV-2 and 
influenza using nonlive/nonreplicating vaccine types (Sub-protocol Sections SLE 6.7, pSS 6.7,
and RA 6.7). 
1.5.5 
Study Termination for Unexpectedly Unfavorable Risk/Benefit Balance 
The Sponsor will evaluate the risk/benefit profile of the study on an ongoing basis. This evaluation 
will be based on all available data – with particular attention to: (i) AEs or other safety trends in 
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this or any other clinical study of branebrutinib whose character, severity, and/or frequency suggest 
that subjects would be exposed to an unreasonable and significant risk of illness or injury; (ii) new 
nonclinical data suggesting unreasonable and significant risk of illness or injury. 
If such evaluation suggests that the risk/benefit profile of the study (or one of its sub-protocols) 
has become unfavorable to subjects, the Sponsor will pause enrollment and/or dosing until further 
assessment of data, and interaction with the appropriate Health Authority(ies) can take place on 
potential actions. Such actions may include (but are not limited to) study continuation, substantial 
amendment, or termination of the entire study or any of its sub-protocols. 
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Page: 31 
 
Protocol Number: IM014029 
 
IND Number: 142401 
 
EX-US Non-IND 
 
EUDRACT Number: 2019-002205-22 
Date: 01-Jul-2019 
Revised Date: 01-Dec-2021 
 
Clinical Protocol IM014029: 
SLE SUB-PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Assess the Efficacy and 
Safety of Branebrutinib Treatment in Subjects with Active Systemic Lupus Erythematosus or 
Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept 
Treatment in Subjects with Active Rheumatoid Arthritis 
Protocol Amendment 04 SLE 
Study Director 
Medical Monitor 
 
 
Bristol Myers Squibb Company 
556 Morris Avenue, Building S5 
Summit, NJ 07901 
 
Telephone (office): 
 
Email: 
 
Medical Monitoring Support Center 
Telephone (office): 
 
Mobile: 
 
 
Fax:
 
 
Email: 
 
 
24-hr Emergency Telephone Number 
USA:
 
International: 
 
 
Bristol Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium 
 
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SLE TABLE OF CONTENTS 
SLE 1 
SUB-PROTOCOL SUMMARY ................................................................................36
 
Synopsis ......................................................................................................................36
 
Schema ........................................................................................................................41
 
Schedule of Activities .................................................................................................42
SLE 2 
INTRODUCTION ......................................................................................................53
 
Background and Research Hypothesis .......................................................................53
 Study Hypothesis .........................................................................................................53
 
Benefit/Risk Assessment ............................................................................................54
SLE 3 
OBJECTIVES AND ENDPOINTS ............................................................................56
SLE 4 
STUDY DESIGN .......................................................................................................57
 
Overall Design ............................................................................................................57
 DMC and Other External Committees .......................................................................58
 
Number of Subjects ....................................................................................................58
 
End of Study Definition ..............................................................................................58
 
Scientific Rationale for Study Design ........................................................................59
 
Justification for Dose ..................................................................................................59
SLE 5 
STUDY POPULATION .............................................................................................60
 
Inclusion Criteria ........................................................................................................60
 
Exclusion Criteria .......................................................................................................66
 
Lifestyle Restrictions ..................................................................................................72
 Meals and Dietary Restrictions ..................................................................................72
 Caffeine, Alcohol, Tobacco, and Cannabinoids .........................................................72
 Activity ........................................................................................................................72
 Screen Failures ...........................................................................................................72
 Rescreening and Retesting During Screening Period ................................................72
SLE 6 
TREATMENT ............................................................................................................73
 
Treatments Administered ............................................................................................74
 
Method of Treatment Assignment ..............................................................................75
 
Blinding ......................................................................................................................75
 
Dosage Modification ..................................................................................................76
 
Preparation/Handling/Storage/Accountability ............................................................76
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 Retained Samples for Bioavailability/Bioequivalence ................................................77
 
Treatment Compliance ................................................................................................77
 
Concomitant Therapy .................................................................................................77
 Prohibited and/or Restricted Treatments ...................................................................77
 Oral Corticosteroid Taper or Rescue for SLE Flare ..................................................81
 Other Restrictions and Precautions ............................................................................81
 
Treatment After the End of the Study .........................................................................81
SLE 7 
DISCONTINUATION CRITERIA ............................................................................81
 
Discontinuation from Study Treatment ......................................................................81
 Permanent Discontinuation from Study Treatment ....................................................81
 Temporary Discontinuation from Study Treatment ....................................................82
 Post-study Treatment Study Follow-up ......................................................................82
 
Discontinuation from the Study ..................................................................................83
 
Lost to Follow-up .......................................................................................................83
SLE 8 
STUDY ASSESSMENTS AND PROCEDURES ......................................................83
 
Efficacy Assessments .................................................................................................84
 Investigator-administered Assessments ......................................................................84
 Patient-reported Outcomes .........................................................................................88
 
Adverse Events ...........................................................................................................89
 AEs of Interest .............................................................................................................89
 Time Period and Frequency for Collecting AE and SAE Information .......................89
 Method of Detecting AEs and SAEs ............................................................................90
 Follow-up of AEs and SAEs ........................................................................................90
 Regulatory Reporting Requirements for SAEs ...........................................................90
 Pregnancy ...................................................................................................................91
 Laboratory Test Result Abnormalities ........................................................................91
 Potential DILI .............................................................................................................91
 Other Safety Considerations .......................................................................................92
 
Overdose .....................................................................................................................92
 
Safety ..........................................................................................................................92
 Physical Examinations ................................................................................................92
 Vital Signs ...................................................................................................................93
 Electrocardiograms ....................................................................................................93
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 TB Screening and Chest Imaging ...............................................................................93
 Clinical Safety Laboratory Assessments .....................................................................93
 Imaging Safety Assessment .........................................................................................95
 
PK of Branebrutinib ....................................................................................................95
 PK of Potential Concomitant Medications ...............................................................101
 
Biomarkers ................................................................................................................101
 Additional Research Collection ................................................................................103
 Pharmacogenomics Testing ......................................................................................105
 
Health Economics OR Medical Resource Utilization and Health Economics .........105
SLE 9 
STATISTICAL CONSIDERATIONS .....................................................................105
 
Sample Size Determination ......................................................................................105
 
Populations for Analyses ..........................................................................................106
 
Endpoints ..................................................................................................................106
 Primary Endpoint .....................................................................................................106
 Secondary Endpoints ................................................................................................106
 Additional Endpoints ................................................................................................107
 PK Endpoints ............................................................................................................107
 Exploratory Endpoints ..............................................................................................107
 
Statistical Analyses ...................................................................................................108
 Efficacy Analyses ......................................................................................................108
 Safety Analyses .........................................................................................................110
 Other Analyses ..........................................................................................................110
 Analysis and Reporting .............................................................................................111
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
35 
SLE LIST OF TABLES 
SLE Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 .................42 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to 
Week 28) ....................................................................................................46 
SLE Table 3 
Objectives and Endpoints ..........................................................................56 
SLE Table 4 
Study Treatments for IM014029 ................................................................73 
SLE Table 5 
Selection and Timing of Dose ....................................................................74 
SLE Table 6 
Prohibited and Restricted Medications ......................................................77 
SLE Table 7 
Clinical Safety Laboratory Assessments ...................................................94 
SLE Table 8 
PK Sampling Schedule for Branebrutinib, Metabolites, and 
Concomitant Medications ..........................................................................98 
 
.103 
SLE Table 10 
 Residual Sample Retention for Additional Research Schedule ..............104 
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930168072
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
36 
SLE 1 
SUB-PROTOCOL SUMMARY 
 
Synopsis 
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to 
Assess the Efficacy and Safety of Branebrutinib Treatment in Subjects with Active Systemic 
Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment 
Followed by Open-label Abatacept Treatment in Subjects with Active Rheumatoid Arthritis
Short Title: 
Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Branebrutinib in 
Systemic Lupus Erythematosus: SLE Sub-protocol 
Study Phase: 
Phase 2a 
SLE Sub-protocol Rationale: 
The Study IM014029 SLE sub-protocol is designed to evaluate the efficacy and safety of 
branebrutinib in addition to background disease therapy in the treatment of subjects with active 
SLE. Based on several underlying molecular mechanisms of SLE targeted by Bruton’s tyrosine 
kinase (BTK) inhibition, this sub-protocol will test the hypothesis that branebrutinib may be 
effective in the treatment of patients with SLE. 
Patients with moderate to severe flares of SLE usually receive immunosuppressive drugs and 
corticosteroids 
(CSs), 
antimalarials, 
immunosuppressants 
(especially 
azathioprine, 
mycophenolate, methotrexate [MTX], leflunomide, and tacrolimus), biologics including 
belimumab (approved in most countries), and other agents (generally prescribed off-label). The 
only FDA-approved treatments for SLE are steroids, antimalarials, aspirin, and belimumab. Other 
SOC treatments were borrowed from other diseases and have not completed a scientifically 
rigorous approval process for patients with SLE. These treatments temporarily control SLE flares 
and are associated with numerous toxicities. Adverse effects of CS use are serious and can include 
increased risk of cardiovascular events, infections, osteoporosis, and many other morbidities. The 
goal in the management of SLE is to achieve disease and symptom control while minimizing 
excessive immunosuppressive drug exposure and limiting CS exposure and treatment-related AEs. 
There remains an unmet need for novel, well-tolerated, orally administered therapies that can 
effectively modify the course and control symptoms, while minimizing CS and 
immunosuppressive drug exposure. In particular, treatment of this difficult disease will be 
improved when agents with clearly understood molecular targets are properly characterized with 
available technology to improve rationale for treatment selection and dosing. The SLE 
sub-protocol in this study will help determine if branebrutinib is biologically active and effective 
in the treatment of patients with active SLE despite receiving SOC treatments. 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
37 
SLE Sub-protocol Study Population: 
The study population will consist of male and female subjects aged 18 years (or age of majority) 
to 75 years inclusive at screening with active SLE. 
SLE Sub-protocol Key Inclusion/Exclusion Criteria 
a) Diagnosed with SLE, which meets the Systemic Lupus Erythematosus Internal Collaborating 
Clinics 2012 (SLICC 2012) classification criteria,  24 weeks before the screening visit 
b) Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) 
DFWLYLW\VFRUH 10 (excluding mucous membrane ulcerations and diffuse non-inflammatory 
alopecia) 
c) For subjects taking CS, the dose cannot exceed 40 mg/day prednisone or equivalent 
d) Subjects with other immune-mediated diseases (eg, scleroderma, mixed connective tissue 
disease, multiple sclerosis, psoriasis, inflammatory bowel disease, etc) are excluded. Subjects 
with Type 1 autoimmune diabetes mellitus, thyroid autoimmune disease, or secondary 
Sjögren’s syndrome are not excluded. 
e) Subjects with drug-induced lupus, or active or unstable lupus activity in the neuropsychiatric 
body system, including but not limited to subjects with a British Isles Lupus Assessment Group 
(BILAG-2004) A grade are excluded, with the exception of subjects with mononeuritis 
multiplex and polyneuropathy, who are allowed with approval by the Medical Monitor or 
 
Lupus Central Review Services. 
f) Subjects with active, severe lupus nephritis (World Health Organization Class III or IV) that 
requires or may require treatment with cytotoxic agents or high-dose CS are excluded. Subjects 
ZLWKSULRUFRQWUROOHGUHQDOGLVHDVHZLWKVHUXPFUHDWLQLQH 2× upper limit of normal (ULN) 
DQG HLWKHU UHVLGXDO SURWHLQXULD  3 g/day or a urine protein/creatinine ratio (UPCR) of 
 3 mg/mg or 339 mg/mmol are allowed. Stability of renal disease must be documented with 
at least 2 measurements of proteinuria or UPCR over the past 6 months or with 2 tests during 
the screening period at least 1 week apart and must be approved by the Medical Monitor. 
g) Active fibromyalgia with pain symptoms or signs that would interfere with joint assessment or 
requiring adjustment in medication within the 3 months before screening to control symptoms; 
subjects with fibromyalgia that is well controlled on stable treatment may be included. 
h) (OHYDWHG
DQWLQXFOHDU
DQWLERGLHV
$1$
 1:80 
or 
positive 
anti-double-stranded 
deoxyribonucleic acid (dsDNA) (excluding results in the equivocal range) or positive 
anti-Smith (Sm), as determined by the central laboratory at the screening visit, are required; if 
initial results for all of these are negative at screening such that a subject would be deemed a 
screen failure, then 1 retest will be allowed for subjects with a documented history of positive 
results. 
i) Subjects hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well as any subjects 
with any sequelae of prior COVID-19 infection at screening, regardless of time since infection, 
are excluded. 
2.0
Approved
930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
38 
SLE Sub-protocol Objectives and Endpoints: 
Objective 
Endpoint 
SLE Sub-protocol 
Primary 
x 
To compare the efficacy of branebrutinib with 
PBO at Week 24 in the treatment of subjects with 
SLE 
Proportion of subjects with: 
50% decrease in mCLASI activity score in subjects 
with a baseline mCLASI score  
AND 
CS (prednisone or equivalent)  10 mg/day at 
Week 20 and Week 24 
Secondary/Additional 
x 
To compare the efficacy of branebrutinib with PBO 
at Week 24 in the treatment of subjects with SLE 
Secondary: 
x 
Change from baseline in SLEDAI-2K score 
Additional: 
x 
Change from baseline in autoantibody titers 
(ANA, anti-dsDNA) 
x 
Change from baseline in C3, C4 
x 
Change from baseline in hsCRP, ESR 
x 
Changes from baseline in PGA and SGA 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
x 
Change from baseline in SLE Pain NRS 
x 
To compare the efficacy of branebrutinib with PBO 
on measures of global and organ-specific clinical 
responses at Week 24 in the treatment of subjects 
with SLE 
Secondary: 
x 
BILAG-based Composite Lupus Assessment 
response 
Additional: 
x 
Change from baseline in the 40-joint count for 
tender, swollen, and tender + swollen joints in 
subjects with arthritis at baseline 
x 
Change from baseline in SDI 
Safety 
x 
To compare the safety and tolerability of 
branebrutinib with PBO in subjects with SLE 
x 
Number and proportion of subjects experiencing 
SAEs, AEs, and abnormalities in laboratory 
parameters, vital signs, and ECGs 
Exploratory 
x 
Time to SLE flare, as measured by BILAG-2004 assessment 
x 
PK of branebrutinib and metabolites of clinical interest 
x 
 
 
 
 
 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
39 
SLE Sub-protocol Objectives and Endpoints: 
Objective 
Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; ANA = antinuclear antibodies; 
; 
 
 
; BICLA = BILAG-based Composite Lupus Assessment; 
BILAG = British Isles Lupus Assessment Group; 
; C = complement; 
CS = corticosteroid; 
 dsDNA = double-stranded deoxyribonucleic acid; 
ECG = electrocardiogram; EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5 Level version; 
ESR = erythrocyte sedimentation rate; hsCRP = high-sensitivity C-reactive protein; 
 
 
; mCLASI = modified Cutaneous Lupus 
Erythematosus Disease Area and Severity Index; NRS = numeric rating score; PBO = placebo; PGA = Physician 
Global Assessment; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information 
System; 
 
 
 
 
 
 
 
 
; 
 
 SAE = serious adverse event; 
 SGA = Subject 
Global Assessment; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease 
Activity Index– 2000; Sm = Smith; 
 
 
SLE Sub-protocol Overall Design: 
x This is a double-blind, PBO-controlled Phase 2a sub-protocol to evaluate the effect of 
branebrutinib (BMS-986195) in subjects with active SLE. All subjects will continue 
background therapy for their primary disease within protocol-defined limits. 
x Subjects will receive double-blind branebrutinib 9 mg or PBO treatment administered orally 
once daily (QD) for 24 weeks (Week 0 to Week 24). 
x Treatment assignment will be conducted by randomization. Subjects will undergo screening 
evaluations to determine eligibility within 28 days prior to administration of study medication. 
Following the screening process, if eligible for study participation, subjects will be randomized 
in the SLE sub-protocol to receive branebrutinib or PBO treatment in a 3:1 ratio. 
Randomization will be stratified by immunosuppressant use (yes/no). 
SLE Sub-protocol Number of Subjects: 
It is expected that 60 subjects will be randomized in the SLE sub-protocol. 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
40 
SLE Sub-protocol Duration: 
The total duration of participation in the SLE sub-protocol is approximately 32 weeks and will be 
divided into the following periods: screening (up to 4 weeks), double-blind PBO-controlled 
treatment for 24 weeks (Week 0 to Week 24), and follow-up (4 weeks). 
SLE Sub-protocol Study Treatment: 
Study Drug for IM014029 
Medication 
Potency 
IP/Non-IP 
Branebrutinib 
9 mg QD, oral 
IP 
PBO 
QD, oral 
IP 
IP = investigational product; PBO = placebo; QD = once daily 
 
SLE Sub-protocol Statistical Methods: 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the SLE sub-protocol 
LVDGHFUHDVHIURPEDVHOLQHP&/$6,DFWLYLW\VFRUHLQVXEMHFts with a baseline mCLASI 
DFWLYLW\VFRUHDW:HHNDQG&6SUHGQLVRQHRUHTXLYDOHQW mg/day at Week 20 and 
Week 24. 
Estimates for PBO response rates, treatment differences, and common standard deviations were 
obtained from the published literature. Sample size justification is as follows: 
Assuming a total sample size of 60 subjects randomized in a blinded fashion in a 3:1 ratio to 
branebrutinib (45 subjects) or PBO (15 subjects) and a treatment difference of 25% with a PBO 
response of 30% for mCLASI at Week 24, the 95% confidence interval (CI) is expected to 
exclude 0 (expected 95% CI based on a z-test = 2%, 56%). 
Categorical data will be summarized by treatment group as frequency counts and percentages. 
Continuous data will be summarized by treatment group using n, mean, standard deviation, 
median, minimum, and maximum unless otherwise specified. Efficacy data will be summarized 
separately for each sub-protocol and with each sub-protocol combined for variables that are similar 
among the sub-protocols. The primary analysis for each sub-protocol will be performed after all 
subjects finish the study within a sub-protocol. There will be no alpha level adjustment for multiple 
endpoint testing. 
Response rates of branebrutinib compared to PBO for binary endpoints will be analyzed using a 
Cochran-Mantel-Haenzsel test stratified by immunosuppressant use (yes/no). The 95% CIs for 
each treatment group response rate and the difference in response rate for branebrutinib compared 
to PBO will be provided. If expected cell counts are not sufficient, then Fisher’s exact test will be 
used. Logistic regression models for the primary endpoint may be used in supportive analyses to 
incorporate additional covariates of interest. 
2.0
Approved
930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
41 
Continuous endpoints (change from baseline values) will be analyzed using analysis of covariance. 
The baseline value of the endpoint being tested will be added into the model as a covariate and 
immunosuppressant use (yes/no) and treatment as fixed effects. Treatment differences based on 
least-squares means and corresponding 2-sided 95% CIs will be provided for the difference 
between branebrutinib and PBO. Mixed model repeated measures (MMRM) analyses may be used 
in supportive analyses for continuous endpoints. Bayesian borrowing to utilize historical controls 
may also be performed as supportive analyses. Details will be provided in the SAP if needed. 
Nonresponder imputation will be used for binary endpoints for subjects who discontinue study 
treatment early, start a protocol-prohibited medication/therapy prior to the specified timepoint, or 
otherwise have missing endpoint data for the specified timepoint. Missing data are addressed in 
these models and assumed to be missing at random. 
Treatment-emergent AEs (TEAEs) and serious adverse events (SAEs) will be summarized using 
counts and percentages of subjects experiencing the event as well as the number of events by 
system organ class, preferred term, and treatment group. Physical examinations findings, vital 
signs, clinical laboratory test results, and electrocardiogram (ECG) test results will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for 
continuous variables and frequency distributions (counts and percentages) for categorical 
variables. Safety data will be summarized separately for each sub-protocol and with all 
sub-protocols combined. 
 
Schema 
 
ANA = antinuclear antibodies; DB = double-blind; dsDNA = double-stranded deoxyribonucleic acid; 
mCLASI = modified Cutaneous Lupus Erythematosus Disease Area and Severity Index; Pd = period; SLE = systemic 
lupus erythematosus; SLICC = Systemic Lupus Erythematosus International Collaborating Clinics 
1RWHP&/$6,H[FOXGHVPXFRXVPHPEUDQHXOFHUDWLRQVDQGGLIIXVHQRQLQIODPPDWRU\DORSHFLD 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
42 
Schedule of Activities 
SLE Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Eligibility Assessments 
Informed Consent 
X 
A subject is considered enrolled only when a protocol-specific ICF is signed; this includes subjects at 
preselected clinical sites consenting to participate in extended PK sampling in addition to the sampling 
scheduled for all study subjects. 
Enroll subject in the IRT system 
X 
Inclusion/Exclusion Criteria 
X 
Includes: 
6/(GLDJQRVLVZHHNVEHIRUHscreening based on SLICC 2012 classification criteria 
(OHYDWHG$1$ 1:80) or positive anti-dsDNA or anti-Smith antibody 
P&/$6, 
SLE History, SLE-related Treatment 
X 
General Medical History 
X 
History of Tobacco Use 
X 
Nonsmoker, light, or heavy smoker. 
Subject-reported Outcomes 
SGA 
X 
Collected on eCOA device; refer to Section SLE 8.1.2.1. 
SLE Pain NRS 
X 
Collected on eCOA device; refer to Section SLE 8.1.2.4. 
EQ-5 D-5 L 
X 
Collected on eCOA device; refer to Section SLE 8.1.2.3. 
PROMIS-Fatigue 6 a 
X 
Collected on eCOA device; refer to Section SLE 8.1.2.2. 
Safety Assessments 
Physical Examination (PE) 
X 
Complete PE. 
Physical Assessments 
X 
Vital Signs 
X 
Includes height (screening only) and weight, body Temperature (ear or oral), respiratory rate, seated BP, 
and seated heart rate. BP and heart rate should be measured after the subject has been sitting quietly for 
at least 5 minutes. 
ECG 
X 
ECGs should be recorded after the subject has been supine for 5 to 10 minutes. Lab work must be done 
after the ECG. 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
43 
SLE Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Chest Imaging (eg, Chest x-ray) 
X 
Chest imaging is required if not performed within 6 months of screening visit; copy of radiology report 
must be on file and reviewed by the investigator. 
Prior and Concomitant Medication 
Usea 
X 
Includes prescription, over-the-counter medications, and herbal supplements. All concomitant 
medications to be reviewed by the Medical Monitor and clinical pharmacology asset lead. 
SAE Assessment 
X 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing or 
subject’s participation in the study if the last scheduled visit occurs at a later time. 
Clinical Assessments 
 
 
SLICC 2012 criteria for SLE 
X 
Entered into EDC by site; refer to Section SLE 8.1.1.1. 
BILAG-2004 Index 
X 
Entered into EDC by site; refer to Section SLE 8.1.1.3. 
SLEDAI-2K  
X 
Entered into EDC by site; refer to Section SLE 8.1.1.6. 
PGA 
X 
Entered into EDC by site; refer to Section SLE 8.1.1.8. 
40-joint count 
X 
Entered into EDC by site; refer to Section SLE 8.1.1.9. 
CLASI 
X 
Entered into EDC by site; refer to Section SLE 8.1.1.7. 
Photography 
X 
All subjects will be photographed. See Photography Manual for details. Can be performed by site staff 
trained on study-specific requirements and delegated by PI accordingly. 
Laboratory Tests 
 
Includes blood and urine samples. 
Hematology 
X 
CBC with differential. 
Serum Chemistry Panel 
X 
Includes liver function testing. 
Lipid Panel 
X 
Nonfasting. 
Urinalysis 
X 
 
HbA1c 
X 
,I+E$FFRQVXOW0HGLFDO0RQLWRU. 
TSH 
X 
If out of normal range (high or low), consult the Medical Monitor. 
UPCR 
X 
 
eGFR 
X 
 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
44 
SLE Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
ESR  
X 
Local laboratory assessment by site. 
C3, C4 
X 
 
HCQ concentration b 
X 
To be reviewed by the Medical Monitor and clinical pharmacology asset lead. 
Coomb’s test (direct) 
X 
Only if clinically indicated. 
ANA 
X 
 
anti-Smith 
X 
 
anti-dsDNA 
X 
 
Infectious Serology 
X 
Includes HCV antibody, HBsAg, HbsAb, HbcAb, and HIV antibodies. 
TB Test (IGRA; eg, QuantiFERON®-
TB Gold) 
X 
 
Pregnancy Test (Serum or Urine) 
X 
WOCBP only. Must have negative pregnancy test within 24 hours prior to the start of treatment. 
Follicle-stimulating hormone  
X 
For those women who require FSH to confirm menopausal status. See APPENDIX 4 for definition and 
Section SLE 5.1 for reproductive status inclusion criteria. 
Breast and cervical cancer screening 
X 
Because most patients with SLE are young women, screening for cervical and breast cancer prior to 
randomization is encouraged as per local guidelines and investigator judgment.  
Biomarker Assessments 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
ANA = antinuclear antibodies; 
BILAG = British Isles Lupus Assessment Group; 
BP = blood pressure; C3, C4 = serum complement C3, C4; CBC = complete blood count; CS = corticosteroids (prednisone or equivalent); 
 
; dsDNA = double-stranded DNA; eCOA = Electronic Clinical Outcome Assessment; EDC = RAVE electronic data capture; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5 Level version; 
2.0
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930168072
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
45 
ESR = erythrocyte sedimentation rate; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c Test for Diabetes; HbcAb = hepatitis B core antibody; 
HbsAb = anti-hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCQ = hydroxychloroquine; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; 
 ICF = informed consent form; IGRA = interferon gamma-release assay; 
; 
IRT = interactive response technology; mCLASI = modified Cutaneous Lupus Erythematosus Disease Area and Severity Index; NRS = numeric rating score; MMP 
= matrix metalloproteinase; PK = pharmacokinetic; PGA = Physician Global Assessment; PI = principal investigator; PROMIS = Patient-reported Outcomes 
Measurement Information System; 
 SAE = serious adverse event; SGA = Subject Global 
Assessment SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000; SLICC= Systemic Lupus 
Erythematosus International Collaborating Clinics; TB = tuberculosis; 
; TSH = thyroid-stimulating hormone; UPCR = urine 
protein:creatinine ratio; WOCBP = women of childbearing potential 
a For subjects receiving CS, the dose must be stable for 2 weeks before the screening visit (signing of the ICF) and throughout the screening period until 
randomization (for additional details, refer to Section SLE 8.1.1.10). 
b For subjects taking HCQ concomitantly, a sample of whole blood will be drawn for HCQ PK analysis. 
 
 
 
 
 
 
 
 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1) Subject-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2) Safety assessments (eg, vitals, AEs) 
3) Investigator-administered Assessments (eg, PGA, joint count, etc) 
4) Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
46 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
Subject-reported Outcomes 
 
 
 
 
 
 
 
 
 
 
SGA 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device; refer to Section 
SLE 8.1.2.1. 
SLE Pain NRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device; refer to Section 
SLE 8.1.2.4. 
EQ-5 D-5 L 
X 
 
 
 
X 
 
 
X 
X 
Collected on eCOA 
device; refer to Section 
SLE 8.1.2.3. 
PROMIS-Fatigue 6 a  
X 
 
 
 
X 
 
 
X 
X 
Collected on eCOA 
device; refer to Section 
SLE 8.1.2.2. 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
X 
See Section SLE 8.4.1. 
Targeted Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
 
See Section SLE 8.4.1. 
Body Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature (ear or oral), 
respiratory rate, seated BP, 
and seated heart rate; BP 
and heart rate should be 
measured after the subject 
has been resting quietly for 
at least 5 minutes. 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGs should be recorded 
after the subject has been 
supine for 5 to 10 minutes. 
Lab work must be done 
after the ECG. 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
47 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
Concomitant Medication Use b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Refer to Section SLE 6.7, 
SLE Table 1. 
AE and SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nonserious AEs must be 
collected from the time of 
the first dose of the study 
drug through the date of 
the follow-up or last visit. 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
SDI 
X 
 
 
 
 
 
 
X 
 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.1. 
BILAG-2004 Index 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.3. 
SLEDAI-2K 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.6. 
PGA 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.8. 
40-joint count 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.9. 
CLASI 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site; 
refer to 
Section SLE 8.1.1.7. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
48 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
Assess suitability for CS taper 
b 
X 
 
X 
X 
X 
X 
 
 
 
(Refer to 
Section SLE 8.1.1.10). CS 
dose must remain stable 
from the Week 16 visit 
through the Week 24 visit. 
Photography 
X 
 
X 
X 
X 
X 
X 
X 
X 
All subjects will be 
photographed. See 
Photography Manual for 
details. Can be performed 
by site staff trained on 
study-specific 
requirements and 
delegated by PI 
accordingly. 
Laboratory Tests  
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panel (Fasting) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Fasting for at least 8 hours 
prior to collection. 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
 
 
 
 
 
 
 
X 
X 
 
UPCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local laboratory 
assessment by site. 
 
 
 
 
 
 
 
 
 
 
 
HCQ concentration 
X 
 
X 
 
 
 
 
 
 
Predose and 2 hours 
postdose; included with 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
49 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
concomitant medications 
PK (refer to Section 
SLE 8.5, SLE Table 8). 
Coomb’s test (direct) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Only if clinically 
indicated. 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
 
 
 
 
 
 
 
 
 
 
Beta-2-microglobulin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TBNK 
X 
X 
X 
 
X 
 
 
X 
X 
 
Anti-ds-DNA antibody 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
, anti-Ro/SSA, 
anti-La/SSB, 
; 
 
 ANA,
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (serum or 
urine) 
X 
 
X 
X 
X 
X 
X 
X 
X 
WOCBP only. Must have 
negative pregnancy test 
within 24 hours prior to the 
start of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
50 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
PK Assessments 
 
 
 
 
 
 
 
 
 
 
Standard blood samples for the 
PK of branebrutinib c 
X 
 
X 
X 
 
X 
 
X 
 
Refer to Section SLE 8.5, 
SLE Table 8. 
Blood samples at preselected 
sites for the PK of 
branebrutinib and metabolites d 
X 
 
 
X 
 
 
 
 
 
Refer to Section SLE 8.5, 
SLE Table 8. 
Blood samples for the PK 
assessment of concomitant 
medications e 
X 
 
X 
 
 
 
 
 
 
Refer to Section SLE 8.5, 
SLE Table 8. 
Biomarker Sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
51 
SLE Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197  
(± 3 d) 
V10 
Safety 
FU 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
Randomize 
X 
 
 
 
 
 
 
 
 
 
Dispense/Administer Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Note: At Week 2 and 
Week 24, the subject is 
requested to bring IP to the 
site visit and IP is 
administered at the site; no 
new kit is dispensed at 
these visits. 
Study Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X g 
 
; AE = adverse event; ANA = antinuclear antibodies; 
 
 
; 
; BILAG = British Isles Lupus Assessment Group; BP = blood pressure; 
; C3, C4 = serum 
complement C3 and C4; CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index; CS = corticosteroids; 
 
 D/d = day; DNA = deoxyribonucleic acid; dsDNA = double-stranded deoxyribonucleic acid; ECG = electrocardiogram; eCRF = electronic case report 
form; eGFR = estimated glomerular filtration rate; EOT = end of treatment; EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5-Level version; 
ESR = erythrocyte sedimentation rate; FU = Follow-up; HbA1c = Hemoglobin A1c; HCQ = hydroxychloroquine; hsCRP = high-sensitivity C-reactive protein; 
 Ig = immunoglobulin; 
; IP = investigational product; MMP = matrix metalloproteinase; NRS = numeric 
rating score; PGA = Physician Global Assessment; PI = principal investigator; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement 
Information System; 
; RF = rheumatoid factor; RNA = ribonucleic acid;
; 
 SAE = serious adverse event; SDI = SLICC/American College of Rheumatology Damage Index; SLE = systemic 
lupus erythematosus; SLEDAI 2K = Systemic Lupus Erythematosus Disease Activity Index 2000; SLICC = Systemic Lupus Erythematosus International 
Collaborating Clinics; Sm = Smith; SGA = Subject Global Assessment; -4 = Systemic Lupus Erythematosus Responder Index -4; SSA = Sjögren’s syndrome 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
52 
antigen A; SSB = Sjögren’s syndrome antigen B; TBNK = T cells, B cells, natural killer cells; 
; UPCR = urine protein:creatinine ratio; 
V = visit; W = Week; WOCBP = women of childbearing potential 
a If the decision has been made for a subject to permanently discontinue treatment before the planned Week 24 visit (Section SLE 7.1.1), the subject should 
undergo a Week 24 EOT visit as specified in the Week 24 column of this table, followed by a Week 28 Safety FU visit, 4 weeks (±3 d) later, as specified in the 
Week 28 column of this table. The appropriate eCRF pages for the EOT and Safety FU visits should be completed accordingly. 
b For subjects receiving CS (prednisone or equivalent), unless a reason for not tapering is documented, the investigator must assess the subject’s suitability for, 
and implement, CS taper at each visit from Week 8 up to, but not including, Week 16 (Section SLE 8.1.1.10). CS dose must remain stable from the Week 16 
visit through the Week 24 visit. CS dose reduction may be started any time after Day 1. 
c Blood samples for the PK assessment of branebrutinib concentrations will be taken predose from all study subjects at Week 0 (Day 1), Week 4 (Day 29), Week 
8 (Day 57), Week 16 (Day 113), and Week 24 (Day 169), and postdose at Week 0 (Day 1), Week 8 (Day 57), and Week 24 (Day 169) at approximately 0.5, 1, 
2, and 4 hours after dosing. 
d At preselected clinical sites only, blood samples for the PK assessment of branebrutinib and its metabolites concentrations will be taken predose at Week 8 (Day 
57); and postdose at Week 0 (Day 1) and Week 8 (Day 57) at approximately 0.5, 1, 2, and 4 hours. In addition, samples will be taken postdose at 6 hours and 
from 8-10 hours (flexible window) and 10-12 hours (flexible window) on the same days. A PK sample will also be drawn at Week 0 (Day 2) at 24 hours after 
dosing (predose of branebrutinib on Day 2). (For these assessments, collected blood samples will be aliquoted into 2 tubes.) 
e Blood samples for PK assessment of relevant concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant drug metabolizing 
enzymes and P-gp transporter may be measured post-hoc. For these concomitant medications, plasma samples will be collected predose and 2 hours postdose at 
Week 0 (Day 1) and Week 4 (Day 29). For subjects taking HCQ on-study, whole blood samples at predose and 2 hours postdose of branebrutinib on both Day 1 
(Week 0) and Day 29 (Week 4) will be collected in addition for the assessment of HCQ level. 
 
 
g Study treatment compliance is to be performed at Week 28 only if the subject’s study participation has completed and the subject failed to return study drug at 
the prior visit. 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1. Subject-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
 
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IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
53 
SLE 2 
INTRODUCTION 
An overall introduction to this protocol employing a master protocol design for 3 separate 
immune-mediated indications is provided in Master Protocol Section 1.2. 
 
Background and Research Hypothesis 
The IM014029 SLE sub-protocol is designed to evaluate the efficacy and safety of branebrutinib 
in subjects with active SLE, when added to background disease therapy within protocol-defined 
limits. Based on several key underlying molecular mechanisms of SLE targeted by BTK inhibition, 
the hypothesis will be tested that branebrutinib is effective in the treatment of SLE. 
SLE is a systemic immune-mediated disease characterized by the production of autoantibodies to 
components of the cell that results in a diverse array of clinical manifestations including 
musculoskeletal, cutaneous, renal, constitutional, hematologic, neurologic, cardiovascular, and 
other vital organ involvement. 
Patients with SLE are treated with immunosuppressive drugs and CS, antimalarials, biologics 
including belimumab, and other agents (generally prescribed off-label). These treatments 
temporarily reduce the signs and symptoms of SLE but do not prevent progression of organ 
damage and may be toxic, particularly with prolonged use. Adverse effects of CS use can be 
serious and can include increased risk of cardiovascular disease, infections, osteoporosis, and 
many other morbidities. The goal in the management of SLE is to achieve disease and symptom 
control while minimizing excessive immunosuppression, CS exposure, and treatment-related AEs. 
There remains an unmet need for novel, well-tolerated orally administered therapies that can be 
optimized to effectively modify the disease course and control symptoms, while minimizing CS 
exposure. 
SLE is associated with the presence of autoreactive ICs that induce pathobiology through the 
DFWLRQRI)FȖUHFHSWRUV3UHFOLQLFDOPRGHOVVXJJHVWWKDW,J*-IC-GULYHQDFWLYDWLRQRI)FȖUHFHSWRUV
may be important in the pathology of SLE via B cell and myeloid cell modulation and relevant as 
an approach to treatment.13 Basophils, when stimulated by autoreactive IgE through the 
BTK-GHSHQGHQW UHFHSWRU )Fİ5,, might also be relevant to lupus nephritis.16 Therefore, BTK 
inhibition may target several underlying molecular mechanisms of SLE, and it is on this basis that 
the BTK inhibitor branebrutinib will be tested. 
The SLE sub-protocol in this study will help determine if branebrutinib is biologically active and 
effective in the treatment of patients with active SLE despite receiving SOC therapies. 
 Study Hypothesis 
BTK plays a role in the pathology of SLE. The hypothesis to be tested is that treatment with 
branebrutinib 9 mg will have greater efficacy than PBO as assessed by mCLASI response, defined 
as a decrease of  50% from baseline mCLASI activity score, in subjects with a baseline mCLASI 
DFWLYLW\VFRUH 10, at Week 24. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
54 
 
Benefit/Risk Assessment
At this early stage in the development of branebrutinib for the treatment of immune-mediated 
disorders, assessments of benefit and risk rely on nonclinical data and data from completed Phase 1 
studies in healthy volunteer subjects. The proposed 9 mg QD dosing regimen reflects 
implementation of appropriate safety margins (> 500× based on the AUC in rats and dogs at the 
NOAEL [20 mg/kg/day and 15 mg/kg/day in rats and dogs, respectively]) and is within the range 
of doses tested in the FIH study (Study IM01400137). 
The effects of BTK inhibition by branebrutinib have been documented in pharmacology studies, 
and the potential for benefit in RA and SLE have been demonstrated by nonclinical studies using 
mouse models of RA and SLE. Branebrutinib demonstrated robust in vivo efficacy in CIA and 
collagen antibody-induced arthritis (CAIA) murine models of RA, protecting against clinically 
evident disease, histological joint damage, and bone mineral density loss. In both models, maximal 
efficacy was observed with t 95% inactivation of BTK in vivo. Similarly, potent efficacy was 
observed in a mouse model (New Zealand Black and New Zealand White) of lupus-induced 
nephritis (see branebrutinib IB Section 4.1.1.212 for further details). 
Findings in nonclinical toxicology studies were consistent with expectations based on the 
pharmacology of branebrutinib and included on-target PD effects such as decreases in B cells, 
suppression of keyhole limpet hemocyanin-specific IgM and IgG responses, and dose-related 
germinal center lymphoid depletion of minimal to moderate severity in the gut-associated 
lymphatic tissue. 
Branebrutinib-related pancreatic toxicity was identified in oral SD rat toxicity studies with up to 
6 months of exposure.39, 40, 41 Findings related to branebrutinib were noted at all doses, and were 
generally islet-centric (see the branebrutinib IB12 for further details). These pancreatic lesions are 
similar to those observed with other BTK inhibitors and represent an exacerbation of an age-related 
pancreatic finding specific to rats.42, 43, 44, 45 As such, these findings were considered nonadverse. 
The FDA has acknowledged that pancreatic lesions observed in rats treated with BTK inhibitors 
are unlikely to have relevance to the safety assessment for human subjects treated with this drug 
class. 
With the exception of an unrelated SAE that was consistent with the subject’s medical history, 
AEs in the FIH study (Study IM01400137) were mild to moderate, reversible, and consistent with 
expectations based on nonclinical experience. 
Based upon the mechanism of action of the compound (immunosuppression), BMS has 
implemented additional assessments and risk mitigation approaches (including careful 
consideration of appropriate exclusion criteria and monitoring of subjects during and after dosing) 
in combination with conventional safety monitoring. In Parts A, B, C, and D of the FIH study,37
there were no dose-related elevations of amylase, lipase, or fasting glucose; no decreases in WBCs
or Ig levels; and no clinically significant infections; however, this protocol continues to stipulate 
exclusion criteria (eg, assessment for LTBI and chronic viral infections) and clinical and laboratory 
monitoring to reduce the risk of infection. 
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BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
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Because of the slow return of BTK activity following the discontinuation of branebrutinib dosing 
(based on post-hoc analyses following Study IM014001), BTK occupancy was found to be 
between 10% and 30% with a steep downward trend following treatment with 10 mg branebrutinib 
for 2 weeks), the duration of postdose follow-up of 4 weeks was chosen to account for the time 
needed to recover BTK activity. 
To minimize risk to participating subjects, this protocol has inclusion and exclusion criteria 
appropriate to the populations and proposed treatments, as well as frequent study visits for safety 
assessments. Blinded safety data will be reviewed on an ongoing basis by the BMS Medical 
Monitor and pharmacovigilance group to look for emerging safety trends or issues, and an 
independent external DMC will be in place for the duration of the study. 
In order to provide active study treatment while receiving PBO treatment for a maximum of 
24 weeks, subjects in the SLE sub-protocol will also receive protocol-defined SOC therapy for 
their primary disease. Although successful CS tapering for those takiQJ  10 mg/day will be 
encouraged as appropriate, inability to taper or a requirement to increase the CS dose to protect a 
subject’s safety or well-being will not be prohibited by the protocol. 
The risk for drug-DDIs with branebrutinib has previously been assessed. The potential for 
clinically relevant DDIs of branebrutinib with substrates of a number of enzymes and transporters 
(cytochrome P450 [CYP]1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and organic anion 
transporting polypeptide OATP1B1 and 1B3) is likely to be minimal based on the low projected 
therapeutic concentration (Cmax < 0.20 μM) and high serum protein binding.46 Based on the 
results of Study IM014013 and in vitro studies, branebrutinib may affect the PK of drugs that are 
sensitive substrates of CYP2C8 and P-glycoprotein (P-gp) as a weak inhibitor. Therefore, until 
more knowledge is gained, drugs that are sensitive substrates of CYP2C8 and P-gp may be 
restricted or excluded based on their therapeutic window and metabolism. 
In vivo studies to evaluate the developmental and reproductive effects of branebrutinib have shown 
developmental toxicity in rabbits (at an exposure multiple of 53u relative to the dose of 9 mg 
proposed for this study) that were associated with maternal mortality (IB Section 4.3.512). At the 
NOAEL of 40 mg/kg/day, the safety margin was 16u compared to the human AUC at 10 mg MAD. 
Branebrutinib was not associated with maternal or developmental toxicity in pregnant rats at 
exposure multiples up to 437u (versus human AUC at 10 mg MAD). Based on the exposure safety 
multiple, there is minimal risk to WOCBP. However, to ensure safety, the study will require 
WOCBP to use highly effective contraception, and pregnant women will not be enrolled in this 
study. It is not known whether branebrutinib passes into human milk. Therefore, breastfeeding 
women will also not be enrolled in this study. The DDI study with oral contraceptives 
(Study IM014023) demonstrated lack of PK interaction,47 which ensures efficacy of hormonal 
contraception co-administered with branebrutinib. 
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BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
56 
SLE 3 
OBJECTIVES AND ENDPOINTS 
SLE Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
x 
To 
compare 
the 
efficacy 
of 
branebrutinib with PBO at Week 24 
in the treatment of subjects with 
SLE 
Proportion of subjects with: 
50% decrease in mCLASI activity score in subjects with a 
baseline mCLASI score  
AND 
CS (prednisone or equivalent)  10 mg/day at Week 20 and 
Week 24 
Secondary/Additional 
x 
To compare the efficacy of 
branebrutinib with PBO at 
Week 24 in the treatment of 
subjects with SLE 
Secondary: 
x 
Change from baseline in SLEDAI-2K score 
Additional: 
x 
Change from baseline in autoantibody titers (ANA, anti-dsDNA) 
x 
Change from baseline in C3, C4 
x 
Change from baseline in hsCRP, ESR 
x 
Changes from baseline in PGA and SGA 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
x 
Change from baseline in SLE Pain NRS 
x 
To compare the efficacy of 
branebrutinib with PBO on 
measures of global and organ-
specific clinical responses at Week 
24 in the treatment of subjects with 
SLE 
Secondary: 
x 
BICLA response 
Additional: 
x 
Change from baseline in the 40-joint count for tender, swollen, 
and tender + swollen joints in subjects with arthritis at baseline 
x 
Change from baseline in SDI 
Safety 
x 
To compare the safety and 
tolerability of branebrutinib with 
PBO in subjects with SLE 
x 
Number and proportion of subjects experiencing SAEs, AEs, and 
abnormalities in laboratory parameters, vital signs, and ECGs 
Exploratory 
x 
Time to SLE flare, as measured by BILAG-2004 Index-defined SLE Flare 
x 
PK of branebrutinib and metabolites of clinical interest 
 
 
 
 
 
 
 
 
 
 
 
 
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BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
57 
SLE Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
x 
 
 
 
 
 
 
 
 
 
 
 
 
; 
 
AE = adverse event; ANA = antinuclear antibodies; 
 
 
 
 BICLA = BILAG-based Composite Lupus Assessment; 
BILAG = British Isles Lupus Assessment Group; 
 C = complement; 
CS = corticosteroid; 
 dsDNA = double-stranded deoxyribonucleic acid; 
ECG = electrocardiogram; EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5 Level version; 
ESR = erythrocyte sedimentation rate; hsCRP = high-sensitivity C-reactive protein; 
 
; 
 
;
 mCLASI = modified Cutaneous Lupus 
Erythematosus Disease Area and Severity Index; NRS = numeric rating score; PBO = placebo; PGA = Physician 
Global Assessment; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information 
System; 
 
 
 
 
 
 
 
 
; 
 
; SAE = serious adverse event; 
; 
; SGA = Subject 
Global Assessment; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease 
Activity Index– 2000; Sm = Smith; 
 
 
SLE 4 
STUDY DESIGN 
Overall Design
x This is a double-blind, PBO-controlled multicenter Phase 2a study to assess the effect of 
branebrutinib treatment in subjects with active SLE when added to background disease therapy 
within protocol-defined limits. 
x Approximately 60 subjects will be randomized in the SLE sub-protocol. Sample size 
considerations are presented in Section SLE 9.1 Sample Size Determination. 
x For the SLE sub-protocol, there will be a 24-week double-blind PBO-controlled treatment 
period during which subjects will receive branebrutinib 9 mg or PBO QD. 
x Blinded treatment assignment will be conducted by randomization on Day 1 and managed by 
IRT. Subjects will undergo screening evaluation within 28 days prior to administration of study 
medication to determine eligibility. After successfully completing screening assessments, 
eligible subjects will be randomized in a blinded manner to receive branebrutinib 9 mg or PBO
in a 3:1 ratio. Randomization will be stratified by immunosuppressant use (yes/no). 
x The duration of participation in the SLE sub-protocol will be approximately 32 weeks divided 
into the following periods: screening (up to 4 weeks), double-blind PBO-controlled treatment 
for 24 weeks (Week 0 to Week 24), and follow-up (4 weeks). 
x Efficacy and safety will be assessed throughout the study (see Section SLE 8.1 Efficacy 
Assessments, Section SLE 8.2 Adverse Events, and Section SLE 8.4 Safety for details of 
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IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
58 
assessments). Blood samples will be collected for PK and biomarker clinical laboratory 
assessments (see Section SLE 8.5 and 
 respectively, for details of 
assessments). 
x An independent DMC will assess study findings on a periodic basis (Section SLE 4.1.1).
The study design schematic for the SLE sub-protocol is presented in Section SLE 1.2. 
 DMC and Other External Committees 
To ensure the safety of study subjects, across all sub-protocols, an external independent DMC 
consisting of 2 experienced rheumatologists, an infectious disease clinician, and a statistician will 
be established for ongoing evaluation of safety assessments, AEs, and laboratory measurements. 
An independent reporting statistician not involved in the conduct of the study will be designated 
to provide the DMC with essential safety data unblinded to treatment during the study, if required.
The DMC will conduct at regular, prespecified intervals and on an ad hoc basis if warranted, safety 
review meetings throughout the study to ensure that the benefit and risks of study participation 
remain acceptable. Ad hoc meetings may be initiated by the DMC or by the Sponsor based on 
emerging new safety information. Based on the DMC’s assessment, recommendations of protocol 
modifications or other actions may occur, including but not limited to sample size adjustment,
study modification, or discontinuation of the study or one or more of the sub-studies. In addition, 
hold of enrollment, pending more detailed assessment may be requested. 
Blinded Suspected, Unexpected Serious Adverse Reactions (SUSARs) will be sent to the DMC 
members on an ongoing basis. SAEs will be sent to the DMC on a monthly basis or on an ongoing 
basis as requested by the DMC. 
The DMC will review safety data including but not limited to SAEs and adverse events of interest 
(AEIs). At the request of the DMC, designated personnel will provide further information on the 
medical assessment for a specific case. 
The DMC may also consider external data from other branebrutinib studies that may be initiated 
in future or from novel scientific information that may be generated on branebrutinib or other BTK 
inhibitors. 
Further details of DMC responsibilities, specific timing of safety reviews, content, and methods of 
data reports, authorities, processes, and procedures will be specified in the DMC charter. 
 
Number of Subjects 
It is expected that approximately 60 subjects will be randomized in the SLE sub-protocol. Details 
regarding sample size determination are provided in Section SLE 9.1. 
 
End of Study Definition 
The start of the study is defined as the date that the first subject signs the informed consent. End 
of the SLE sub-protocol is defined as the last visit of the last subject to complete the study or the 
final scheduled procedure shown in the Schedule of Activities (SoA; Section SLE 1.3). Study 
completion for the SLE sub-protocol is defined as the final date on which data for the primary 
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endpoint was or is expected to be collected, if this is not the same. The master protocol study will 
be reported only after the last endpoint has been analyzed for all 3 sub-protocols. 
The total duration of study participation for subjects in the SLE sub-protocol is expected to be 
approximately 32 weeks. 
Scientific Rationale for Study Design
(Please refer to Master Section 1.2 for rationale supporting the choice of a master protocol design 
to evaluate the safety and efficacy of branebrutinib in 3 immune-mediated/autoantibody-related 
diseases.) 
The pathology of SLE involves several signaling events regulated by BTK, as described in 
Section SLE 2.1. It is therefore hypothesized that BTK inhibition will have clinical benefits in 
subjects with SLE. 
In the SLE sub-protocol, all subjects will continue their existing therapies for SLE except for 
prohibited medications (see Section SLE 6.7.1). Rescue treatments are permitted as needed (with 
a few protocol-specified limitations; see Section SLE 6.7.2) for subject safety. A plan for CS 
tapering is included to allow subjects to use the lowest dose that meets their needs, consistent with 
SOC; however, doses are to be held stable for 8 weeks before the Week 24 assessments (primary 
efficacy endpoint). 
A PBO control will be included in the SLE sub-protocol to allow the effects of treatment, both 
desired and adverse, to be appropriately compared against active treatment, with effort to minimize 
treatment period on PBO, as well as to allow continuation of certain background therapy within 
protocol-defined limits (see Section SLE 5.1, Inclusion criterion #4). 
 
Justification for Dose 
The selection of the branebrutinib dose and regimen to be assessed in this study was based on 
findings of the FIH and nonclinical studies. 
In the MAD panels (Part B) of the FIH study (Study IM014001), healthy subjects received 
branebrutinib orally QD for 14 days at 4 dose levels (0.3, 1, 3, and 10 mg; n = 6 per dose).37
Increases in Cmax and AUC(TAU) were approximately dose proportional within the dose levels 
tested. The mean T-HALF was shorter than 2 hours across the dose range tested, indicating that 
branebrutinib was rapidly eliminated from the body. Consequently, as expected, accumulation at 
steady-state after multiple daily dosing was negligible. 
The safety between branebrutinib 3 mg and 10 mg doses in Study IM014001 demonstrated lack of 
dose effects on safety. The drug was well-tolerated at both dose levels with most AEs also observed 
for the subjects treated with PBO. The AEs mainly included headache and upper respiratory tract 
infection. Based on the AUC in rats at the NOAEL (61,900 QJKP/ WKH VDIHW\ PXOWLSOH LQ
humans after multiple doses of 10 mg is > 500×.12 In this study, the dose level of branebrutinib 
will be 9 mg; therefore, the safety margin is sufficient for humans participating in the study. 
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The dose for branebrutinib was selected based on data from biomarkers obtained in post-hoc 
analysis of Study IM014001. The biomarkers evaluated were BTK occupancy by branebrutinib, 
inhibition of ex vivo stimulated CD69 expression, and plasma CXCL13 levels. The maximum 
RFFXSDQF\UHDFKHGDWEUDQHEUXWLQLEGRVHVRI mg and above (100%; maximum occupancy 
DWGRVHV 3 mg); however, the time to reach maximum occupancy was faster and maintained for 
a longer duration at 3 mg and 10 mg doses (solution formulation). The variability of the effect was 
lower for the higher dose of 10 mg. A similar result was obtained for CD69 inhibition, while the 
largest median inhibition in CD69 expression was observed at the branebrutinib 10 mg dose. The 
highest inhibition of plasma levels of CXCL13 was also obtained at the 10 mg dose level. 
Considering the higher variability and expression of BTK in patients with immune-mediated 
disorders,4 the higher dose is expected to sustain more stable inhibition of BTK for chronic 
treatment of heterogenous patients. 
The comparison of exposure between the branebrutinib 10 mg solution formulation from 
Study IM014001 and the branebrutinib 9 mg capsule formulation (3 × 3 mg) from Day 1 Cycle 2 
in Study IM014023 demonstrated comparable exposure for Cmax and AUC(TAU) with only slight 
delay in Tmax for capsule formulation. Thus, the use of 3 × 3 mg capsules of branebrutinib is 
expected to be equivalent to the 10 mg solution formulation in terms of exposure, safety, and PD 
effects considering the specifics of the patient population. 
The exposure for this dose level is also much lower than the safety limit for exposure identified in 
preclinical studies; as previously mentioned, based on the AUC in rats at the NOAEL, the safety 
multiple in humans after multiple doses of 10 mg is > 500×. 
In summary, the dose to evaluate the PD response with optimal safety and efficacy was chosen to 
be branebrutinib 9 mg administered as 3 × 3 mg capsules (details of treatment administration are 
provided in Section SLE 6.1). 
SLE 5 
STUDY POPULATION 
Eligibility criteria for this sub-protocol have been carefully considered for the safety of the study 
subjects and to ensure that the results of the study can be interpreted. It is imperative that 
randomized subjects meet all eligibility criteria. 
Screening evaluations must be completed and reviewed by the investigator to confirm whether 
potential subjects are eligible. The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. Subject eligibility will be reviewed and confirmed by the Medical Monitor or 
 
Lupus Central Review Services prior to randomization. 
 
Inclusion Criteria 
In order to be eligible to participate in this SLE sub-protocol, an individual must meet all of the 
following criteria: 
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1) Signed Written Informed Consent: SLE Sub-protocol 
a) Willing to participate in the study after completing all informed consent procedures and 
sign the informed consent form (ICF). 
b) Willing and able to complete all study-specific procedures and visits. 
2) Age and Reproductive Status: SLE Sub-protocol 
a) Not Applicable per Revised Protocol 02 - Male and female patients, aged 18 (or age of 
majority) to 65 years, inclusive 
b) Not Applicable per Revised Protocol 02 - WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic 
JRQDGRWURSLQ>ȕ-HCG]) within 24 hours prior to the start of study treatment. 
c) Not Applicable per Revised Protocol 02 - Women must not be breastfeeding. 
d) Not Applicable per Revised Protocol 02 - WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) 
branebrutinib or PBO, 30 days before screening and 33 days posttreatment completion or 
longer based on country-specific label for other background therapy. 
e) Not Applicable per Revised Protocol 02 - Male subjects who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception and fetal 
protection (APPENDIX 4) for the duration of treatment with study treatment(s) 
(branebrutinib or PBO) plus 33 days after the final dose of study treatment, or longer based 
on country-specific label for other background therapy. In addition, male subjects must be 
willing to refrain from sperm donation during this time. 
f) Not Applicable per Revised Protocol 02 - WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements, and still must undergo 
pregnancy testing as described in this section. 
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention, the implications of an unexpected pregnancy and the 
potential of fetal toxicity occurring due to transmission of study drug, present in seminal fluid, to 
a developing fetus, even if the participant has undergone a successful vasectomy or if the partner 
is pregnant. 
x The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention. 
x Local laws and regulations may require the use of alternative and/or additional contraception 
methods. 
g) Not Applicable per Revised Protocol 03 - Female Participants 
h) Not Applicable per Revised Protocol 03 - Male Participants 
i)  Female Subjects 
i) Females ages 18 years or local age of majority to 75 years, inclusive. 
ii) Women who are not of childbearing potential are exempt from contraceptive 
requirements. Women subjects must have documented proof that they are not of 
childbearing potential. 
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iii) WOCBP must have a negative highly sensitive pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study 
treatment. 
1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
iv) Additional requirements for pregnancy testing during and after study intervention are 
located in Section SLE 1.3, SoA 
v) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
vi) WOCBP must agree to follow instructions for method(s) of contraception defined in 
APPENDIX 4 and as described below and included in the ICF. 
vii) WOCBP are permitted to use hormonal contraception methods (as described in 
APPENDIX 4). 
viii) 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
1) Is not a WOCBP 
OR 
2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year) preferably with low user dependency, as described in 
APPENDIX 4 during the intervention period, for at least 30 days before screening 
and at least 33 days posttreatment completion or longer based on country-specific 
label for other background therapy and agrees not to donate eggs (ova, oocytes) for 
the purpose of reproduction for the same time period. 
j) Male Subjects 
 
 
i) Males ages 18 years or local age of majority to 75 years, inclusive 
ii) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in APPENDIX 4 and as described below. 
iii) Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. 
iv) Male subjects will be required to always use a latex or other synthetic condom during 
any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the subjects have 
undergone a successful vasectomy or if their partner is already pregnant or 
breastfeeding. Males should continue to use a condom during the intervention period 
and for at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
v) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 
33 days after the last dose of study intervention in the male participant or longer based 
on country-specific label for other background therapy. 
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vi) Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, 
oral) even if the subjects have undergone a successful vasectomy, during the 
intervention period and for at least 33 days after the last dose of study intervention or 
longer based on country-specific label for other background therapy. 
vii) Male subjects must refrain from donating sperm during the intervention period and for 
at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
viii) Breastfeeding partners should be advised to consult their healthcare providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms. 
3) Type of Subject and Target Disease Characteristics: SLE Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Meets Systemic Lupus Erythematosus 
International Collaborating Clinics (SLICC) classification criteria for SLE and diagnosed 
ZLWK6/( 24 weeks before the screening visit. 
b) Not Applicable per Revised Protocol 03 - (OHYDWHGDQWLQXFOHDUDQWLERGLHV$1$ 1:80 
or positive (per central laboratory excluding results in the equivocal range) 
anti-double-stranded deoxyribonucleic acid (dsDNA) or positive anti-Sm, as determined 
by the central laboratory, at the screening visit; if initial results for any of these are negative 
at screening such that a subject would be deemed a screen failure, then 1 retest will be 
allowed for subjects with a documented history of positive results. 
c) P&/$6, DFWLYLW\ VFRUH  10 (excluding mucous membrane ulcerations, and diffuse 
non-inflammatory alopecia) 
d) Not Applicable per Revised Protocol 03 - &6SUHGQLVRQHRUHTXLYDOHQW 40 mg/day 
e)  Meets SLICC 2012 classification criteria for SLE anGGLDJQRVHGZLWK6/( 24 weeks 
before the screening visit. 
f (OHYDWHG DQWLQXFOHDU DQWLERGLHV $1$  1:80 or positive anti-double-stranded 
deoxyribonucleic acid (dsDNA) (excluding results in the equivocal range) or positive 
anti-Smith (Sm), as determined by the central laboratory at the screening visit; if initial 
results for all of these are negative at screening such that a subject would be deemed a 
screen failure, then 1 retest will be allowed for subjects with a documented history of 
positive results. 
g) For subjects taking CS, the dose cannot exceed 40 mg/day prednisone or equivalent 
4) Medications for Target Disease: SLE Sub-protocol 
a) Requirements for subjects who are receiving chronic therapy with nonsteroidal 
anti-inflammatory drugs (NSAIDs; including marketed cyclooxygenase-2 inhibitors) are 
as follows; exceptions or changes may be possible with approval by the 
 Medical 
Monitor: 
i.  Doses must be stable for 14 days before the screening visit and must remain stable until 
randomization and throughout the study. 
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ii. No more than 1 oral NSAID may be used concurrently during the study and may be 
combined with topical NSAIDs. 
iii. Use of 1 or more topical NSAIDs is permitted but must follow a stable regimen 
throughout the study. 
b) Not applicable per Revised Protocol 03 - Standard of care that is allowed in this study 
PXVWKDYHEHHQWDNHQIRU 12 weeks before the screening visit and must be at a stable dose 
IRU  8 weeks before the screening visit and remain stable until randomization and 
throughout study participation. Details for specific medications are as follows: 
Antimalarials: chloroquine, HCQ, or quinacrine; monotherapy is permitted. Also see 
exclusion criteria below regarding HCQ dose limitation and exclusionary screening HCQ 
levels. Patients on HCQ must have an ophthalmology assessment within 6 months prior to 
randomization, confirming no findings of HCQ induced retinal toxicity. 
Immunosuppressants (combinations of these are NOT permitted): 
i. 
Azathioprine (maximum 200 mg per day). 
ii. 
6-mercaptopurine (6-MP, maximum 1.5 mg/kg per day). 
iii. 
MTX: Subjects are permitted to continue MTX provided that the dose is stable for 
 12 weeks prior to randomization and remains stable throughout the study. 
Decrease in dose or discontinuation is permitted for AEs or intolerance. 
iv. 
Leflunomide (20 mg per day). 
v. 
Mycophenolate mofetil/mycophenolic acid (MMF). Note: Subjects who are 
receiving MMF may participate in the study only if administered as a maintenance 
therapy and up to a maximum of 2 g/day (or equivalent); in subjects of African 
ancestry, 3 g/day (or equivalent) is acceptable. 
vi. 
Dapsone (maximum 100 mg per day). 
c) Not applicable per Revised Protocol 03 - CS (prednisone or equivalent) background 
therapy is permitted but not required. For subjects taking CS, the dose must be stable for 
 2 weeks before the screening visit, cannot exceed 40 mg/day at screening, and must 
remain stable until randomization. Further specifications are as follows: 
o Topical and inhaled CS use is permitted but must follow a stable regimen throughout 
the study and cannot be used on an as-needed basis. Discontinuation of topical steroids 
should be allowed if lesions/rash resolve completely. Inhaled CS for nonlupus 
conditions will not count against the maximum CS dose. 
o Patients are ineligible if they received intramuscular (IM), intra-articular (IA), 
intrabursal, IV, and modified-release CS use within 4 weeks prior to randomization. 
d) SOC that is allowed in this study must include at least one of the following: 
Antimalarials, Immunosuppressants, or oral CS 
$QWLPDODULDOVDQGRU,PPXQRVXSSUHVVDQWVPXVWKDYHEHHQWDNHQIRU 12 weeks before the 
VFUHHQLQJYLVLWDQGPXVWEHDWDVWDEOHGRVHIRU 8 weeks before the screening visit and remain 
stable until randomization and throughout study participation. Details for Antimalarials and/or 
Immunosuppressants are as follows: 
x Antimalarials: chloroquine, HCQ, or quinacrine; monotherapy is permitted. Also see 
exclusion criteria below regarding HCQ dose limitation and exclusionary screening 
HCQ levels. Subjects on HCQ must have an ophthalmology assessment within 
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6 months prior to randomization, confirming no findings of HCQ induced retinal 
toxicity. 
x Immunosuppressants (combinations of these are NOT permitted): 
o Azathioprine (maximum 200 mg per day). 
o 6-mercaptopurine (6-MP, maximum 1.5 mg/kg per day). 
o MTX: Subjects are permitted to continue MTX provided that the dose is stable for 
 12 weeks prior to randomization and remains stable throughout the study. 
Decrease in dose or discontinuation is permitted for AEs or intolerance. 
o Leflunomide (20 mg per day). 
o Mycophenolate mofetil/mycophenolic acid (MMF). Note: Subjects who are 
receiving MMF may participate in the study only if administered as a maintenance 
therapy and up to a maximum of 2 g/day (or equivalent); in subjects of African 
ancestry, 3 g/day (or equivalent) is acceptable. 
o Dapsone (maximum 100 mg per day). 
e) CS (prednisone or equivalent), as follows: 
o )RUVXEMHFWVWDNLQJRUDO&6DVPRQRWKHUDS\&6PXVWKDYHEHHQWDNHQIRUZHHNV
prior tRWKHVFUHHQLQJYLVLWDWDGRVH PJGD\DQG mg/day prednisone (or 
SUHGQLVRQHHTXLYDOHQWPXVWEHDWDVWDEOHGRVHIRUZHHNVSULRUWRWKHVFUHHQLQJ
visit and remain stable until randomization. 
o For subjects taking oral CS not as monotherapy, the CS dose must be stable for 
 2 weeks before the screening visit, cannot exceed 40 mg/day at screening, and 
must remain stable until randomization. 
o Topical and inhaled CS use is permitted but must follow a stable regimen 
throughout the study and cannot be used on an as-needed basis. Discontinuation of 
topical steroids should be allowed if lesions/rash resolve completely. Inhaled CS 
for nonlupus conditions will not count against the maximum CS dose. 
o Subjects are ineligible if they received IM, IA, intrabursal, IV, and modified-release 
CS use within 4 weeks prior to randomization. 
5) Other Inclusion Criteria: SLE Sub-protocol 
a) Subject re-enrollment (rescreening): This study permits the re-enrollment of a subject who 
has discontinued the study as a pretreatment (screening) failure (ie, subject has not been 
randomized/has not been treated). If re-enrolled, the subject must be re-consented. 
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Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in the 
SLE sub-protocol: 
1) General Medical Conditions and History: SLE Sub-protocol 
a) Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, psychiatric) or 
local active infection/infectious illness that, in the investigator’s judgment, will 
substantially increase the risk to the subject if he or she participates in the study. 
b) Any major surgery within the last 30 days before the first dose of study treatment, or any 
surgery planned during the course of the study. 
c) Cancer or history of cancer or lymphoproliferative disease (other than adequately treated 
cutaneous basal cell or squamous cell carcinoma with no evidence of recurrence within the 
previous 5 years), including pre-lymphoma (pseudolymphoma of the orbit and small 
intestine, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, and 
lymphoid interstitial pneumonitis). 
d) Class III or IV congestive heart failure as defined by the New York Heart Association 
(NYHA) or any recent onset of heart failure resulting in NYHA Class III/IV symptoms 
e) Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or any 
history of significant cerebrovascular disease within 24 weeks before the screening visit. 
f) Current or recent (within 3 months before randomization) gastrointestinal disease, 
including gastrointestinal surgery, that could impact the absorption of study treatment. 
g) Not Applicable per Revised Protocol 03 - Subjects with non-SLE concomitant illness 
that, in the opinion of the investigator, is likely to require additional systemic 
glucocorticosteroid therapy during the study (eg, asthma). 
h) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks before 
randomization. 
i) Inability to tolerate oral medication. 
j) Inability to tolerate venipuncture and/or inadequate venous access. 
k) Recent (within 6 months before randomization) drug or alcohol abuse as defined by the 
Diagnostic Criteria for Drug and Alcohol Abuse in the Diagnostic and Statistical Manual 
of Mental Disorders 5 (DSM 5). 
l) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator. 
m) Subjects with a diagnosis of antiphospholipid antibody syndrome. 
n) Any prior history of atrial fibrillation or flutter. 
o) Subjects with non-SLE concomitant illness that, in the opinion of the investigator, is likely 
to require additional systemic CS therapy during the study (eg, asthma). 
2) Findings Related to Possible Infection: SLE Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Any of the following TB criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment. 
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o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) during 
screening as judged by the investigator. 
– Any imaging of the chest (eg, chest x-ray, chest computed tomography [CT] scan) 
obtained during the screening period, or anytime within 6 months prior to 
screening, with documentation showing evidence of current active or old 
pulmonary TB 
o LTBI defined as positive IFN gamma-release assay (IGRA), by QuantiFERON-TB 
Gold testing at screening, in the absence of clinical manifestations Note: Subject may 
be eligible if (i) there are no current signs or symptoms of active TB and (ii) the subject 
has received adequate documented treatment for LTBI within 5 years of screening. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB must 
be retested for confirmation. If the second test is again indeterminate the subject will 
be excluded from the study. If the retest is positive, the subject should be treated as 
having LTBI. If the retest is negative, subject may be eligible provided no other 
exclusion criteria for TB are met. 
b) Hepatitis C virus (HCV), hepatitis B virus (HBV), or human immunodeficiency virus 
(HIV) infection as demonstrated by a positive blood screen for HCV antibody confirmed 
by positive reflex HCV RNA test, hepatitis B surface antigen (HBsAg), hepatitis B core 
antibody (HbcAb), or HIV-1 and -2 antibody. Subjects who have been vaccinated for 
hepatitis B (hepatitis B surface antibody [HbsAb]-positive) are not excluded. 
Note: Subjects who are newly found to be HIV-positive should be directed to appropriate 
follow-up care. 
c) History of congenital or acquired immunodeficiency. 
d) Known active infection, or any major episode of infection requiring hospitalization or 
treatment with parenteral (IM or IV) antimicrobial agents (eg, antibiotics, antiviral, 
antifungal, or antiparasitic agents) within 30 days of randomization, or completion of oral 
antimicrobial agents within 2 weeks of randomization. 
e) Previous history of recurrent herpes zoster (more than 1 episode), disseminated herpes 
simplex, or influenza infection within 12 weeks before randomization or a history of 
disseminated/complicated herpes zoster infection (multidermatomal involvement, 
ophthalmic zoster, central nervous system involvement, or postherpetic neuralgia). 
f) Chronic infection within 4 weeks of randomization (eg, pneumocystis, cytomegalovirus 
[CMV], invasive bacterial or fungal infections, or atypical mycobacteria). 
g) Any of the following TB criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment. 
o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) during 
screening as judged by the investigator. 
- Any imaging of the chest (eg, chest x-ray, chest CT scan) obtained during the 
screening period, or anytime within 6 months prior to screening, with 
documentation showing evidence of current active or old pulmonary TB. 
o LTBI defined as positive IGRA, by QuantiFERON-TB Gold testing at screening, in the 
absence of clinical manifestations. Note: Subject may be eligible if (i) there are no 
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current signs or symptoms of active TB and (ii) the subject has received adequate 
documented treatment for LTBI within 5 years of screening; this treatment must have 
been completed as defined by local guidance and documented in the subject study file. 
Incomplete or ongoing treatment is unacceptable. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB must 
be retested for confirmation. If the second test is again indeterminate, the subject will 
be excluded from the study, unless there is documentation of a local negative TB Spot 
test result. If the retest is positive, the subject should be treated as having LTBI. If the 
retest is negative, the subject may be eligible provided no other exclusion criteria for 
TB are met. 
h) Subjects hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well as any subjects 
with any sequelae of prior COVID-19 infection at screening, regardless of time since 
infection. 
3) Allergies and Adverse Drug Reaction: SLE Sub-protocol 
a) History of allergy to BTK inhibitors or related compounds 
b) History of any serious condition induced by drug allergy (such as anaphylaxis or 
hepatotoxicity) 
4) Target Disease Exclusions/Exceptions: SLE Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Subjects with other immune-mediated diseases 
(eg, scleroderma, mixed connective tissue disease, multiple sclerosis, psoriasis, 
inflammatory bowel disease, etc) are excluded. Subjects with Type 1 autoimmune diabetes 
mellitus, thyroid autoimmune disease, antiphospholipid syndrome, or secondary Sjögren’s 
syndrome are not excluded. 
b) Not Applicable per Revised Protocol 03 - Subjects with drug-induced lupus, or active or 
unstable lupus neuropsychiatric manifestations, including but not limited to any condition 
defined by British Isles Lupus Assessment Group (BILAG) A criteria, are excluded, with 
the exception of subjects with mononeuritis multiplex and polyneuropathy, which are 
allowed with approval by the Medical Monitor or Lupus Central review Services 
 
c) Not Applicable per Revised Protocol 03 - Subjects with active, severe lupus nephritis 
(World Health Organization Class III or IV) that requires or may require treatment with 
cytotoxic agents or high-dose CS are excluded. Subjects with prior controlled renal disease 
ZLWKVHUXPFUHDWLQLQH 2× upper limit of normal (ULN) and either residual proteinuria 
 3 JGD\RUDXULQHSURWHLQFUHDWLQLQHUDWLR83&5RI 3 mg/mg or 339 mg/mmol are 
allowed. Stability of renal disease must be documented with at least 2 measurements of 
proteinuria or UPCR over the past 6 months or with 2 tests during the screening period at 
least 1 week apart and must be approved by the Medical Monitor. 
d) Active fibromyalgia with pain symptoms or signs that would interfere with joint 
assessment or requiring adjustment in medication within the 3 months before screening to 
control symptoms. Subjects with fibromyalgia that is well controlled on stable treatment 
may otherwise be included. 
e) Subjects with other immune-mediated diseases (eg, scleroderma, mixed connective tissue 
disease, multiple sclerosis, psoriasis, inflammatory bowel disease, etc) are excluded. 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
69 
Subjects with Type 1 autoimmune diabetes mellitus, thyroid autoimmune disease, or 
secondary Sjögren’s syndrome are not excluded. 
f) Subjects with drug-induced lupus, or active or unstable lupus activity in the 
neuropsychiatric body system, including but not limited to those resulting in a British Isles 
Assessment Group (BILAG-2004) A grade are excluded, with the exception of subjects 
with mononeuritis multiplex and polyneuropathy, which are allowed with approval by the 
Medical Monitor or 
 Lupus Central Review Services. 
g) Subjects with active, severe lupus nephritis (World Health Organization Class III or IV) 
that requires or may require treatment with cytotoxic agents or high-dose CS are excluded. 
6XEMHFWVZLWKSULRUFRQWUROOHGUHQDOGLVHDVHZLWKVHUXPFUHDWLQLQH 2× ULN and either 
UHVLGXDO SURWHLQXULD  3 g/day or a UPCR RI  3 mg/mg or 339 mg/mmol are allowed. 
Stability of renal disease must be documented with at least 2 measurements of proteinuria 
or UPCR over the past 6 months or with 2 tests during the screening period at least 1 week 
apart and must be approved by the Medical Monitor. 
5) Prior/Concomitant Therapy: SLE Sub-protocol 
a) Inability to comply with restrictions and prohibited treatments as listed in Section SLE 6.7 
Concomitant Therapy; inability to comply with discontinuation requirements 
(Section SLE 7.1). 
b) Not applicable per Revised Protocol 03 - Prior exposure to BTK inhibitors such as 
ibrutinib, acalabrutinib, or experimental drugs (eg, tirabrutinib, vecabrutinib, zanibrutinib, 
ARQ-531, GDC-0853, or others). 
c) Other investigational agents must be discontinued at least 12 weeks or 5 half-lives before 
the screening visit, whichever is longer. 
d) Exposure to JAK inhibitors such as tofacitinib, baricitinib, filgotinib, or upadacitinib within 
8 weeks prior to randomization or during the study. 
e) Required discontinuation periods for immunomodulatory drugs (eg, cyclosporine, 
tacrolimus, etc) or biologic drugs (including those specifically listed below) are provided 
in SLE Table 6. If a drug is not specifically listed, consult the 
 Medical Monitor for 
guidance. Usual discontinuation periods are 4 weeks or 5 half-lives, whichever is longer. 
f) Belimumab therapy within 6 months before randomization or during the study 
g) Subjects who have taken rituximab within 12 months prior to randomization; for subjects 
who received rituximab prior to this 12-month period, the B cell count should be within 
normal range. Rituximab is prohibited during the study. 
h) Abatacept therapy within 6 months prior to randomization or during the study. 
i) Therapy with other biologics such as tocilizumab and anakinra within 8 weeks prior to 
randomization or during the study. 
j) Cyclosporine or tacrolimus therapy within 8 weeks prior to randomization or during the 
study. 
k) Therapy with sulfasalazine, or similar drugs within 8 weeks prior to randomization or 
during the study. 
l) IV immunoglobulin (IVIG) within 8 weeks prior to randomization or during the study. 
m) Diquafosol or rebamipide therapy within 4 weeks before randomization or during the 
study. 
2.0
Approved
930168072
2.0
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Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
70 
n) For oral CS restrictions, see Section SLE 5.1. 
o) IM, IV, IA, intrabursal, or modified-release CS treatment within 4 weeks prior to 
randomization or during the study. 
p) Not Applicable per Revised Protocol 01 - Treatment with disease-modifying 
antirheumatic drugs (DMARD) treatments or immunomodulators other than 
MTX < 8 ZHHNVSULRUWRUDQGRPL]DWLRQ7KH07;GRVHPXVWEHVWDEOHIRU 12 weeks; 
new initiation or dose changes during treatment are not permitted. 
q) Not Applicable per Revised Protocol 03 - Antimalarial treatments (chloroquine and 
quinacrine) are permitted but must be stable; new initiation or change in dose during 
treatment is not permitted. HCQ whole blood concentration > 2 μg/mL (at screening 
only) is exclusionary. HCQ dose > 400 mg/day, new initiation, or dose increases during 
treatment are not permitted. 
r) Anti-TNF therapy such as adalimumab, certolizumab, etanercept, golimumab, infliximab, 
or TNF biosimilars within 3 months prior to randomization or during the study. 
s) Not applicable per Revised Protocol 03 - Administration of a live vaccine within 90 days 
or an inactivated vaccine within 30 days before randomization; furthermore, live or 
inactivated vaccines should not be used during treatment or within the 14 days following 
last dose. 
t) Treatment with anticoagulant or antiplatelet therapies, including aspirin for 
cardioprotection, within 2 weeks prior to randomization or during the study. 
u) Prior exposure to BTK inhibitors such as ibrutinib, acalabrutinib, or experimental drugs 
(eg, tirabrutinib, vecabrutinib, zanubrutinib, ARQ-531, fenebrutinib [GDC-0853], or 
others). 
v) Not applicable per Revised Protocol 03 - Treatment with DMARDs (excluding HCQ) or 
immunomodulators within 4 weeks before randomization; MTX treatment within 
12 weeks before randomization or during the study. HCQ whole blood concentration 
>2 μg/mL (at screening only) is exclusionary. HCQ dose > 400 mg/day, new initiation 
or dose increases during treatment are not permitted. 
w) Antimalarial treatments (chloroquine, HCQ, and quinacrine) are permitted but must be 
stable; new initiation or change in dose during treatment is not permitted. HCQ whole 
blood concentration > 2 μg/mL (at screening only) is exclusionary. HCQ dose 
> 400 mg/day, new initiation, or dose increases during treatment are not permitted. 
x) Administration of all live vaccines is prohibited within 90 days before randomization. 
Administration of inactivated vaccines and nonlive vaccines, including those for influenza 
and SARS-CoV-2, is prohibited within 30 days before randomization. See SLE Table 6 for 
corresponding on-treatment and posttreatment restrictions. 
y) Treatment with DMARDs (excluding HCQ) or immunomodulators beyond required 
washout period before randomization; MTX treatment within 12 weeks before 
randomization or during the study. HCQ whole blood concentration > 2 μg/mL (at 
screening only) is exclusionary. HCQ dose > 400 mg/day, new initiation, or dose 
increases during treatment are not permitted. 
6) Physical and Laboratory Test Findings: SLE Sub-protocol 
a) Clinically significant abnormalities on chest x-ray or ECG 
2.0
Approved
930168072
2.0
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Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
71 
b) Clinically significant abnormalities in laboratory tests including the following: 
i. 
Serum alanine aminotransferase (ALT) > 2× ULN 
ii. 
Serum aspartate aminotransferase (AST) > 2× ULN 
iii. 
Serum total bilirubin > 1.5× ULN (does not apply to subjects with Gilbert’s 
syndrome) 
iv. 
Hemoglobin < 8 g/dL (< 80 g/L) or, if due to hemolytic anemia related to SLE, 
< 7 g/dL (< 70 g/L) 
v. 
Proteinuria > 3.0 g/day (> 3,000 mg/day) or equivalent level of proteinuria as 
assessed by UPCR (3 mg/mg or 339 mg/mmol) 
vi. 
Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 as calculated by 
the central laboratory 
vii. 
Serum creatinine > 2.0 mg/dL (> 177 ȝPRO/ 
viii. 
Absolute WBC count < 2.5× 103ȝ/ 2.5× 109/L) 
ix. 
Neutrophil count < ȝ/ 1.0× 109/L) 
x. 
Platelet count < 75× 103ȝ/ 75× 109/L), if considered part of SLE disease activity 
without increased risk of bleeding 
c) Any other significant laboratory or procedure abnormalities that, in the opinion of the 
investigator, might pose unacceptable risk to the subject during the study 
d) Blood pressure (BP) > Grade 1 hypertension (> 159 mmHg systolic and > 99 mmHg 
diastolic) according to the 2018 ESC/ESH Guidelines for the management of arterial 
hypertension. 
e) The following exclusionary ECG observations: 
i. 
QT interval with Fridericia's correction (QTcF): > 480 msec 
ii. 
QRS: > 120 msec 
iii. 
Complete heart block 
iv. 
Left bundle branch block 
v. 
Mobitz II second-degree atrioventricular block 
vi. 
Atrial fibrillation or flutter 
7) Other Exclusion Criteria: SLE Sub-protocol 
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances and subject to local law a person who has been imprisoned may be included 
or permitted to continue as a subject. Strict conditions apply and BMS approval is 
required.) 
b) Subjects who are employed by the Sponsor, clinical research organizations, or study site 
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
d) Inability to comply with the study protocol 
e) Inability to comply with restrictions as listed in Section SLE 5.3 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
72 
 
Lifestyle Restrictions 
Study restrictions for contraception use by WOCBP and male subjects who are partners of 
WOCBP (APPENDIX 4) are required for this study. 
 Meals and Dietary Restrictions 
With the exception of the 8-hour fasting requirement prior to blood sample collection for lipid 
panel and fasting glucose blood testing, no meal or dietary restrictions are required for this study. 
However, subjects are advised to consume in moderation (avoiding more than a single serving a 
day) cruciferous vegetables, such as cabbage, brussels sprouts, watercress, etc, as well as grapefruit 
and Seville oranges. Quinine (tonic water), St. John’s wort and herbal medications are not allowed. 
 Caffeine, Alcohol, Tobacco, and Cannabinoids 
With the exception of cannabinoid products, which are not allowed, and prohibited alcohol abuse 
as defined by the Diagnostic Criteria for Drug and Alcohol Abuse in the DSM 5 within six months 
prior to randomization, and prohibited alcohol use in subjects receiving MTX therapy 
(see Section SLE 5.2), there are no restrictions on caffeine, alcohol, or tobacco use for this study. 
However, subjects who use tobacco or alcohol should be counseled for potential contraindications 
with nonstudy treatments as appropriate, and continued study participation should be based on 
investigator judgment. Subjects are advised to abstain from excessive consumption of 
caffeine-containing drinks. 
 Activity 
With the exception of the restrictions surrounding the use of contraceptives during sexual activity 
mentioned above and included in the SoA (Section SLE 1.3), no activity restrictions are required 
for this study. 
 Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but who are 
not subsequently randomized or entered in the study or included in the analysis population. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any SAEs. Additional screening data from screen failure subjects, such as clinical data for disease 
assessment, laboratory tests, and other clinically relevant data, may be required. 
 Rescreening and Retesting During Screening Period 
This SLE sub-protocol permits the rescreening of a subject who has been previously screen failed. 
If rescreened, the subject must be re-consented and will be assigned a new identification number, 
and a full screening visit must be performed again. A subject can only be rescreened 1 time (ie, if 
the subject fails 1 rescreening attempt, no additional rescreening is allowed). 
2.0
Approved
930168072
2.0
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Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
73 
Laboratory parameters and/or other assessments that are included in SLE Table 1 (Screening 
Procedural Outline for SLE sub-protocol) that initially do not meet eligibility requirements within 
the screening period may be repeated once in an effort to find all possible well-qualified subjects. 
Consultation with the Medical Monitor or 
 Lupus Central Review Services may be needed to 
identify whether repeat testing of any particular parameter is clinically relevant. 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the subject’s most current clinical state. 
SLE 6 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), PBO, or 
medical device intended to be administered to a study subject according to the study randomization 
or treatment allocation. 
Study 
treatment 
includes 
both 
Investigational 
(Medicinal) 
Product 
(IP/IMP) 
and 
Noninvestigational (Medicinal) Product (non-IP/Non-IMP) and is shown in SLE Table 4. 
An IP, also known as IMP in some regions, is defined as a pharmaceutical form of an active 
substance or PBO being tested or used as a reference in a clinical study, including products already 
with a marketing authorization but used or assembled (formulated or packaged) differently than 
the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs. 
SLE Table 4 Study Treatments for IM014029 
Product 
Description and 
Dosage Forma
Potency 
IP/ 
Non-IP 
Blinded or 
Open-Label 
Packaging/ 
Appearance 
Storage 
Conditions 
(Per Label) 
Branebrutinib 
oral capsule 
3 mg dose × 3 
capsules 
(9 mg total 
dose) 
IP 
Blinded 
HDPE bottles 
(33 capsules/bottle) with 
child-resistant cap and heat-
induction seal (tamper-
evidence and moisture 
barrier); size #0 hard gelatin 
capsules 
Store refrigerated 
at 2°C to 8°C 
(36°F to 46°F) in 
original 
packaging; 
protected from 
moisture 
PBO matching 
Branebrutinib 
oral capsule 
NA 
IP 
Blinded 
HDPE bottles 
(33 capsules/bottle) with 
child-resistant cap and heat-
induction seal (tamper-
evidence and moisture 
barrier); size #0 hard gelatin 
capsules 
Store refrigerated 
at 2°C to 8°C 
(36°F to 46°F) in 
original 
packaging; 
protected from 
moisture 
HDPE = high-density polyethylene; IP = investigational product; NA = not applicable; PBO = placebo 
a Dosages of 0.5 mg are also available but are not planned for use in this protocol.
2.0
Approved
930168072
2.0
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Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
74 
 
Treatments Administered 
The investigator must ensure that the IP will be used only in accordance with the protocol. The 
selection and timing of dose for each subject is shown in SLE Table 5. Study treatment will be 
supplied in bottles (branebrutinib and PBO). If a subject forgets a dose, but remembers within 
12 hours of the expected dose, the dose should be taken. Any dose > 12 hours should be missed, 
and the next expected dose should be taken at the usual time. No dose reductions or modifications 
are allowed. 
SLE Table 5 
Selection and Timing of Dose 
Study Treatment 
Unit Dose Strength 
Dosage Formulation Frequency of 
Administration 
Route of 
Administration 
Branebrutinib 9 mg 
3 mg 
3 active capsules; QD 
Oral 
PBO 
0 mg 
3 PBO capsules; QD 
Oral 
PBO = placebo; QD = once daily 
Note: At all study visits, the study treatment should not be taken at home but should be taken to 
the site by the subject; at the site, the study treatment should be taken only when instructed by the 
site study staff according to the schedule listed below. These requirements also apply to 
concomitant medications at Day 1 and Week 4 only; at these visits, concomitant medications will 
be administered together with the study treatment at the site. 
When multiple assessments are conducted at a single visit, the following is the order in which they 
should be performed: 
1. Patient-reported Outcomes (eg, Subject Global Assessment [SGA], EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, Physician Global Assessment [PGA], joint count, 
etc)
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
Doses of branebrutinib at 9 mg (3x3 mg capsules) or matching placebo are to be administered 
orally q24h (one time/day) with water and may be taken with or without food. The drug should be 
taken every morning at approximately the same time. 
On Day 1 and at Weeks 4, 8, 16, and 24, study drug will be administered in the morning at the 
study site after blood samples have been collected and questionnaires have been completed. In 
addition, on Day 1 and at Week 4, branebrutinib will be administered together with concomitant 
medications to allow predose sampling for concomitant medication. Branebrutinib and 
concomitant medications are to be taken together with water. 
2.0
Approved
930168072
2.0
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Approved
1.0
v


Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
75 
 
Method of Treatment Assignment 
Subjects will be centrally randomized according to a computer-generated block randomization 
scheme using IRT to the SLE sub-protocol depending on disease type determined at screening. 
Subjects in this sub-protocol will be randomized in a 3:1 ratio to receive double-blind 
branebrutinib 9 mg or PBO QD from Week 0 to Week 24. 
At the time of the screening visit, after written informed consent is obtained and before any 
study-related procedures are performed, the investigative site will access the enrollment option of 
the IRT system for assignment of a subject number. This number is assigned sequentially by the 
system and will be unique across all sites. If a potential subject is rescreened, a new identification 
number will be used. 
Randomized schedules will be generated by the IRT vendor. 
Randomization will be stratified by immunosuppressant use (yes/no). 
Before the study is initiated, each investigator will receive log-in information and directions on 
how to access the IRT. Study treatment will be dispensed at the study visits as listed in the SoA
(Section SLE 1.3). 
 
Blinding 
Blinded treatment assignments will be managed using IRT. All capsules (branebrutinib 3 mg and 
PBO) are identical in appearance. Capsules will be supplied in tamper-evident high-density 
polyethylene (HDPE) bottles with each daily dose made up of either active or PBO capsules (as 
presented in SLE Table 4). Investigative site staff, Sponsor and designee personnel, and subjects 
and their families will remain blinded to treatment assignments. 
 
 
 
 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the IP 
is critical to the subject’s management, the blind for that subject may be broken by the investigator. 
The subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded 
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the IP, the 
problem may be properly managed by assuming that the subject is receiving active product. It is 
highly desirable that the decision to unblind treatment assignment be discussed with the Medical 
Monitor, but the investigator always has ultimate authority for the decision to unblind. The 
Principal Investigator (PI) should only call in for emergency unblinding AFTER the decision to 
discontinue the subject has been made. 
2.0
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930168072
2.0
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1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
76 
In case of an emergency, the investigator has unrestricted access to randomization information via 
IRT and is capable of breaking the blind through the IRT system without prior approval from the 
Sponsor. After the unblinding, the investigator shall notify the Medical Monitor and/or study 
director. For information on how to unblind in an emergency, consult the IRT manual. Subject and 
unblinded treatment information and the reason for the blind being broken must be recorded on 
the appropriate study status page of the electronic case report form (eCRF). After unblinding via 
IRT, the investigator shall notify the Medical Monitor. 
Any request to unblind a subject for nonemergency purposes should be discussed with the Medical 
Monitor. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. 
Designated staff of BMS Company may be unblinded (obtain the randomization codes) prior to 
database lock to facilitate the bioanalytical analysis of PK samples and immunogenicity. A 
bioanalytical scientist in the Bioanalytical Sciences department of BMS Company (or a designee 
in the external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. 
 
Dosage Modification 
There is no provision for dose modification of study treatment. If a subject interrupts or temporarily 
discontinues treatment due to an AE, study treatment can be restarted in consultation with the 
Medical Monitor. 
 
Preparation/Handling/Storage/Accountability 
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and BMS or designee should be contacted immediately. 
Branebrutinib and PBO should be stored per labeled conditions in tamper-evident HDPE bottles 
(see SLE Table 4). 
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
Further guidance and information for final disposition of unused study treatment are provided in 
APPENDIX 2. 
 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
77 
 Retained Samples for Bioavailability/Bioequivalence 
At the time of receipt of the IP by the investigator or designee, BMS will specify the appropriate 
number of containers or units to select for retention, the conditions of sample storage, required 
duration of sample retention, and provisions for returning or disposing of the IP. When samples 
are selected, containers or units should be placed in packaging with a tamper-evident seal provided 
by BMS. Package labeling should clearly identify the contents as bioavailability/bioequivalence 
(BA/BE) samples and state that the IP should be stored in the restricted area with limited access. 
 
Treatment Compliance 
Study treatment compliance will be periodically monitored using standard drug accountability 
procedures (comparing the number of capsules returned to number dispensed, considering the 
expected regimen and any reported missed doses). Drug accountability will be reviewed by the 
site study staff at each visit to confirm treatment compliance. Site staff will discuss discrepancies 
with the subject at each on-treatment study visit and remind the subject of the importance of 
compliance with the assigned regimen. See Section SLE 8.3 for information related to treatment 
overdose. 
 
Concomitant Therapy 
 Prohibited and/or Restricted Treatments 
Table 1 in the IM014029 Master Protocol lists exclusions and restrictions for all concomitant 
medications, regardless of indication. SLE Table 6 presents prohibited and/or restricted 
medications taken by subjects with SLE prior to or during study treatment administration with 
branebrutinib. All prior concomitant medications taken for SLE since diagnosis must be recorded 
on the eCRF. All prior and/or concomitant medications taken for any indication within 4 weeks 
prior to study drug administration must be recorded on the eCRF. The prior use of medications 
after a sufficient washout period prior to study randomization is allowed for some medications, as 
indicated in the table, and must be recorded in the eCRF. Details of prohibited (excluded) and/or 
restricted medications are provided in Section SLE 5.2. 
SLE Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
BTK inhibitors 
Marketed drugs, eg, 
ibrutinib, acalabrutinib 
Experimental drugs, eg, 
tirabrutinib, vecabrutinib, 
zanubrutinib, ARQ-531, 
GDC-0853, and any others 
Prohibited lifetime use 
Not applicable 
JAK inhibitors 
Tofacitinib, baricitinib, 
filgotinib, and upadacitinib 
Prohibited during the study 
8 weeks 
Oral CS
Prednisone or equivalent
For subjects taking oral CS as 
monotherapy, CS must have 
EHHQWDNHQIRU 6 weeks prior to 
4 weeks if not 
continuing as 
background SOC 
2.0
Approved
930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
78 
SLE Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
the screening visit at a dose 
 7.5 PJGD\DQG 40 mg/day 
prednisone (or prednisone 
equivalent), must be at a stable 
GRVHIRU 2 weeks prior to the 
screening visit and remain stable 
until randomization. 
For subjects taking oral CS not 
as monotherapy, the CS dose 
PXVWEHVWDEOHIRU 2 weeks 
before the screening visit, cannot 
exceed 40 mg/day at screening, 
and must remain stable until 
randomization. 
Other CS 
IM, IA, intrabursal, IV, and 
oral modified-release CS 
Prohibited during the study 
4 weeks 
 
Topical and inhaled CS 
Topical and inhaled CS use is 
permitted but must follow a 
stable regimen throughout the 
study and cannot be used on an 
as-needed basis. Discontinuation 
of topical steroids should be 
allowed if lesions/rash resolve 
completely. Inhaled CS for 
nonlupus conditions will not 
count against the maximum CS 
dose.. 
Not applicable 
Antimalarial drugs 
Chloroquine and quinacrine 
0XVWKDYHEHHQWDNHQIRU 12 
weeks before the screening visit 
and must be at a stable dose for 
 8 weeks before the screening 
visit and remain stable until 
randomization and throughout 
study participation. New 
initiation or change in dose 
during treatment is not permitted 
12 weeks if not 
continuing as 
background SOC 
 
Hydroxychloroquine (HCQ) 
Doses of > 400 mg/day are not 
permitted 
New initiation or dose increase 
during treatment is not 
permitted. Whole blood levels at 
screening must be  2 μg/mL 
12 weeks if not 
continuing as 
background SOC 
Anticoagulant or 
Antiplatelet therapies 
Anticoagulant or antiplatelet 
therapies, including aspirin 
for cardioprotection 
Treatment with anticoagulant or 
antiplatelet therapies, including 
aspirin for cardioprotection, 
within 2 weeks prior to 
randomization or during the 
study 
2 weeks 
2.0
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930168072
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
79 
SLE Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
Anti-TNF therapy 
Adalimumab, certolizumab, 
etanercept, golimumab, 
infliximab, and TNF 
biosimilars 
Prohibited during the study 
3 months 
Biologics 
Rituximab 
Prohibited during the study 
12 months 
 
Belimumab 
Prohibited during the study 
6 months 
 
Abatacept 
Prohibited during the study 
6 months 
 
Other Biologics, including 
tocilizumab, anakinra 
 
8 weeks 
 
IVIG 
Prohibited during the study 
8 weeks 
Immunosuppressants 
(allowed) 
 
Note: combinations 
of 
immunosuppressants 
are not allowed 
Azathioprine, 6-MP, MTX, 
leflunomide, MMF 
Must have been taken for 
 12 weeks before the screening 
visit and must be at a stable dose 
IRU 8 weeks before the 
screening visit and remain stable 
until randomization and 
throughout study participation. 
New initiation or dose changes 
during treatment are not 
permitted. 
12 weeks if not 
continuing as 
background SOC, 
except leflunomide 
36 weeks before 
screening 
Immunosuppressants 
(prohibited) 
Cyclosporine, tacrolimus, 
thalidomide and similar 
(oral); topical calcineurin 
inhibitors (tacrolimus, 
pimecrolimus) 
Prohibited during the study 
8 weeks 
Cyclophosphamide 
Prohibited during the study 
24 weeks 
Other DMARDs 
(prohibited) 
Sulfasalazine and similar 
Prohibited during the study 
8 weeks 
 
Other DMARDs 
(allowed) 
Dapsone 
Must have been taken for 
 12 weeks before the screening 
visit and must be at a stable dose 
IRU 8 weeks before the 
screening visit and remain stable 
until randomization and 
throughout study participation. 
New initiation or dose changes 
during treatment are not 
permitted. 
8 weeks, if not 
continued as 
background SOC 
NSAIDs 
Ibuprofen, etc 
Only 1 oral NSAID is allowed 
concurrently. 
Can be combined with 1 or more 
topical NSAID but must be on a 
stable regimen 
Not allowed on days 
of study visits until 
after study 
assessments are 
performed 
Nonnarcotic 
analgesics 
Acetaminophen 
Brief course for up to 7 days 
allowed 
Not applicable 
Narcotic analgesics 
Oxycodone and, 
hydrocodone 
Prohibited during the study 
Not applicable 
Immunization against 
agents other than 
All live vaccines 
 
 
Prohibited during the study 
90 days before and 
28 days after EOT 
 
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SLE Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
influenza or SARS-
CoV-2 
Nonlive vaccines 
unassociated with influenza 
or SARS-CoV-2 
30 days before and 
14 days after EOT 
Immunization for 
influenza or SARS-
CoV-2 
All live vaccines 
 
 
Nonlive vaccines for 
influenza or SARS-CoV-2 
Prohibited during the study 
 
Not allowed during the 
screening period within 30 days 
prior to randomization 
 
During the Treatment and 
Follow-up Periods, vaccine 
doses must be given at least 
5 days before a study visit. 
Doses may be given on a study 
visit day once all 
protocol-specified procedures 
are complete. 
90 days before and 
28 days after EOT 
Other treatments 
Diquafosol, rebamipide 
Prohibited during the study 
4 weeks 
BTK = Bruton’s tyrosine kinase; CS = corticosteroid; DMARD = disease-modifying antirheumatic drug; 
EOT = end of treatment; IA = intra-articular; IM = intramuscular; IV = intravenous; IVIG = intravenous 
immunoglobulin; JAK = Janus kinase; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; 
SLE = systemic lupus erythematosus; SOC = standard of care; TNF = tumor necrosis factor 
 
Chronic medications, such as statins and antidepressants, that could be sensitive to the modulation 
of CYP2C8/P-gp, (and other potentially relevant drug metabolizing enzymes that may lead to 
drug-drug interaction with branebrutinib) and with sufficient representation in the study population 
(eg, > 10% per sub-protocol) are allowed in the study for accompanying conditions. For optional 
measurement of the concentrations of these medications, PK samples will be collected predose 
and 2 hours postdose at Week 0 (Day 1) and Week 4 (Day 29) for potential post-hoc analysis. 
These analyses will be based on the totality of information about the frequency of use of the drugs, 
clinical manifestations of possible interactions, availability of validated bioanalytical assays and 
therapeutic index. When performed, the results of these analyses, will be reported separately, along 
with the reasons for the selection. Concentrations of HCQ will also be measured and reported. 
The dosing of allowed chronic medications must be maintained at the same level throughout the 
study unless safety concerns arise. Any changes of dose will be recorded, and additional PK 
sampling may be performed as a result. 
Tobacco use will be allowed in the study. Branebrutinib concentrations will be compared between 
smoking and nonsmoking subgroups to evaluate the effect of smoking on glutathione-s-transferase 
mediated metabolism of branebrutinib. 
No new concomitant medications (prescription, over-the-counter, or herbal) are to be administered 
during the study unless they are prescribed for treatment of specific clinical events. Any 
concomitant therapies must be recorded on the eCRF. 
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For subjects on immunosuppressant background therapy, the investigator must refer to the label 
for any potential interaction with concomitant medications: 
 Oral Corticosteroid Taper or Rescue for SLE Flare 
Oral CS taper is detailed in Section SLE 8.1.1.10. 
A maximum of 1 burst of oral CS rescue therapy is permitted in response to increased SLE disease 
activity up to Week 12 during the treatment period at the investigator’s discretion. 
x Rescue therapy must not exceed 40 mg/day prednisone or equivalent and must return within 
10 days to the previous CS dose used before initiation of rescue therapy. 
x Rescue therapy other than prednisone or equivalent is not permitted. 
If a subject requires CS rescue therapy after the first 12 weeks, the subject will be considered a 
nonresponder for analysis purposes but will continue to receive study treatment. 
 Other Restrictions and Precautions 
No other restrictions and precautions have been identified. 
 
Treatment After the End of the Study 
At the end of the study, BMS will not continue to provide BMS-supplied study treatment to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate SOC to treat the condition under study. 
SLE 7 
DISCONTINUATION CRITERIA 
 
Discontinuation from Study Treatment 
 Permanent Discontinuation from Study Treatment 
Subjects MUST discontinue study treatment (and non-IP at the discretion of the investigator) for 
any of the following reasons: 
x A subject requests to stop study treatment – Subjects who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified 
follow-up procedures. The only exception to this is when a subject specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the subject to 
provide this information. 
x Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject; if treatment is discontinued due to an AE, the AE eCRF must be completed to show 
that the AE caused discontinuation. 
x Termination of the study program by BMS. 
x Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. 
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x Unblinding of a subject’s treatment assignment for any reason (emergency or 
nonemergency). 
x Inability or failure to comply with protocol requirements. 
x Pregnancy. 
Discontinuation of the study treatment should be considered by the investigator for abnormal liver 
tests indicative of drug-induced liver injury (DILI; see Section SLE 8.2.8 for definition) when the 
DILI meets one of the conditions necessary to be defined as an SAE outlined in APPENDIX 3, or 
if the investigator believes that discontinuation is in the best interest of the subject. 
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the Medical Monitor/designee of this event. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (eg, dose tapering, if necessary, for 
subject safety). Refer to Section SLE 8.2.6. 
All subjects who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in the SoA (Section SLE 1.3). The only exception to this requirement is 
when a subject withdraws consent for all study procedures including posttreatment study follow-up 
or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness). Following the decision to permanently 
discontinue a subject from treatment, an EOT visit should be performed as soon as possible, 
followed by a Safety follow-up (FU) visit approximately 4 weeks later – both according to Table 2 
of Section SLE 1.3. 
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate eCRF page. 
Temporary Discontinuation from Study Treatment
Branebrutinib may be discontinued temporarily at the discretion of the investigator/Medical 
Monitor due to AE, laboratory abnormality, or overdose (SLE 8.3). 
Branebrutinib may be discontinued temporarily due to concomitant medication use 
(Master Protocol Table 1), as follows: 
x Digoxin, “For acute use only; exclude at baseline; limit highest dose and monitor trough 
concentrations; stop treatment with branebrutinib during treatment with digoxin and for 3 days 
afterwards.” 
x Posaconazole: “Dose up to 300 mg QD can be used as maintenance dose, for acute infections 
stop using branebrutinib until dosing with posaconazole is discontinued.” 
 Post-study Treatment Study Follow-up 
Subjects who discontinue study treatment will not be followed beyond the planned Safety FU Visit. 
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Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
x Subjects should notify the investigator of the decision to withdraw consent from future follow-
up in writing, whenever possible. 
x The withdrawal of consent should be explained in detail in the medical records by the 
investigator and entered on the appropriate eCRF page. 
x In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
x If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
The following procedures must be performed upon subject withdrawal: 
x Assessments for the end of treatment (EOT) visit must be performed, provided that the subject 
has not withdrawn consent for these activities. 
x All required eCRF pages must be completed, including the date of and explanation for the 
withdrawal.
 
Lost to Follow-up 
x All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject. 
x Lost to follow-up is defined by the inability to reach the subject after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by subject to 1 registered 
mail letter. All attempts should be documented in the subject’s medical records. 
x If it is determined that the subject has died, the site will use permissible local methods to obtain 
date and cause of death. 
x If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. 
x The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
x If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records. 
SLE 8 
STUDY ASSESSMENTS AND PROCEDURES 
x Study procedures and timing are summarized in the SoA (Section SLE 1.3). 
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x Protocol waivers or exemptions are not allowed. 
x All immediate safety concerns must be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue treatment. 
x Adherence to the study design requirements, including those specified in the SoA
(Section SLE 1.3), is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria before randomization. The investigator will maintain a screening 
log to record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
x Procedures conducted as part of the subject’s routine clinical management (eg, BP, physical 
examination, medical history) on the day of the screening visit and obtained before signing of 
the informed consent may be used for screening provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the SoA 
(Section SLE 1.3). 
 
Efficacy Assessments 
The PI, or sub-investigator, designated by the PI and confirmed by the Sponsor, should perform 
all clinical assessments at a site visit. The sub-investigator may be a Doctor of Medicine or Doctor 
of Osteopathy, Physician’s Assistant, or Nurse Practitioner with experience in the diagnosis and 
management of subjects with SLE. 
All assessments should be performed or administered prior to study drug administration unless 
otherwise indicated. Other conditions include: 
x Every effort must be made to ensure the same investigator performs all of the 
investigator-administered assessments for a given subject at each visit and throughout the study 
to minimize inter-observer variation. 
x If the investigator is unable to complete the assessment at a given visit, the approved back-up 
investigator may complete the assessment. 
x Assessments are to be conducted at approximately the same time of day throughout the 
duration of the study for each subject. 
x Visits should be scheduled with the availability of the specific investigator managing a given 
subject taken into account. 
Assessments conducted on Day 1, Week 0 must be performed per protocol (assessments performed 
as part of SOC may not be used in lieu of these assessments). Procedures not specified in the 
protocol that are part of standard care may be performed if they do not interfere with study 
procedures; any data arising from such procedures are not to be reported in the eCRF. 
 Investigator-administered Assessments 
 
 SLICC 2012 Classification Criteria for SLE 
For diagnosis of SLE in this study, the following SLICC 2012 criteria for SLE classification76 are 
required: Fulfillment of at least 4 criteria with at least 1 clinical criterion and 1 immunologic 
criterion (criteria are cumulative and need not be presented concurrently) (APPENDIX 5). 
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SLICC/ACR Damage Index 
The SLICC/ACR Damage Index (SDI) assesses damage based on a weighted scoring system for 
assessments in the following areas: ocular, neuropsychiatric, renal, pulmonary, cardiovascular, 
gastrointestinal, musculoskeletal, skin, gonadal, endocrine, and malignancy. Damage is defined as 
nonreversible change, not related to active inflammation, occurring since the onset of lupus, 
ascertained by clinical assessment and present for at least 6 months unless otherwise stated. Repeat 
episodes must occur at least 6 months apart to score 2. The same lesions cannot be scored twice 
(APPENDIX 6). 
 
BILAG–2004 Index 
The BILAG-2004 Index is a translational index with 97 items in 9 organ systems (Constitutional, 
Mucocutaneous, 
Neuropsychiatric, 
Musculoskeletal, 
Cardiorespiratory, 
Gastrointestinal, 
Ophthalmic, Renal and Hematological) and is based on the principle of the physician’s intention 
to treat. It captures changing severity of clinical manifestations comparing the current monthly 
activity to prior monthly activity. Only active SLE manifestations are scored. Damage, or 
manifestations due to non-SLE conditions are not scored. The investigator scores items based on 
Index definitions, from which an organ system grade is derived. 
x Grade A represents severe disease activity 
x Grade B represents moderate disease activity 
x Grade C indicates mild stable disease 
x Grade D indicates inactive disease but previously affected 
x Grade E indicates system never involved 
BILAG Grading will be performed by 
 Central Review Services based on investigator scoring 
after data has been reviewed, discrepancies resolved and data confirmed complete (APPENDIX 
7). 
 
BILAG-based Composite Lupus Assessment 
BILAG-based composite lupus assessment (BICLA) response is defined as: 
1. 
At least one gradation of improvement in baseline BILAG scores in all body systems with 
moderate or severe disease activity at entry (eg, all A (severe disease) scores falling to B 
(moderate), C (mild), or D (no activity) and all B scores falling to C or D); 
2. 
No new BILAG A or more than one new BILAG B scores; 
3. 
No worsening of total SLEDAI score from baseline; 
4. 
No significant deterioration (< 10%) in PGA and 
5. 
No treatment failure (initiation of nonprotocol treatment). 
 
BILAG–2004 Index-defined SLE Flare 
x The BILAG-2004 SLE flare is calculated programmatically (see also SLE 3); severity of flare 
is defined as: 
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x Severe flare: Any BILAG-2004 A grade in any body system due to 1 or more items that are 
scored new or worse 
x 0RGHUDWHIODUH 2 B grades that are each due to 1 or more items scored new or worse 
x 0LOGIODUH%JUDGHGXHWRLWHPVWKDWDUHVFRUHGQHZRUZRUVHRU 3 new or recurrent 
C grades due to items that are scored new or worse
x No flare: Meeting none of the criteria for mild, moderate, or severe 
 
SLE Disease Activity Index 2000 (SLEDAI-2K) 
The SLEDAI-2K is used to describe changes in disease activity from one monthly visit to the next. 
It is meant to convey manifestations due to active SLE and not due to damage or due to non-SLE 
comorbidities, effects of therapies, etc. This index has been validated for use over a 10-day period 
as well as over a 30-day period. 
The SLEDAI-2K is a global index providing a total score of overall disease activity ranging from 
0 to 105, with higher scores representing more active disease. A total of 24 manifestations of SLE 
are included on the SLEDAI-2K, including both clinical and laboratory parameters. Each 
manifestation is documented as either present or absent. Findings are considered present if they 
have met the SLEDAI-2K definition not just on the day of the visit but at any time during the 
interval period from one monthly visit to the next. Each manifestation that is present on the 
SLEDAI-2K is given a weighted score and the sum of these is the total SLEDAI-2K score 
(APPENDIX 8). 
 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
(CLASI) 
The CLASI assesses cutaneous disease activity and damage by regions of the body, demarcated 
for areas most commonly affected by SLE rash; points are given for presence of erythema, scale, 
hypertrophy, mucous membrane lesions, recent hair loss, and physician-observed alopecia. For the 
damage assessments, points are given for dyspigmentation, extent of scarring, and scarring 
alopecia. 
The modified CLASI (mCLASI) used in this study is defined as the activity portions of CLASI 
that describe skin erythema and scale/hypertrophy and inflammation of the scalp. Damage, oral 
ulcers, diffuse alopecia without scalp inflammation, and recent hair loss (alone or with diffuse 
noninflammatory alopecia) are excluded from the mCLASI score. The percentage of patients who 
entered the study ZLWKDSRVLWLYHP&/$6,DFWLYLW\VFRUHDQGZKRDFKLHYHGDGHFUHDVH
from baseline at Week 24 is considered to likely represent a clinically meaningful improvement77
(APPENDIX 9). 
 
Physician Global Assessment (PGA) of SLE Disease Activity 
The investigator will rate the overall status of the subject in response to the following statement: 
“How do you assess your patient’s (the subject’s) current SLE activity as compared to the 
activity and Physician Global Assessment at the last visit?” (APPENDIX 10). 
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SLE 40-joint Count 
The SLE 40-joint count includes bilateral wrists, elbows, ankles, knees, interphalangeal joints of 
the thumb, individual proximal interphalangeal joints of the hand, second through fifth 
metacarpophalangeal joints of the hand, and individual metatarsophalangeal joints of the feet 
(which make up the 36-joint count).13, 14, 15 To allow the 28-joint count evaluation, bilateral first 
metacarpophalangeal joints and shoulders are also included, bringing the total joint count to 40. 
Each joint is evaluated based upon the presence or absence of tenderness, swelling, and both 
tenderness and swelling related to SLE disease activity. The eCRF includes questions regarding 
the effect on function due to active SLE arthritis. 
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
screening visit and will be excluded from evaluation during the study. The locations (or a listing) 
of surgical procedures should be documented in the subject’s source documents/eCRF pages. 
 Corticosteroid Taper 
For subjects taNLQJRUDO&6DVPRQRWKHUDS\&6PXVWKDYHEHHQWDNHQIRUZHHNVSULRUWRWKH
VFUHHQLQJYLVLWDWDGRVH PJGD\DQG mg/day prednisone (or prednisone equivalent). The 
dose PXVW EH VWDEOH IRU   ZHHNV SULRU WR WKH VFUHHQLQJ YLVLW DQG must remain stable until 
randomization. 
)RUVXEMHFWVWDNLQJRUDO&6QRWDVPRQRWKHUDS\WKH&6GRVHPXVWEHVWDEOHIRUZHHNVEHIRUH
the screening visit, cannot exceed 40 mg/day at screening, and must remain stable until 
randomization. 
For subjects receiving CS (prednisone or equivalent), Investigators must assess the subject’s 
suitability for CS taper at each visit, and the rules for CS tapering during the treatment period are 
as follows: 
x Tapering of CS may begin at any time after the first dose of IP on Day 1, must be started by 
Week 8, and completed by the Week 16 visit. 
x )RUDOOVXEMHFWVWKH&6GRVHPXVWEH mg/day prednisone or equivalent by Week 16. If 
this is not possible, the subject will remain on CS treatment, but will be defined as a 
nonresponder for analysis purposes. 
x During CS taper from Week 8 through Week 16, the CS dose must be tapered unless the 
following is observed: 
x Scoring of new or worse in any of the parameters that support BILAG A or B. 
x Tapering is required if disease activity has not worsened. The investigator must document 
justification for any decision not to taper on the appropriate eCRF at each appropriate visit. 
x The CS dose must remain stable from Week 16 until Week 24. 
During the CS tapering process, stepping back to the previous dose level (if needed to adequately 
manage disease activity) is not considered rescue. During CS taper, however, a requirement to 
return to a CS dose 2 or more prior dose levels is considered to be rescue, and the subject will be 
considered a nonresponder for analysis purposes. 
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 Patient-reported Outcomes 
Patient-reported questionnaires studied in SLE have included generic general health 
questionnaires, rheumatology questionnaires, and SLE disease-specific questionnaires. Patient-
reported outcomes will be recorded electronically in eCOA devices provided by the Sponsor or 
designee to the sites. 
 
Subject Global Assessment of Disease Activity (SGA) 
The SGA is a visual analog scale (VAS) (10 cm/100 mm) used to assess the subject’s overall 
assessment of Lupus disease (APPENDIX 11). 
 
Patient-Reported Outcomes Measurement Information 
System-Fatigue Instrument Form 6a 
The Patient-Reported Outcomes Measurement Information System (PROMIS™), Form 6a, 
provides item banks that offer the potential for patient-reported outcomes (PRO) measurement that 
is efficient (minimizes item number without compromising reliability), flexible (enables optional 
use of interchangeable items), and precise (has minimal error in estimate) measurement of 
commonly studied PROs.78, 79, 80, 81 In the health outcomes measurement perspective, for example, 
fatigue is divided conceptually into the experience of fatigue (such as its intensity, frequency, and 
duration), and the impact of fatigue upon physical, mental, and social activities. The fatigue item 
bank consists of 95 items assessing the intensity, frequency, and impact of fatigue. Most PROMIS 
items employ response scales with 5 options (APPENDIX 12). 
 
Euro Quality of Life Five Dimensions Questionnaire: 5-Level 
Version (EQ-5 D-5 L) 
The EQ-5 D-5 L consists of 2 parts – the EQ-5 D-5 L descriptive system and the EQ VAS. The 
descriptive system comprises the same 5 dimensions as the EQ-5 D-3 L (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems; slight 
problems; moderate problems; severe problems; and extreme problems. The respondent indicates 
his/her health state by ticking in the box against the most appropriate statement in each of the 
5 dimensions. The resulting 1-digit number expresses the level selected for that dimension. The 
digits for all 5 dimensions can then be combined in a number describing the respondent’s health 
state. 
The numbers 1 through 5 have no arithmetic properties and should not be used as a cardinal score. 
During the development of the EQ-5 D-5 L, the opportunity was also taken to improve some of 
the wording in the dimensions to enhance consistency and facilitate understanding. For example, 
the old wording of “confined to bed” to indicate the upper extreme in the EQ-5 D-3 L has been 
replaced with “I am unable to walk about,” which is more consistent with the wording within the 
Mobility dimension and with the extreme levels on other dimensions. 
The EQ VAS records the respondent’s self-rated health on a 20-cm vertical VAS with endpoints 
labeled “the best health you can imagine” and “the worst health you can imagine.” This 
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information can be used as a quantitative measure of health as judged by the individual 
respondents. The instructions for the EQ VAS task have also been simplified (APPENDIX 13). 
 
SLE Pain Numeric Rating Score 
In this assessment, subjects use a numeric rating score (NRS) to assess the level of pain they 
attribute to their Lupus, overall, in the past week (APPENDIX 14). 
 
Adverse Events 
The definitions of an AE or SAE can be found in APPENDIX 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver or surrogate). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the subject to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in APPENDIX 3. 
 AEs of Interest 
AEIs are AEs for a particular product or class of products that a Sponsor may wish to monitor 
carefully. AEIs may be serious or nonserious. Such events may require further investigation to 
better characterize and understand them. In the branebrutinib clinical development program, 
infection AEs have been identified as potential AEIs; however, there has been no definitive 
assessment on the causal relationship between these events and treatment with branebrutinib. 
Therefore, additional information about infection AEs may be collected on the eCRF in order to 
better characterize and understand them. 
 Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 
discharge, at the timepoints specified in the SoA (Section SLE 1.3). Nonserious AE information 
should also be collected from the start of a PBO lead-in period or other observational period 
intended to establish a baseline status for the subjects. The Reference Safety Information in 
Sections 5.6.1 and 5.6.2 of the IB12 should be used to determine the expectedness of SAEs for 
expedited reporting. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing or 
subject’s participation in the study if the last scheduled visit occurs at a later time. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
x Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the designated eCRF. 
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BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
90 
x All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in APPENDIX 3. 
x The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study treatment 
or study participation, the investigator must promptly notify the Sponsor. 
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in APPENDIX 3. 
 Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) Nonserious SLE-related AEs 
will be collected solely on the disease assessment instruments and will not be reported as AEs, 
unless they are characterized as SAEs. 
 Follow-up of AEs and SAEs 
x Nonserious AEs should be followed to resolution, stabilization, or reported as SAEs if they 
become serious (see APPENDIX 3). 
x Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
x All identified nonserious AEs must be recorded and described on the nonserious AE page 
of the eCRF. Completion of supplemental eCRFs may be requested for AEs and/or 
laboratory abnormalities that are reported/identified during the course of the study. 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and nonserious AEIs (as defined in Section SLE 8.2.1) will 
be followed until resolution, until the condition stabilizes, until the event is otherwise explained, 
or until the subject is lost to follow-up (as defined in Section SLE 7.3). 
Further information on follow-up procedures is provided in APPENDIX 3. 
 Regulatory Reporting Requirements for SAEs 
x Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of subjects and the safety of a 
product under clinical investigation are met.
x An investigator who receives an investigator safety report describing SAEs or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), if appropriate according to local requirements. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
91 
The Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations (CFR) 21 CFR Parts 312 and 320. A SUSAR is a subset of SAEs and will be 
reported to the appropriate regulatory authorities and investigators following local and global 
guidelines and requirements. 
 Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify 
 Drug 
Safety of this event and complete and forward a Pregnancy Surveillance Form to 
 Drug Safety 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in APPENDIX 3. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study subject should be reported to 
 
Drug Safety. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
 Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the AE eCRF page. 
x Any laboratory test result that is clinically significant or meets the definition of an AE or SAE 
x Any laboratory test result abnormality that required the subject to have study treatment 
discontinued or interrupted 
x Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy 
If a laboratory test result meets the definition of an AE or SAE, the laboratory test result should be 
reported as an AE or SAE and submitted to 
 Drug Safety, as specified in APPENDIX 3. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value). 
 Potential DILI 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (see Section SLE 8.2 and APPENDIX 3 for reporting 
details). 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
92 
Potential DILI is defined as: 
1) ALT or AST elevation > 3×ULN 
AND 
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, preexisting chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 Other Safety Considerations 
Any significant worsening of a preexisting medical condition noted during interim or final physical 
examination, electrocardiogram (ECG), x-ray filming, or any other potential safety assessment 
required or not required by protocol should also be recorded as a nonserious AE or SAE, as 
appropriate, and reported accordingly. 
 
Overdose 
For this study, any dose of branebrutinib greater than 2 daily doses of study treatment within a 
24-hour time period will be considered an overdose. See APPENDIX 3 for AE assessment and 
reporting procedures regarding suspected overdose and intentional overdose. 
Based on the IB, there has been no clinical experience with overdose of branebrutinib.12 There is 
no known specific antidote for overdose with branebrutinib. 
In the event of an overdose, the investigator should: 
1) Contact the Medical Monitor immediately. 
2) Closely monitor the subject for AEs/SAEs and laboratory abnormalities. 
3) Obtain a plasma sample for PK analysis within 4 hours of the overdose if requested by the 
Medical Monitor (determined on a case-by-case basis). 
4) Document the quantity of the excess dose as well as the duration of the overdosing in the source 
documentation. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 
 
Safety 
Planned time points for all safety assessments are listed in the SoA (Section SLE 1.3). 
 Physical Examinations 
A complete physical examination will include general appearance, vital signs, eyes, ears, nose, 
mouth, throat, neck, respiratory, cardiovascular, respiratory, gastrointestinal/abdomen, lymphatic, 
musculoskeletal, skin, psychiatric, and neurologic examinations. A targeted physical examination 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
93 
will include any organ system associated with an AE, a laboratory abnormality, or an SLE activity 
that cannot be captured on the 40-joint Count or CLASI at a clinical site visit. 
 Vital Signs 
Refer to SoA (Section SLE 1.3). 
 Electrocardiograms 
A 12-lead ECG will be performed at the visits indicated in the SoA (Section SLE 1.3). The subject 
will remain supine for 5 to 10 minutes prior to the ECG and must have lab work done after the 
tracing so that the ECG results remain as accurate as possible. The ECG results will be read by the 
primary study investigator or a designee. 
 TB Screening and Chest Imaging 
A subject must not have active signs or symptoms of TB, as judged by the investigator, to be 
eligible for the study. 
In addition to a complete physical examination and medical history to evaluate exposure to TB, all 
subjects will have a screening test, an IGRA (eg, QuantiFERON®-TB Gold) performed centrally. 
A subject with an indeterminate IGRA test result from the central laboratory must be retested for 
confirmation. If the second result is again indeterminate, the subject will be excluded from the 
study, unless there is documentation of a local negative TB Spot test result. If the second result 
from the central laboratory is positive, the subject should be considered as having LTBI provided 
there are no signs or symptoms of active TB. If the second result is negative, the subject may be 
eligible provided no other exclusion criteria for TB are met. A chest x-ray is also required if one 
has not been performed within 6 months of screening; a copy of the radiology report must be on 
file and reviewed by the investigator. If unable to obtain central laboratory results, an IGRA test 
could be obtained locally, after consultation with the 
 Medical Monitor. 
 Clinical Safety Laboratory Assessments 
A central laboratory will perform assessments of safety laboratory assessments (except urine 
pregnancy tests and ESR) and provide reference ranges and laboratory reports. Investigators must 
document their reviews of each laboratory safety report. Any laboratory test result that the 
investigator considers clinically relevant is to be recorded on the appropriate AE page of the eCRF 
(Section SLE 8.2.7). Additional safety assessments may be performed at local laboratories at the 
investigator’s discretion. The laboratory parameters to be assessed are included in SLE Table 7. 
In addition, serum or urine pregnancy testing will be performed for WOCBP. 
 
 
 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
94 
SLE Table 7 
Clinical Safety Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including manual differential 
Platelet count 
Red blood cell count 
Prothrombin time/INR 
PTT 
aPTT 
Serum Chemistry 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyltransferase 
High-sensitivity C-reactive protein 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Lactate dehydrogenase 
Creatinine 
Blood urea nitrogen 
Uric acid 
Fasting glucose (nonfasting at screening only) 
Creatinine clearance – screening only 
Estimated glomerular filtration rate 
Total Protein 
Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphorus 
Magnesium 
Creatine kinasea 
Fasting lipid panel (total cholesterol, high-density lipoprotein, 
low-density lipoprotein, and triglycerides; nonfasting at 
screening only) 
Urinalysis 
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH 
Microscopic examination of sediment  
Urine chemistry – Spot urine for UPCR 
Infectious Serologies 
Anti-HCV antibodies with reflex testing of HCV RNA if positive 
HBsAg 
Anti-HbsAb 
Anti-HbcAb 
Anti-HIV-1 and anti-HIV-2 antibody  
Other Analyses 
 
 
Tuberculosis test (QuantiFERON®-TB Gold) at screening 
Direct Coomb’s test (only if clinically indicated) 
Whole blood HCQ level (in subjects taking HCQ) 
3UHJQDQF\7HVWIRU:2&%3VHUXPRUXULQHȕ-HCG test every 4 weeks) 
Follicle-stimulating hormone if needed to confirm menopausal status (see APPENDIX 4), at screening 
HbA1c 
Thyroid-stimulating hormone (if above normal reference range, test free T4; if below normal range, test free T4 
and T3) 
 
Erythrocyte sedimentation rate 
RF 
C3, C4 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
95 
SLE Table 7 
Clinical Safety Laboratory Assessments 
Autoantibodies (ANA, anti-dsDNA, 
 
 
 
) 
T cells, B cells, natural killer cells 
Beta-2-microglobulin 
; ANA = antinuclear antibody; aPTT = activated partial 
WKURPERSODVWLQ WLPH ȕ-HCG = beta-human chorionic gonadotropin; C3, C4 = serum complement C3 and C4; 
DNA = deoxyribonucleic acid; dsDNA = double-stranded deoxyribonucleic acid; HbcAb = hepatitis B core 
antibody; HbsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
; IR = international 
normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; RF = rheumatoid factor; 
RNA = ribonucleic acid; 
; 
 
 T3 = tri-iodothyronine; T4 = thyroxine; TB = tuberculosis; ULN = upper 
limit of normal; UPCR = urine protein/creatinine ratio; WOCBP = women of childbearing potential 
a If the creatine kinase is > 2.5× ULN, reflex testing of creatine kinase-MB and troponin I will be required. 
 Imaging Safety Assessment 
Any incidental findings of potential clinical relevance on chest x-ray or any additional imaging 
performed that is not directly associated with the objectives of the protocol should be evaluated 
and handled by the study investigator as per standard medical/clinical judgment. Images may be 
requested for submission to the assigned imaging core lab for central analysis. 
 
PK of Branebrutinib 
The PK sampling schedule for branebrutinib, its metabolites, and concomitant medications will be 
harmonized among all treatments and sub-protocols where applicable. 
For the predose and postdose PK assessments of branebrutinib and metabolites, samples will be 
collected from 2 groups of subjects—all study subjects who receive branebrutinib comprise one 
group; and subjects enrolled at preselected clinical sites only and who will also have extended PK 
sampling comprise the second group (SLE Table 8). 
Samples collected from all study subjects who receive branebrutinib will be analyzed for 
branebrutinib PK only, including samples drawn on days scheduled solely for predose samples. 
Samples collected from subjects at the preselected clinical sites will be analyzed for both 
branebrutinib and metabolites as indicated in SLE Table 8, and will be divided into 2 collection 
tubes, one tube for branebrutinib and one tube for metabolites analysis. 
In general, predose (trough) concentrations will be assessed to evaluate the attainment of 
steady-state and accumulation. It is expected that steady-state will be achieved for all analytes at 
Week 4, after 28 days of continuous dosing. 
Pharmacokinetic samples may also be used in correlation analyses for evaluation of PK/PD and 
the effect of pharmacogenomics (PGx), and may be used for other correlation analyses as well. 
The sampling schedule is based on available information on branebrutinib and its metabolites. 
(Samples for PK analysis collected from subjects receiving PBO will not be analyzed for 
branebrutinib or metabolites). 
Branebrutinib and Metabolite Analysis: 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
96 
Branebrutinib PK samples will be analyzed by a vendor using a validated assay. Plasma samples 
for metabolites will be analyzed by the BMS bioanalytical laboratory. These analyses will be 
reported separately. The BMS laboratory will be unblinded before the end of the study and will 
not communicate unblinded information to the BMS or 
 study teams. Where the data allow, 
individual subject PK parameter values for branebrutinib and its metabolites will be derived from 
plasma concentration data versus time by noncompartmental methods with a validated PK analysis 
program. Actual times will be used for the analyses. 
For all study subjects, the branebrutinib PK parameters listed below will be calculated and 
summarized with data up to 4 hours postdose. Accumulation ratios for Cmax and AUC(0-4) will 
also be calculated. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
Ctrough 
Trough observed plasma concentration 
AUC(0-4) 
Area under the plasma concentration-time curve from time zero to the 
4-hour dosing period 
 
For subjects at preselected sites with extended sampling, separate plasma concentrations of 
branebrutinib and select metabolites at all timepoints will be summarized by time point. The 
branebrutinib and its metabolites PK parameters listed below will be calculated and summarized. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
AUC(0-T) 
Area under the plasma concentration-time curve from time zero to time of 
last quantified concentration 
AUC(TAU) 
Area under the concentration-time curve to the end of the dosing period 
Ctrough 
Trough observed plasma concentration 
 
SLE Table 8 lists the complete sampling schedule for assessment of the PK of branebrutinib, 
metabolites, and concomitant medications in subjects with SLE. 
To assess steady-state concentrations of branebrutinib, a total of 5 predose PK samples 
(approximately 4 mL each) will be drawn from all study subjects at Week 0 (Day 1), Week 4 
(Day 29), Week 8 (Day 57), Week 16 (Day 113), and Week 24 (Day 169). (Note that these samples 
will be drawn within a 1-hour window before the next dose is administered.) For subjects at 
preselected sites with extended sampling, predose PK samples collected at Week 8 (Day 57) will 
also be aliquoted to assess metabolite concentrations. 
For postdose sampling, all study subjects will have branebrutinib PK samples drawn at Week 0 
(Day 1), Week 8 (Day 57), and Week 24 (Day 169) at the 0.5, 1, 2, and 4-hour time points, a total 
of 14 samples. (Note that these samples will be drawn within ±15 min from the given time points.) 
For subjects at preselected sites with extended sampling, postdose PK samples will be aliquoted 
to assess metabolite concentrations at these time points. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
97 
In addition, for subjects at preselected sites with extended sampling, a total of 7 postdose PK 
samples will be drawn and assessed for both branebrutinib and metabolite concentrations at 
Week 0 (Day 1) and Week 8 (Day 57) at approximately 06:00 hours, from 08:00 to 10:00 hours 
(flexible window), and from 10:00 to 12:00 hours (flexible window). Samples will also be 
collected at Week 0 (Day 2) approximately 24:00 hours postdose (predose of branebrutinib on 
Day 2). Efforts should be made to collect the samples within these windows; however, any sample 
drawn outside the prespecified windows will not be considered a protocol deviation. Both planned 
and actual time points at which the blood samples will be taken will be recorded and used in 
analysis and modeling. 
Concomitant Medications 
Concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant 
drug metabolizing enzymes that may have a drug-drug interaction with branebrutinib and P-gp 
transporter may be measured (post-hoc) in subjects receiving PBO and active treatment. Samples 
for the PK assessment of the concentrations of relevant concomitant medications will be collected 
at Week 0 and Week 4 from all study subjects. Samples for PK analysis collected from subjects 
receiving branebrutinib or PBO will be analyzed for HCQ and other relevant concomitant 
comedications provided that these subjects are receiving HCQ and other relevant concomitant 
comedications. 
Detailed instructions for the collection, labeling, processing, storage, shipping, and disposition of 
all PK blood samples are provided in the Laboratory Manual. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
98 
SLE Table 8 
PK Sampling Schedule for Branebrutinib, Metabolites, and Concomitant Medications 
Study 
Day 
Study 
Week 
Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites only) 
Concom 
Meds a,b,c 
Comments 
1 
0 
Predosed 
00:00 
X 
 
X a,b,c 
Predose PK samples will be collected from all study subjects to 
assess branebrutinib and relevant concomitant medications; 
)RUVXEMHFWVRQ+&4ZKROHEORRGVDPSOHVZLOOEHFROOHFWHGIRU
HCQ level assessment. 
1 
0 
Postdosee 
00:30 
X 
X 
 
Postdose PK samples collected from all study subjects at these 
time points will be assessed for branebrutinib; 
3RVWGRVH3.VDPSOHVFROOHFWHGDWWKHVHWLPHSRLQWVIURPVXEMHFWV
at preselected clinical sites will also be assessed for metabolites; 
3RVWGRVe PK samples collected at 2 hours after dosing will be 
assessed for relevant concomitant medications; 
)RUVXEMHFWVRQ+&4ZKROHEORRGVDPSOHVZLOOEHFROOHFWHGIRU
HCQ level assessment. 
1 
0 
Postdose 
01:00 
X 
X 
 
1 
0 
Postdose 
02:00 
X 
X 
X a,b,c 
1 
0 
Postdose 
04:00 
X 
X 
 
1 
0 
Postdose 
06:00 
X 
X 
 
3RVWGRVH3.VDPSOHVFROOHFWHGIURP subjects at preselected 
clinical sites only will be assessed for branebrutinib and metabolites 
at these time points. 
1 
0 
Postdose 
08:00-10:00 
X 
X 
 
1 
0 
Postdose 
10:00-12:00 
X 
X 
 
2 
0 
Postdosef  
24:00 
X 
X 
 
29 
4 
Predose 
00:00 
X 
 
X a,b,c 
Predose PK samples will be collected from all study subjects for 
assessment of branebrutinib and concomitant medications; 
)RUVXEMHFWVRQ+&4ZKROHEORRGVDPSOHVZLOOEHcollected for 
HCQ level assessment. 
29 
4 
Postdose 
02:00 
 
 
X a,b,c 
3ODVPDVDPSOHVZLOOEHFROOHFWHGIURPDOOVWXG\VXEMHFWVDW
2 hours after dosing for assessment of relevant concomitant 
medications; 
)RUVXEMHFWVRQ+&4ZKROHEORRGVDPSOHVZLOOEHcollected in 
addition for HCQ level assessment. 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
99 
SLE Table 8 
PK Sampling Schedule for Branebrutinib, Metabolites, and Concomitant Medications 
Study 
Day 
Study 
Week 
Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites only) 
Concom 
Meds a,b,c 
Comments 
57 
8 
Predose 
00:00 
X 
X 
 
3UHGRVHDQGSRVWGRVH3.VDPSOHVFROOHFWHGIURPDOOVWXG\
subjects will be assessed at these time points for branebrutinib only; 
3UHGRVHDQGSRVWGRVH3.VDPSOHVFROOHFWHGDWthese time points 
from subjects at preselected clinical sites will also be assessed for 
metabolites. 
 
57 
8 
Postdose 
00:30 
X 
X 
 
57 
8 
Postdose 
01:00 
X 
X 
 
57 
8 
Postdose 
02:00 
X 
X 
 
57 
8 
Postdose 
04:00 
X 
X 
 
57 
8 
Postdose 
06:00 
X 
X 
 
Postdose PK samples collected from subjects at preselected 
clinical sites only will be assessed for branebrutinib and metabolites 
at these time points. 
57 
8 
Postdose 
08:00-10:00 
X 
X 
 
57 
8 
Postdose 
10:00-12:00 
X 
X 
 
113 
16 
Predose 
00:00 
X 
 
 
3UHGRVH3.samples taken from all study subjects will be assessed 
for branebrutinib only. 
169 
24 
Predose 
00:00 
X 
 
 
3UHGRVH3.VDPSOHVWDNHQIURPDOOVWXG\VXEMHFWVZLOOEHDVVHVVHG
for branebrutinib only. 
169 
24 
Postdose 
00:30 
X 
 
 
3RVWGRVH3.6DPSOHVWDNHQfrom all study subjects will be 
assessed at these time points for branebrutinib only. 
169 
24 
Postdose 
01:00 
X 
 
 
169 
24 
Postdose 
02:00 
X 
 
 
169 
24 
Postdose 
04:00 
X 
 
 
PK = pharmacokinetic; Concom Meds = concomitant medications; HCQ = hydroxychloroquine. 
a Concentrations of Concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant drug metabolizing enzymes that may have a 
drug-drug interaction with branebrutinib and P-gp transporter may be evaluated post-hoc for subjects receiving PBO and active treatment at predose of 
branebrutinib on Day 1 and Day 29 (see Section SLE 8.5.1). 
b For subjects taking HCQ on-study, whole blood samples will be taken at predose and 2 hours after dosing with the IP on Day 1 (Week 0) and Day 29 (Week 4) 
(see Section SLE 8.5.1). 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
100 
c Subjects who are on HCQ will be informed to bring HCQ to the clinic on Day 1 and Day 29 for simultaneous dosing with branebrutinib and not to take it at 
home on those 2 days. Similarly, subjects who are on other prescription concomitant medications will also be informed to bring them to the clinic on Day 1 and 
Day 29 for simultaneous dosing with branebrutinib, but only when it is safe for subjects and operationally feasible. This should be based on the investigator’s 
discretion with consideration that the medications which should not be delayed until the time of dosing in the clinic should be taken at home. The self-reported 
time for all prescription medications taken at home should be recorded as accurately as possible. 
d Predose sample to be drawn within 1 hour before dose administration. 
e Postdose sample to be drawn within ±15 min of the given time points. 
f PK sample must be drawn before the IP dose is administered on Day 2. 
 
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Clinical Protocol 
IM014029 - SLE 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
101 
 PK of Potential Concomitant Medications 
Concentrations of concomitant medications that are sensitive substrates of CYP2C8 and other 
potentially relevant drug metabolizing enzymes and P-gp transporter may be evaluated for subjects 
receiving PBO and active treatment with the bioanalytical analysis as part of a retrospective 
analysis. HCQ will be among the concomitant medications. The retrospective analysis will be 
conducted after review of the enrollment records, reported concomitant medication use within the 
enrolled population and on the incidence threshold and relevance to drug interaction with 
branebrutinib based on preclinical and clinical data. Other confounding factors will be evaluated 
as part of the analysis to avoid inclusion of bias or artifact results. Subjects who are on HCQ will 
be informed to bring HCQ to the clinic on Day 1 and Day 29 for simultaneous dosing with 
branebrutinib and not to take it at home on those 2 days. Similarly, subjects who are on other 
prescription concomitant medications will also be informed to bring them to the clinic on Day 1 
and Day 29 for simultaneous dosing with branebrutinib, but only when it is safe for subjects and 
operationally feasible. This should be based on the investigator’s discretion with consideration that 
the medications which should not be delayed until the time of dosing in the clinic should be taken 
at home. The self-reported time for all prescription medications taken at home should be recorded 
as accurately as possible. 
Concentrations of the relevant concomitant medications will be measured post-hoc using samples 
collected predose of branebrutinib or placebo on both Day 1 and Day 29 (Week 4; at which point 
accumulation of branebrutinib and its metabolites is expected to achieve steady-state). In addition 
to predose samples on Day 1 and Day 29, samples will also be collected at 2 hours after dosing 
with branebrutinib or placebo to evaluate the concentration of relevant concomitant medications, 
including HCQ. Bioanalytical analysis of all relevant concomitant medications will be conducted 
post-hoc. The doses of the concomitant drugs and the time they are taken, will be carefully 
recorded at all times (including Day 1 on Week 0 and on Day 29 on Week 4). Actual and 
dose-normalized concentrations will be listed, summarized, and compared between posttreatment
and pretreatment of branebrutinib and PBO separately; other covariates such as MTX use, gender, 
etc. can be added to the comparison as needed. 
Detailed instructions for PK sample collection for the relevant concomitant medications, labeling, 
processing, storage, shipping, and disposition are provided in the Laboratory Manual. While blood 
samples will be used for the analysis of HCQ, plasma samples will be analyzed for the other 
relevant concomitant medications by available validated assays. The results of these post hoc 
analyses will not be recorded in the clinical study report (CSR). 
 
 
 
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Health Economics OR Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
SLE 9 
STATISTICAL CONSIDERATIONS 
 
Sample Size Determination 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the SLE sub-protocol 
is GHFUease from baseline mCLASI activity score in subjects with a baseline mCLASI 
DFWLYLW\VFRUH DW:HHNDQG&6SUHGQLVRQHRUHTXLYDOHQW mg/day at Week 20 and 
Week 24. 
Estimates for PBO response rates, treatment differences, and common standard deviations were 
obtained from the published literature. 75 
Assuming a total sample size of 60 subjects randomized in a blinded fashion in a 3:1 ratio to 
branebrutinib (45 subjects) or PBO (15 subjects) and a treatment difference of 25% with a PBO 
response of 30% for mCLASI at Week 24, the 95% CI is expected to exclude 0 (expected 95% CI 
based on a z-test = 2%, 56%). 
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Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled Set 
All subjects who sign informed consent. 
Full Analysis 
Set (FAS) 
All subjects who were randomized. Following the intent-to-treat principle, 
subjects will be analyzed according to the treatment assigned at randomization. 
The FAS will be the primary efficacy analysis population. This is the same as 
the intent-to-treat population. 
Per Protocol 
Set (PPS): 
A subset of the FAS who are compliant with study treatment and who do not 
have any statistically relevant protocol deviations that may impact the primary 
efficacy endpoint assessments. The PPS will be analyzed according to the 
treatment assigned at randomization. The PPS may be a supportive efficacy 
analysis population. 
Safety 
Analysis Set 
All randomized subjects who receive at least 1 dose of double-blind study 
treatment. Subjects will be analyzed according to treatment received. 
PK 
All randomized subjects who receive at least 1 dose of branebrutinib and have 
any available branebrutinib concentration data. Subjects will be analyzed 
according to the treatment received during the PK collection. 
Biomarker 
All randomized subjects who receive at least 1 dose of double-blind study 
treatment and have at least 1 posttreatment biomarker measurement. 
 
Endpoints 
The following sections outline the efficacy endpoints for the SLE sub-protocol. 
 Primary Endpoint 
Proportion of subjects with 
x   50% decrease from baseline mCLASI activity score in subjects with a baseline mCLASI 
DFWLYLW\VFRUH 10, at Week 24 
AND 
x CS (prednisone or equivalent)  10 mg/day at Week 20 and Week 24 
 Secondary Endpoints 
The following are the secondary efficacy endpoints as defined at Week 24: 
x Change from baseline in SLEDAI-2K score 
x BICLA response 
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 Additional Endpoints 
The following are the additional efficacy endpoints as defined at Week 24: 
x Change from baseline in: 
o Autoantibody titers (ANA, anti-dsDNA) 
o Complement (C3, C4) 
o High-sensitivity C-reactive protein (hsCRP) 
o Erythrocyte sedimentation rate (ESR) 
o SGA of Disease Activity 
o PGA of Disease Activity 
o Tender joint counts (TJC), swollen joint counts (SJC), and TJC + SJC in subjects with 
arthritis at baseline 
o SDI (also change from baseline at the EOT visit, if prior to Week 24) 
o EQ-5 D-5 L score 
o PROMIS Fatigue 6 a 
o Pain NRS 
 PK Endpoints 
x Concentration values and PK parameters of branebrutinib and metabolites of clinical interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analyses 
The SAP will be developed and finalized before database lock. Section SLE 9.4.1 provides a 
summary of planned statistical analyses of the primary and secondary endpoints. Additional and 
exploratory endpoints will be summarized in a descriptive manner. 
 Efficacy Analyses 
Efficacy data will be summarized using the FAS. Data will be summarized using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum), unless otherwise 
specified, for continuous variables, and frequency distributions (counts and percentages) for 
categorical variables. Efficacy data will be summarized separately for the SLE sub-protocol and 
with each sub-protocol combined for variables that are similar among the sub-protocols. 
For the SLE sub-protocol, data will be presented for the following treatments: 
x
Branebrutinib
x
PBO
Endpoint 
Statistical Analysis Methods 
Primary 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for the primary endpoint will 
be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by 
immunosuppressant use (yes/no). The 95% CI for each treatment group 
response rate and the difference in response rate for branebrutinib compared to 
PBO will be provided. If expected cell counts are not sufficient, then Fisher’s 
exact test will be used. Since this sub-protocol is not powered to determine 
statistical significance, P-values will be added descriptively. 
Supportive Analyses 
Supportive analyses using logistic regression for the primary endpoint may be 
performed to incorporate additional covariates of interest and to confirm 
primary analysis results. The odds ratio and the corresponding 95% CI will be 
provided. Bayesian borrowing to utilize historical controls may also be 
performed as supportive analyses. Details will be provided in the SAP if 
needed. 
Imputation Method 
Nonresponder imputation will be used for binary endpoints for subjects who 
discontinue 
study 
treatment 
early, 
start 
a 
protocol-prohibited 
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Endpoint 
Statistical Analysis Methods 
medication/therapy prior to the specified timepoint, or otherwise have missing 
endpoint data for the specified timepoint. 
Other imputation methods may be considered for sensitivity analyses and will 
be described in the SAP if used. 
Secondary/ 
Additional 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for binary endpoints will be 
analyzed using a CMH test stratified by immunosuppressant use (yes/no). The 
95% CI for each treatment group response rate and the difference in response 
rate for branebrutinib compared to PBO will be provided. If expected cell 
counts are not sufficient, then Fisher’s exact test will be used. 
Continuous endpoints (change from baseline values) will be analyzed using 
analysis of covariance. The baseline value of the endpoint being tested will be 
added into the model as a covariate. Treatment differences based on least-
squares means and corresponding 2-sided 95% CIs will be provided for the 
difference between branebrutinib and PBO. 
Supportive Analyses 
Supportive analyses using logistic regression for the primary endpoint may be 
performed to incorporate additional covariates of interest and to confirm 
primary analysis results. The odds ratio and the corresponding 95% CI will be 
provided. 
Supportive analyses for continuous endpoints may be performed using MMRM 
to investigate response over time. 
Imputation Method 
Nonresponder imputation will be used for binary endpoints for subjects who 
discontinue 
study 
treatment 
early, 
start 
a 
protocol-prohibited 
medication/therapy prior to the specified timepoint, or otherwise have missing 
endpoint data for the specified timepoint. Other imputation methods may be 
considered for sensitivity analyses and will be described in the SAP if used. 
Testing Strategy for Secondary Endpoints 
There will be no alpha level adjustment for multiple endpoint testing. 
 
Subgroup Analyses 
Subgroup analyses will be conducted for the primary and secondary efficacy endpoints on the FAS 
population. Subgroups that may be evaluated include the following: 
x Gender 
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x Race 
x Tobacco use 
Additional subgroups defined for descriptive summaries may be specified in the SAP. 
 Safety Analyses 
Safety data will be descriptive in nature and will be summarized using the Safety Analysis Set. 
Data will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum), unless otherwise specified, for continuous variables and frequency 
distributions (counts and percentages) for categorical variables. Safety data will be summarized 
separately for each sub-protocol and with all sub-protocols combined. 
Data will be presented for the following treatments: 
x Branebrutinib 
x PBO 
 
Adverse Events 
TEAEs are defined as AEs that occur after the subject received first dose of study treatment or if 
a preexisting condition worsens in severity or becomes serious after receiving the first dose of 
study treatment up to 30 days after the last dose of study treatment. All reported TEAEs, SAEs, 
deaths, AEs leading to study treatment discontinuation, and AEIs will be summarized by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. AEIs in 
this study may include infections, influenza, tuberculosis, and herpes. 
 
Clinical Laboratory Tests 
Laboratory parameters will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities summarized by visit and shift tables will also be provided. For clinical 
laboratory test results, marked abnormalities will be defined in the SAP. 
 
Vital Signs and ECGs 
Vital signs and ECGs will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities will be summarized by visit as well. For vital signs and ECGs, marked 
abnormalities will be defined in the SAP. 
 Other Analyses 
The PK, PD, and exploratory biomarker analyses will be described in the SAP finalized before 
database lock. Any population PK analysis and PD analyses will be presented separately from the 
main CSR. 
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 Analysis and Reporting 
After all subjects in the SLE sub-protocol have finished the study and the data have been locked 
for the sub-protocol, analyses of the efficacy and safety data for the sub-protocol will be performed
in order to aid in planning for subsequent clinical development. Details of these analyses will be 
described in the SAP. The study team responsible for managing the study, including Medical 
Monitors, will remain blinded to treatment assignment and the results of safety analysis until full 
database lock and treatment unblinding has occurred. The data will be reported only after 
completion of all 3 sub-protocols. 
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Page: 112 
 
Protocol Number: IM014029 
 
IND Number: 142401 
 
EX-US Non-IND 
 
EUDRACT Number: 2019-002205-22 
Date: 01-Jul-2019 
Revised Date: 01-Dec-2021 
 
Clinical Protocol IM014029: 
PSS SUB-PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Assess the Efficacy and 
Safety of Branebrutinib Treatment in Subjects with Active Systemic Lupus Erythematosus or, 
Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept 
Treatment in Subjects with Active Rheumatoid Arthritis 
Protocol Amendment 04 pSS 
Study Director 
Medical Monitor 
 
 
Bristol Myers Squibb Company 
556 Morris Avenue, Building S5 
Summit, NJ 07901 
 
Telephone (office): 
 
Email: 
 
Medical Monitoring Support Center 
Telephone (office): 
 
Mobile: 
 
 
Fax: 
 
 
Email: 
 
 
24-hr Emergency Telephone Number 
USA: 
 
International: 
 
 
Bristol Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium 
 
 
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pSS TABLE OF CONTENTS
PSS 1 
SUB-PROTOCOL SUMMARY ..............................................................................116
pSS 1.1 
Synopsis ....................................................................................................................116
pSS 1.2 
Schema ......................................................................................................................122
pSS 1.3 
Schedule of Activities ...............................................................................................123
PSS 2 
INTRODUCTION ....................................................................................................134
pSS 2.1 
Background and Research Hypothesis .....................................................................134
Study Hypotheses ......................................................................................................135
pSS 2.2 
Benefit/Risk Assessment ..........................................................................................135
PSS 3 
OBJECTIVES AND ENDPOINTS ..........................................................................138
PSS 4 
STUDY DESIGN .....................................................................................................139
pSS 4.1 
Overall Design ..........................................................................................................139
DMC and Other External Committees .....................................................................140
pSS 4.2 
Number of Subjects ..................................................................................................141
pSS 4.3 
End of Study Definition ............................................................................................141
pSS 4.4 
Scientific Rationale for Study Design ......................................................................141
pSS 4.5 
Justification for Dose ................................................................................................141
PSS 5 
STUDY POPULATION ...........................................................................................142
pSS 5.1 
Inclusion Criteria ......................................................................................................143
pSS 5.2 
Exclusion Criteria .....................................................................................................147
pSS 5.3 
Lifestyle Restrictions ................................................................................................153
Meals and Dietary Restrictions ................................................................................153
Caffeine, Alcohol, Tobacco, and Cannabinoids .......................................................153
Activity ......................................................................................................................154
pSS 5.4 
Screen Failures ..........................................................................................................154
Retesting During Screening Period ..........................................................................154
PSS 6 
TREATMENT ..........................................................................................................154
pSS 6.1 
Treatments Administered ..........................................................................................155
pSS 6.2 
Method of Treatment Assignment ............................................................................156
pSS 6.3 
Blinding ....................................................................................................................156
pSS 6.4 
Dosage Modification ................................................................................................157
pSS 6.5 
Preparation/Handling/Storage/Accountability ..........................................................158
Retained Samples for Bioavailability/Bioequivalence ..............................................158
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pSS 6.6 
Treatment Compliance ..............................................................................................158
pSS 6.7 
Concomitant Therapy ...............................................................................................158
Prohibited and/or Restricted Treatments .................................................................158
Oral Corticosteroid Rescue ......................................................................................162
Other Restrictions and Precautions ..........................................................................162
pSS 6.8 
Treatment After the End of the Study .......................................................................162
PSS 7 
DISCONTINUATION CRITERIA ..........................................................................163
pSS 7.1 
Discontinuation from Study Treatment ....................................................................163
Permanent Discontinuation from Study Treatment ..................................................163
Temporary Discontinuation from Study Treatment ..................................................164
Post-study Treatment Study Follow-up ....................................................................164
pSS 7.2 
Discontinuation from the Study ................................................................................164
pSS 7.3 
Lost to Follow-up .....................................................................................................164
PSS 8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................165
pSS 8.1 
Efficacy Assessments ...............................................................................................165
Investigator-administered Assessments ....................................................................166
Patient-reported Assessments ...................................................................................168
Salivary Gland Ultrasonography .............................................................................170
170
pSS 8.2 
Adverse Events .........................................................................................................171
AEs of Interest ...........................................................................................................171
Time Period and Frequency for Collecting AE and SAE Information .....................171
Method of Detecting AEs and SAEs ..........................................................................172
Follow-up of AEs and SAEs ......................................................................................172
Regulatory Reporting Requirements for SAEs .........................................................173
Pregnancy .................................................................................................................173
Laboratory Test Result Abnormalities ......................................................................173
Potential DILI ...........................................................................................................174
Other Safety Considerations .....................................................................................174
pSS 8.3 
Overdose ...................................................................................................................174
pSS 8.4 
Safety ........................................................................................................................175
Physical Examinations ..............................................................................................175
Vital Signs .................................................................................................................175
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Electrocardiograms ..................................................................................................175
TB Screening and Chest Imaging .............................................................................175
Clinical Safety Laboratory Assessments ...................................................................175
Imaging Safety Assessment .......................................................................................177
pSS 8.5 
PK of Branebrutinib ..................................................................................................177
PK of Potential Concomitant Medications ...............................................................181
 
182
185
186
pSS 8.7 
Health Economics OR Medical Resource Utilization and Health Economics .........186
PSS 9 
STATISTICAL CONSIDERATIONS .....................................................................187
pSS 9.1 
Sample Size Determination ......................................................................................187
pSS 9.2 
Populations for Analyses ..........................................................................................187
pSS 9.3 
Endpoints ..................................................................................................................188
Primary Endpoint .....................................................................................................188
Additional Endpoints ................................................................................................188
PK Endpoints ............................................................................................................189
189
pSS 9.4 
Statistical Analyses ...................................................................................................190
Efficacy Analyses ......................................................................................................190
Safety Analyses .........................................................................................................191
Other Analyses ..........................................................................................................192
Analysis and Reporting .............................................................................................192
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pSS LIST OF TABLES 
pSS Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 ...............123 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to 
Week 28) ..................................................................................................127 
pSS Table 3 
Objectives and Endpoints ........................................................................138 
pSS Table 4 
Study Treatments for IM014029 ..............................................................155 
pSS Table 5 
Selection and Timing of Dose ..................................................................155 
pSS Table 6 
Prohibited and Restricted Medications ....................................................159 
pSS Table 7 
Clinical Safety Laboratory Assessments .................................................176 
pSS Table 8 
PK Sampling for Branebrutinib, Metabolites, and Concomitant 
Medications ..............................................................................................179 
 
184 
 
186 
 
PSS 1 
SUB-PROTOCOL SUMMARY 
pSS 1.1 
Synopsis 
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to 
Assess the Efficacy and Safety of Branebrutinib Treatment in Subjects with Active Systemic 
Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment 
Followed by Open-label Abatacept Treatment in Subjects with Active Rheumatoid Arthritis 
Short Title: 
Placebo-Controlled, Double-Blind Study to Assess the Efficacy and Safety of Branebrutinib in 
Primary Sjögren’s Syndrome: pSS Sub-protocol 
Study Phase: 
Phase 2a 
pSS Sub-protocol Rationale: 
The Study IM014029 primary Sjögren’s syndrome (pSS) sub-protocol is designed to evaluate the 
efficacy and safety of branebrutinib in addition to background disease therapy in the treatment of 
subjects with moderate to severe pSS. Based on several key underlying molecular mechanisms of 
pSS targeted by inhibition of Bruton’s tyrosine kinase (BTK), branebrutinib may be effective in 
the treatment of pSS. 
There is no currently approved treatment that targets the underlying mechanism(s) of pSS, 
indicating a clear unmet medical need in this patient population. 
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The European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index 
(ESSDAI), which is designed to measure systemic disease activity across 12 organ-specific 
domains, and the EULAR Sjögren’s Syndrome Patients Reported Index (ESSPRI), which 
measures subjective symptoms of dryness, pain, and fatigue, have recently been developed and 
validated for evaluation of therapeutic agents in pSS. Subsequent work has defined the 
patient-level relevant cut-offs for change for both the ESSDAI and ESSPRI scores for use in 
clinical studies. The disease activity levels for ESSDAI were defined (low activity < 5; moderate 
DFWLYLW\   WR   DQG KLJK DFWLYLW\  14). The minimum clinically important improvement 
0&,,IRU(66'$,ZDVGHILQHGDVDQLPSURYHPHQWRISRLQWVDQGIRU(6635,WKH0&,,ZDV
defined as a decrease of at least one point or 15%. 
ESSDAI-defined disease activity levels will enable the enrollment of patients with moderate to 
severe disease activity in this sub-protocol (66'$, 6). Limiting the population to those subjects 
ZLWKDQ(66'$,RIDWOHDVWZLOOHQDEOHDGHTXDWHGHWHFWLRQRI0&,,RI 3 points to discriminate 
between the effects of active treatment and placebo (PBO). Considering the small sample size and 
the relatively short treatment duration (24 weeks) of this study, ensuring sufficient patients are 
enrolled who have disease characteristics amenable to improvement will enable better signal 
detection for this asset to help guide future development. 
In an early phase clinical study, it is critical to ensure that as many subjects as possible enter the 
study with multiple active, “responsive” ESSDAI domains, so that treatment effects might be 
observed in as many domains as possible. This will provide a more robust dataset to aid the design 
of subsequent clinical studies. To meet this end, all subjects will be required to have a positive 
score in at least 1 of the following “responsive” domains (articular, biological, glandular, 
hematological, or lymphadenopathy) contributing to their composite ESSDAI score of 6 or more 
to enter the study. In addition, positive score(s) from any of the other 7 ESSDAI domains will help 
ensure an interpretable study. 
pSS Sub-protocol Study Population: 
The study population will include male and female subjects aged 18 (or age of majority) to 75 years 
inclusive at screening with moderate to severe pSS. 
pSS Sub-protocol Key Inclusion/Exclusion Criteria: 
a) 'LDJQRVHGZLWKS66 7 years before screening 
b) Subjects diagnosed or classified as having pSS (defined as Sjögren’s syndrome in the absence 
of another immune-mediated disease or rheumatologic condition) based on the 2016 American 
College of Rheumatology (ACR)-EULAR Classification Criteria for pSS, with disease 
duration from time since diagnosis of at least 16 weeks prior to screening, with moderate to 
severe activity per ESSDAI 
c) (66'$,VFRUHRI 6, including disease activity (any score > 0) in at least one of the following 
domains: glandular, articular, hematological, biological, lymphadenopathy 
d) Positive anti-Ro/Sjögren’s syndrome-associated antigen A (SSA), plus at least one of the 
following at screening, as determined by central laboratory: 
o 
 
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o 
 
o positive rheumatoid factor (RF) 
o positive cryoglobulin test (must be performed at local laboratory) 
o IgG > 16 g/L 
e) A stimulated salivary flow rate > 0.05 mL/minute or unstimulated salivary flow rate 
> 0.01 mL/minute at screening and randomization 
f) Subjects with a diagnosis of a systemic immune-mediated disease other than pSS, such as RA, 
SLE, mixed connective tissue disease, or systemic sclerosis that can better explain the majority 
of the symptoms (ie, secondary SS) are excluded 
g) Subjects who have another immune-mediated disease or inflammatory condition that could 
interfere with assessment of response of pSS to therapy (eg, immunoglobulin G4-related 
disease, systemic sclerosis, inflammatory bowel disease, gout) are excluded. 
h) Subjects with any other medical condition associated with sicca syndrome (eg, history of head 
and neck radiation treatment, diabetes mellitus, sarcoidosis, chronic graft-versus-host disease), 
and subjects with sicca symptoms secondary to ongoing medication use based on the 
investigator’s assessment, are excluded. 
i) Subjects with active fibromyalgia with pain symptoms or signs that would interfere with joint 
assessment or requiring adjustment in medication within the 3 months before screening to 
control symptoms are excluded. Subjects with fibromyalgia that is well controlled on stable 
treatment may otherwise be considered. 
j) Subjects with severe complications of pSS at the time of screening, including, but not restricted 
to, the following, are excluded: 
o Vasculitis with renal, digestive, cardiac, pulmonary or central nervous system (CNS) 
involvement characterized as severe (note: cutaneous vasculitis is allowed) 
o Active CNS or peripheral nervous system involvement requiring moderate to high-dose 
corticosteroids (CS > 10 mg/day) 
o Renal disease including but not limited to the following: 
– Interstitial nephritis 
– Glomerulonephritis 
– Nephrotic syndrome with proteinuria > 3 g/day or UPCR > 339 mg/mmol and/or 
VHUXPFUHDWLQLQH 2.0 mg/dL; interstitial nephritis with proteinuria < 1.5 g/day or 
UPCR < 169.5 mg/mmol and serum creatinine < 1.5 mg/dL may be included 
o Severe pulmonary disease based on the investigator’s assessment 
o Active myositis requiring more than the maximum dose of CS 
o Any type of lymphoma 
k) Subjects hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well as any subjects 
with any sequelae of prior COVID-19 infection at screening, regardless of time since infection, 
are excluded. 
 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
119 
pSS Sub-protocol Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
x 
To compare the efficacy 
of branebrutinib with 
PBO at Week 24 in the 
treatment of subjects 
with pSS 
Proportion of subjects with at least 3 of the following at Week 24: 
x 
'HFUHDVHRISRLQWRUIURPEDVHOLQHLQWKH(6635,7RWDO6FRUH 
x 
'HFUHDVHRISRLQts from baseline in ESSDAI score 
x 
'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRULIQRUPDOVFRUH
at baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x 
Improvement in one or more serological markers (RF, IgG, complement C3 
or C4, cryoglobulin) 
Additional 
x 
To compare the efficacy 
of branebrutinib with 
PBO at Week 24 in the 
treatment of subjects 
with pSS 
x 
'HFUHDVHRISRLQWRULQWKH(6635,7RWDO6FRUH 
x 
'HFUHDVHRISRLQWVIURPEDVHOLQHLQESSDAI score 
x 
'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRULIQRUPDOVFRUH
at baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQ6FKLUPHU¶VWHVWVFRUHRULIQRUPDOVFRUH
at baseline no change to abnormal 
x 
,QFUHDVHRIIURm baseline in tear break-up time (TBUT), or if normal 
score at baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x 
Improvement in one or more serological markers (RF, IgG, complement C3 
or C4, cryoglobulin) 
x 
Change from baseline in autoantibody titers, hsCRP, and ESR 
x 
Change from baseline in DAS28-CRP 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
x 
Changes from baseline in PGA and SGA 
x 
Changes from baseline in NRS for Mouth and Eye Dryness 
Safety 
x 
To compare the safety 
and tolerability of 
branebrutinib with PBO 
in subjects with pSS 
x 
Number and proportion of subjects experiencing SAEs, AEs, and 
abnormalities in laboratory parameters, vital signs, and ECGs 
Exploratory 
 
 
 
 
 
 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
120 
pSS Sub-protocol Objectives and Endpoints: 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse 
event; 
ANA 
= 
antinuclear 
antibody; 
a
 
; 
; 
; BTK = Bruton’s tyrosine kinase; 
 
; dsDNA = double-stranded deoxyribonucleic acid; ECG = electrocardiogram; 
EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5 Level version; ESR = erythrocyte 
sedimentation rate; ESSDAI = European League Against Rheumatism Disease Activity Index; ESSPRI = European 
League 
Against 
Rheumatism 
Patient-reported 
Index; 
hsCRP = high-sensitivity 
C-reactive 
protein; 
 
; Ig = immunoglobulin; IL = interleukin; 
 
 NRS = numeric rating score; PBO = placebo; PGA = Physician Global Assessment; 
PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; pSS = primary 
Sjögren’s syndrome; 
 
 
SAE = serious adverse event; 
; SGA = Subject Global 
Assessment; 
 
 TBUT = tear break-up time; 
 
pSS Sub-protocol Overall Design: 
x This is a double-blind, PBO-controlled Phase 2a study sub-protocol to evaluate the effect of 
branebrutinib (BMS-986195) in subjects with pSS. All subjects will receive background 
therapy for their primary disease as appropriate. 
x Subjects will receive double-blind oral branebrutinib 9 mg or PBO treatment once daily for 
24 weeks (Week 0 to Week 24). 
x Treatment assignment will be conducted by randomization. Subjects will undergo screening 
evaluations to determine eligibility within 28 days prior to administration of study medication. 
Following the screening process, if eligible for study participation, subjects will be randomized 
to receive branebrutinib or PBO treatment in a 2:1 ratio. Randomization will be stratified by 
hydroxychloroquine (HCQ) use (yes/no). 
pSS Sub-protocol Number of Subjects: 
It is expected that approximately 45 subjects will be randomized in the pSS sub-protocol. 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
121 
pSS Sub-protocol Duration: 
The total duration of participation in the pSS sub-protocol is approximately 32 weeks and will be 
divided into the following periods: screening (up to 4 weeks), double-blind PBO-controlled 
treatment for 24 weeks (Week 0 to Week 24), and follow-up (4 weeks). 
pSS Sub-protocol Study Treatment: 
Study Drug for IM014029 
Medication 
Potency 
IP/Non-IP 
Branebrutinib 
9 mg QD, oral 
IP 
Branebrutinib PBO 
QD, oral 
IP 
IP = investigational product; PBO = placebo; QD = once daily 
pSS Sub-protocol Statistical Methods 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the pSS sub-protocol 
is pSS composite response at Week 24. 
Estimates for response rates were obtained from the published literature. Sample size justification 
is provided below: 
Assuming a total sample size of 45 subjects randomized in a blinded fashion at a 2:1 ratio to 
branebrutinib (30 subjects) or PBO (15 subjects) and a treatment difference of 30% with a PBO 
response of 20% for the pSS composite response at Week 24, the 95% CI is expected to exclude 0 
(expected 95% CI based on a z-test = 3%, 57%). 
Categorical data will be summarized by treatment group as frequency counts and percentages. 
Continuous data will be summarized by treatment group using n, mean, standard deviation, 
median, minimum, and maximum unless otherwise specified. Efficacy data will be summarized 
separately for each sub-protocol and with each sub-protocol combined for variables that are similar 
among the sub-protocols. Primary analysis for each sub-protocol will be performed after all 
subjects finish the study within a sub-protocol. There will be no alpha level adjustment for multiple 
endpoint testing. 
The primary endpoint will be analyzed using analysis of covariance. The baseline value of the 
endpoint being tested will be added into the model as a covariate and HCQ use (yes/no) and 
treatment as fixed effects. Treatment differences based on least-squares means and corresponding 
2-sided 95% CIs will be provided for the difference between branebrutinib and PBO. The mixed 
model repeated measures analyses may be used in supportive analyses for continuous endpoints. 
Bayesian borrowing to utilize historical controls may also be performed as supportive analyses. 
Details will be provided in the SAP if needed. 
Missing data are addressed in these models and assumed to be missing at random. 
TEAEs and SAEs will be summarized using counts and percentages of subjects experiencing the 
event as well as the number of events by system organ class, preferred term, and treatment group. 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
122 
Physical examinations findings, vital signs, clinical laboratory test results, and electrocardiogram 
results will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) for continuous variables and frequency distributions (counts and 
percentages) for categorical variables. Safety data will be summarized separately for each 
sub-protocol and with all sub-protocols combined. 
pSS 1.2 
Schema 
ACR = American College of Rheumatology; Anti-SSA = anti-Sjögren’s Syndrome-associated antigen A antibody; 
ESSDAI = European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index; ESSPRI = European 
League Against Rheumatism Patient-reported Index; EULAR = European League Against Rheumatism; 
IgG = immunoglobulin G; OSS = ocular staining score; pSS = primary Sjögren’s syndrome 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
123 
pSS 1.3 
Schedule of Activities 
pSS Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Eligibility Assessments 
Informed Consent 
X 
A subject is considered enrolled only when a protocol-specific ICF is signed; this includes subjects at 
preselected clinical sites consenting to participate in extended PK sampling in addition to the sampling 
scheduled for all study subjects. 
Enroll subject in the IRT system 
X 
 
Inclusion/Exclusion Criteria 
X 
Includes: 
S66GLDJQRVLV 7 years before screening) based on 2016 ACR-EULAR criteria. 
Positive anti-Ro/SSA autoantibody (2016 ACR-EULAR Classification Criteria for pSS) plus at least 1 of the 
following: low C3, low C4, positive RF, positive cryoglobulin test or IgG > 16 g/L a 
(66'$,VFRUH 
pSS History, pSS-related 
Treatment 
X 
 
General Medical History 
X 
 
History of Tobacco Use 
X 
Nonsmoker, light or heavy smoker. 
Patient-reported Outcomes 
Mouth Dryness (NRS) 
X 
Collected on eCOA device. 
Eye Dryness (NRS) 
X 
Collected on eCOA device. 
ESSPRI 
X 
Collected on eCOA device. 
SGA 
X 
Collected on eCOA device. 
EQ-5 D-5 L 
X 
Collected on eCOA device. 
PROMIS-Fatigue 6 a 
X 
Collected on eCOA device. 
Clinical Assessments 
ESSDAI 
X 
Entered into EDC by site. 
Stimulated/unstimulated salivary 
flow 
X 
Entered into EDC by site (refer to Section pSS 8.1.1.2 for details). Can be performed by site staff trained on 
study-specific requirements and delegated by PI accordingly. 
2.0
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930168072
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
124 
pSS Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Tender (68)/swollen (66) joint 
count 
X 
Entered into EDC by site. 
PGA 
X 
Entered into EDC by site. 
Salivary Gland Ultrasonography (SG-US)  
SG-US 
X 
Perform approximately 14 days prior to randomization to allow review and perform repeat, if required b. 
Safety Assessments 
Physical Examination (PE) 
X 
Complete PE. 
Physical Assessments  
X 
 
Vital Signs 
X 
Includes height (screening only) and weight, body temperature (ear or oral), respiratory rate, seated BP, and 
seated heart rate. BP and heart rate should be measured after the subject has been resting quietly for at least 5 
minutes. 
ECG 
X 
ECGs should be recorded after the subject has been supine for at least 5 minutes. 
Chest imaging (eg, chest x-ray) 
X 
Chest imaging is required if not performed within 6 months of screening visit; copy of radiology report must 
be on file and reviewed by the investigator. 
Prior and Concomitant 
Medication Use 
X 
Includes prescription, over-the-counter medications, and herbal supplements. All concomitant medications to 
be reviewed by the Medical Monitor and clinical pharmacology asset lead. 
SAE Assessment 
X 
All SAEs must be collected from the time of signing the consent, including those thought to be associated with 
protocol-specified procedures and within 30 days of discontinuation of dosing or subject’s participation in the 
study if the last scheduled visit occurs at a later time. 
Laboratory Tests 
 
Includes blood and urine samples. 
Hematology 
X 
CBC with differential. 
Serum Chemistry Panel 
X 
Includes liver function testing. 
Lipid Panel 
X 
Nonfasting. 
Urinalysis 
X 
 
HbA1c 
X 
,I+E$FFRQVXOW0HGLFDO0RQLWRU. 
TSH 
X 
If out of normal range (high or low), consult the Medical Monitor. 
UPCR 
X 
 
2.0
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930168072
2.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
125 
pSS Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
eGFR 
X 
 
ESR 
X 
Local laboratory assessment by site. 
 
 
 
HCQ concentration c 
X 
To be reviewed by the Medical Monitor and clinical pharmacology asset lead. 
 
 
 
Anti-dsDNA 
X 
 
Anti-Ro/SSA 
X 
 
Anti-La/SSB 
X 
 
Cryoglobulin test 
X 
Local laboratory assessment by site. 
 
 
 
  
 
 
Infectious Serology 
X 
Includes HCV antibody, HBsAg, HBsAb, HBcAb, and HIV antibodies. 
TB Test (IGRA; eg, 
QuantiFERON®-TB Gold) 
X 
 
Pregnancy Test (Serum or Urine) 
X 
WOCBP only. Must have negative pregnancy test within 24 hours prior to the start of treatment. 
FSH 
X 
For select women only; serum FSH level will be determined to confirm menopausal status. See APPENDIX 
4 for definition and Section pSS 5.1 for reproductive status inclusion criteria. 
Biomarker Sampling 
 
  
 
 
 
 
 
 
 
2.0
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2.0
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1.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
126 
pSS Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
 
  
 
 
 
 
 
 anti-La/SSB = Sjögren’s syndrome-associated antigen B; anti Ro/SSA = Sjögren’s syndrome-associated antigen A;; 
 
; 
; BP = blood pressure; 
; CBC = complete blood count; 
 DNA = deoxyribonucleic acid; dsDNA = double-stranded deoxyribonucleic acid; ECG = electrocardiogram; 
eGFR = estimated glomerular filtration rate; ESR = erythrocyte sedimentation rate; EQ-5 D-5 L = Euro Quality of Life 5 Dimensions Questionnaire: 5-Level version; 
ESSDAI = EULAR Sjögren’s Syndrome Disease Activity Index; ESSPRI = EULAR Sjögren’s Syndrome Patient-reported Index; EULAR = European League 
Against Rheumatism; FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; HCQ = hydroxychloroquine; HIV = human immunodeficiency virus;
; ICF = informed 
consent form; IGRA = interferon gamma-release assay; IL = interleukin; IRT = interactive response technology; 
; NRS = numeric 
rating score; PGA = Physician Global Assessment; PI = principal investigator; PK = pharmacokinetic; 
 
; 
 SAE = serious adverse event; SGA = subject’s global assessment; TB = tuberculosis; 
; TSH = thyroid-stimulating hormone; UPCR = urine protein:creatinine ratio; WOCBP = women of childbearing potential 
a Testing for anti-Ro/SSA and anti-La/SSB autoantibodies may be repeated once during screening for subjects who otherwise qualify according to inclusion criteria 
but have initial negative anti-Ro/SSA and anti-La/SSB. 
b Perform approximately 14 days prior to randomization to allow review and perform repeat, if required. 
c For subjects taking HCQ concomitantly, a sample of whole blood will be drawn for HCQ PK analysis. 
 
 
 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1) Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2) Safety assessments (eg, vitals, AEs) 
3) Investigator-administered Assessments (eg, PGA, joint count, etc) 
4) Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
 
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
127 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
Patient-reported Outcomes 
SGA 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device. 
ESSPRI  
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device. 
Mouth dryness (NRS) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device. 
Eye dryness (NRS) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected on eCOA 
device. 
EQ-5 D-5 L 
X 
 
 
 
X 
 
 
X 
X 
Collected on eCOA 
device. 
Fatigue (PROMIS-
Fatigue 6 a) 
X 
 
 
 
X 
 
 
X 
X 
Collected on eCOA 
device. 
Safety Assessments 
Complete Physical 
Examination (PE) 
X 
 
 
 
 
 
 
 
X 
 
Targeted Physical 
Examination 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Body Weight  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Temperature (ear or oral), 
respiratory rate, seated 
BP, and seated heart rate; 
BP and heart rate should 
be measured after the 
subject has been resting 
quietly for at least 
5 minutes. 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGs should be recorded 
after the subject has been 
supine for at least 
5 minutes. 
2.0
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
128 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
Concomitant Medication 
Use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE and SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nonserious AEs must be 
collected from the time of 
the first dose of the study 
drug through the date of 
the follow-up or last visit. 
Clinical Assessments 
ESSDAI 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site. 
Stimulated/unstimulated 
salivary flow 
X 
 
 
 
X 
 
 
X 
X 
Entered into EDC by site 
(refer to 
Section pSS 8.1.1.2 for 
details). Can be 
performed by site staff 
trained on study-specific 
requirements and 
delegated by PI 
accordingly. 
Tender (68)/swollen (66) 
joint count 
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site. 
PGA  
X 
 
X 
X 
X 
X 
X 
X 
X 
Entered into EDC by site. 
DAS28-CRP  
X 
 
X 
X 
X 
X 
X 
X 
X 
Scores calculated 
programmatically. 
LGF: Tear Break-up Time, 
Ocular Staining Score, 
Schirmer’s Test  
X 
 
 
 
X 
 
 
X 
 
LGF/Ocular staining tests 
must be done within 
5 days prior to Day 1 or, 
if done on Day 1, must be 
done before 
administration of IP; on-
study LGF assessments 
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
129 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
have a 5-day window 
around Week 12/24 visits. 
Salivary/Parotid Gland Biopsy (Optional Substudy) 
Salivary/Parotid Gland 
Biopsy 
28-day window 
X 
 
 
 
 
 
 
X 
 
Subject consent required. 
Salivary Gland Ultrasonography (SG-US) 
SG-US b 
7-day window 
 
 
 
 
X 
 
 
X 
 
Parotid and 
submandibular glands on 
both sides. 
Laboratory Tests  
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panel (Fasting) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
 
 
 
 
 
 
 
X 
X 
 
UPCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local laboratory 
assessment by site. 
 
 
 
 
 
 
 
 
 
 
 
HCQ concentration 
X 
 
X 
 
 
 
 
 
 
Predose and 2 hours 
postdose. 
Collected as part of 
concomitant medications 
PK (refer to 
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930168072
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
130 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
Section pSS 8.5, 
pSS Table 8). 
 
X 
 
X 
X 
X
X 
X 
 
 
 
Cryoglobulin test 
X 
 
X 
X 
X 
X 
X 
X 
X 
Local laboratory 
assessment by site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Beta-2-microglobulin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TBNK 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (serum or 
urine) 
X 
 
X 
X 
X 
X 
X 
X 
X 
WOCBP only. Must have 
negative pregnancy test 
within 24 hours prior to 
the start of treatment. 
 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
. 
PK Assessments 
 
 
 
 
 
 
 
 
 
Standard blood samples for 
the PK of branebrutinib c 
X 
 
X 
X 
 
X 
 
X 
 
Refer to Section pSS 8.5, 
pSS Table 8 for details. 
2.0
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930168072
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Clinical Protocol 
IM014029 - pSS 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
131 
pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
Blood samples at 
preselected sites for the PK 
of branebrutinib and 
metabolites d 
X 
 
 
X 
 
 
 
 
 
Refer to Section pSS 8.5, 
pSS Table 8 for details. 
Blood samples for the PK 
assessment of concomitant 
medications e 
X 
 
X 
 
 
 
 
 
 
Refer to Section pSS 8.5, 
pSS Table 8 for details. 
Biomarker Sampling 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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pSS Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 28) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
W16 
D113 
(± 3 d) 
V7 
W20 
D141 
(± 3 d) 
V8 
W24 
D169 
(± 3 d) 
V9 
(EOT) a 
W28 
D197 (± 3 d) 
V10 
Safety FU 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
Randomize 
X 
 
 
 
 
 
 
 
 
 
Dispense/Administer Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
 
Note: At Week 2 and 
Week 24 the subject is 
requested to bring IP to 
the site visit and IP is 
administered at the site; 
no new kit is dispensed at 
these visits. 
Study Treatment 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X h 
 
; AE = adverse event; ANA = antinuclear antibody; 
;
 
 BP = blood pressure; BTK = Bruton’s tyrosine kinase; 
; 
; 
d = day; DAS28-CRP = Disease Activity Score-28 C-reactive protein; dsDNA = double-stranded DNA; ECG = electrocardiogram; eCRF = electronic case report 
form; EDC = RAVE electronic data capture; eGFR = estimated glomerular filtration rate; EOT = end of treatment; EQ-5 D 5 L = EuroQol-5 D-5 L; ESR = erythrocyte 
sedimentation rate; ESSDAI = EULAR Sjögren’s Syndrome Disease Activity Index; ESSPRI = EULAR Sjögren’s Syndrome Patient-reported Index; FU = follow-up; 
hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; 
; IP = investigational product; LGF = lacrimal gland 
function; NRS = numeric rating score; PGA = Physician Global Assessment; PI = principal investigator; PK = pharmacokinetic; PROMIS = Patient-Reported 
Outcomes Measurement Information System; 
;
 RNA = ribonucleic acid; 
; SAE = serious adverse event; SGA = Subject Global Assessment; SG-US = salivary gland ultrasonography; 
SSA = Sjögren’s syndrome-associated antigen A; SSB = Sjögren’s syndrome-associated antigen B; SG-US = salivary gland ultrasonography; TBNK = T, B, and 
natural killer cells; UPCR = urine protein:creatinine ratio; V = visit; WOCBP = women of childbearing potential 
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a  If the decision has been made for a subject to permanently discontinue treatment before the planned Week 24 visit (Section pSS 7.1.1), the subject should undergo 
a Week 24 EOT visit as specified in the Week 24 column of this table, followed by a Week 28 Safety FU visit, 4 weeks (±3 d) later, as specified in the Week 28 
column of this table. The appropriate eCRF pages for the EOT and Safety FU visits should be completed accordingly. 
b  Subjects who terminate the study early require a SG-86H[DPLQDWLRQDWWKH(27YLVLWRQO\LIWKDWYLVLWLVZHHNVIURPWKHGDWHRIUDQGRPL]DWLRQRUZHHNV
from Week 12 and should have the EOT SG-US examination NO MORE than 7 days from the EOT visit. 
c  Blood samples for the PK assessment of branebrutinib concentrations will be taken predose from all study subjects at Week 0 (Day 1), Week 4 (Day 29), Week 8 
(Day 57), Week 16 (Day 113), and Week 24 (Day 169), and postdose at Week 0 (Day 1), Week 8 (Day 57), and Week 24 (Day 169) at approximately 0.5, 1, 2, 
and 4 hours after dosing. 
d At preselected clinical sites only, blood samples for the PK assessment of branebrutinib and its metabolites concentrations will be taken predose at Week 8 
(Day 57); and postdose at Week 0 (Day 1) and Week 8 (Day 57) at approximately 0.5, 1, 2, and 4 hours. In addition, samples will be taken postdose at 6 hours and 
from 8-10 hours (flexible window) and 10-12 hours (flexible window) on the same days. A PK sample will also be drawn at Week 0 (Day 2) at 24 hours after 
dosing (predose of branebrutinib on Day 2). (For these assessments, collected blood samples will be aliquoted into 2 tubes.) 
e Blood samples for PK assessment of relevant concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant drug metabolizing 
enzymes and P-gp transporter may be measured post-hoc. For these concomitant medications, plasma samples will be collected predose and 2 hours postdose at 
Week 0 (Day 1) and Week 4 (Day 29). For subjects taking HCQ on-study, whole blood samples at predose and 2 hours postdose of branebrutinib on both Day 1 
(Week 0) and Day 29 (Week 4) will be collected in addition for the assessment of HCQ level. 
 
 
 
 
 
h Study treatment compliance is to be performed at Week 28 only if the subject’s study participation has completed and the subject failed to return study drug at the 
prior visit. 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1. Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
 
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PSS 2 
INTRODUCTION 
An overall introduction to this protocol employing a master protocol design for 3 separate 
immune-mediated indications is provided in Section Master 1.2. 
pSS 2.1 
Background and Research Hypothesis 
The pSS sub-protocol for Study IM014029 is designed to evaluate the efficacy and safety of 
branebrutinib in addition to background disease therapy in the treatment of subjects with moderate 
to severe pSS. Based on several key underlying molecular mechanisms of pSS targeted by BTK 
inhibition, we will test the hypothesis that branebrutinib is effective in the treatment of subjects 
with pSS. 
pSS is a complex chronic, systemic, immune-mediated disease affecting the exocrine glands 
characterized by lymphocytic infiltration of salivary and lacrimal glands, systemic manifestations 
including renal, pulmonary and neurological complications, and increased incidence of 
lymphoma.17 The disease is chronic and damage is slowly progressive, often initially presenting 
as persistent dryness of the mouth and eyes due to functional impairment of the salivary and 
lacrimal glands. While the disease was previously considered to be a localized or glandular disease, 
pSS is now increasingly recognized as a systemic disease. More than half of pSS patients 
experience extraglandular symptoms, including overwhelming fatigue, arthralgias and myalgias, 
and Raynaud’s phenomenon. Extraglandular manifestations may also involve the joints, lungs, 
skin, kidneys, and nervous system, and are responsible for many of the primary salient features of 
disease reported by subjects. The disease is heterogeneous, and not all subjects exhibit all of the 
same symptoms. Similarly, as our understanding of the pathophysiology of the disease improves, 
it is clear that various immunologic mechanisms drive disease. 
B and T cells play key roles in the pathobiology of pSS.17 As evidenced by 
hypergammaglobulinemia, alterations in B cell subpopulations, ectopic germinal center-like 
structures in the affected glands, and increased risk of lymphoma, B cells are critical in driving the 
disease.17 B cells produce autoantibodies such as anti-Ro/SSA and anti-La/SSB that can amplify 
the production of Type I IFNs and deposit at sites of inflammation in the glands, leading to the 
production of pro-inflammatory cytokines.17 Within salivary glands, ectopic germinal center-like 
structures have been identified, which likely serve as primary sites for B cell-T cell interactions.18 
BlyS, which drives B cell proliferation and survival, has been shown to be elevated both in the 
serum and salivary glands of pSS subjects.19, 20, 21 Recently, increased levels of BTK protein have 
been observed in circulating B cells of patients with pSS and appear to correlate with RF levels 
and parotid gland T cell infiltration.4 Since BTK plays an essential role in the mediation of BCR 
response to autoantigen and pro-inflammatory signaling in B cells, BTK inhibition may target key 
underlying molecular mechanisms of pSS. On this basis, the BTK inhibitor branebrutinib will be 
tested for efficacy in the treatment of this patient population. 
There is no currently approved treatment that targets the underlying mechanism(s) of pSS, 
indicating a clear unmet medical need in this patient population. 
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The European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index 
(ESSDAI), which is designed to measure systemic disease activity across 12 organ-specific 
domains, and the EULAR Sjögren’s Syndrome Patient-reported Index (ESSPRI), which measures 
subjective symptoms of dryness, pain, and fatigue, have recently been developed and validated for 
evaluation of therapeutic agents in pSS. Subsequent work has defined the patient-level relevant 
cut-offs for change for both the ESSDAI and ESSPRI scores for use in clinical studies. The disease 
activity levels for ESSDAI were defined (low activity < PRGHUDWHDFWLYLW\ DQG 13, and 
KLJKDFWLYLW\ 7KH0&,,IRU(66'$,ZDVGHILQHGDVDQLPSURYHPHQWRI 3 points, and for 
ESSPRI, the minimally clinically important improvement (MCII) was defined as a decrease of at 
least one point or 15%. 
ESSDAI-defined disease activity levels will enable the enrollment of a moderate to severe disease 
activity sub-protocol in WKLVVWXG\(66'$, 6). Limiting the population to subjects with an 
(66'$,RIDWOHDVWZLOOHQDEOHDGHTXDWHGHWHFWLRQRIWKH0&,,RI 3 points to discriminate 
between the effects of active treatment and PBO. Considering the small sample size and the 
relatively short treatment duration (24 weeks) of this study, ensuring sufficient patients are 
enrolled who have disease characteristics amenable to improvement will enable better signal 
detection for this asset to help guide future development. 
In the context of an early phase clinical study, it is reasonable to ensure that as many subjects as 
possible enter the study with multiple active, responsive ESSDAI domains, so that treatment 
effects might be observed in as many domains as possible, as this will provide a more robust dataset 
to aid the design of subsequent clinical studies. To meet this end, all subjects will be required to 
have a positive score in at least 1 of the following responsive domains (articular, biological, 
glandular, hematological, or lymphadenopathy) contributing to their composite ESSDAI score of 
6 or more to enter the study, in addition to positive score(s) from any of the other 7 ESSDAI 
domains that may be active in qualifying patients. 
 
Study Hypotheses 
Since BTK plays a central role in the pathology of pSS, the hypothesis of this study is that BTK 
inhibition will provide benefit in the treatment of subjects with moderate to severe pSS. 
pSS 2.2 
Benefit/Risk Assessment 
At this early stage in the development of branebrutinib for the treatment of immune-mediated 
disorders, assessments of benefit and risk rely on nonclinical data and data from completed Phase 1 
studies in healthy volunteer subjects. The proposed 9 mg QD dosing regimen reflects 
implementation of appropriate safety margins (> 500× based on the AUC in rats and dogs at the 
NOAEL [20 mg/kg/day and 15 mg/kg/day in rats and dogs, respectively]) and is within the range 
of doses tested in the FIH study (Study IM01400137). 
The effects of BTK inhibition by branebrutinib have been documented in pharmacology studies, 
and the potential for benefit in RA and SLE have been demonstrated by nonclinical studies using 
mouse models of RA and SLE. branebrutinib demonstrated robust in vivo efficacy in CIA and 
CAIA murine models of RA, protecting against clinically evident disease, histological joint 
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damage, and bone mineral density loss. In both models, maximal efficacy was observed with 
t 95% inactivation of BTK in vivo. Similarly, potent efficacy was observed in a mouse model 
(New Zealand Black and New Zealand White) of lupus-induced nephritis (see branebrutinib IB 
Section 4.1.1.212 for further details). 
Findings in nonclinical toxicology studies were consistent with expectations based on the 
pharmacology of branebrutinib and included on-target PD effects such as decreases in B cells, 
suppression of keyhole limpet hemocyanin-specific IgM and IgG responses, and dose-related 
germinal center lymphoid depletion of minimal to moderate severity in the gut-associated 
lymphatic tissue. 
branebrutinib-related pancreatic toxicity was identified in oral SD rat toxicity studies with up to 
6 months of exposure.39, 40, 41 Findings related to branebrutinib were noted at all doses, and were 
generally islet-centric (see the branebrutinib IB12 for further details). These pancreatic lesions are 
similar to those observed with other BTK inhibitors and represent an exacerbation of an age-related 
pancreatic finding specific to rats.42, 43, 44, 45 As such, these findings were considered nonadverse. 
The FDA has acknowledged that pancreatic lesions observed in rats treated with BTK inhibitors 
are unlikely to have relevance to the safety assessment for human subjects treated with this drug 
class. 
With the exception of an unrelated SAE that was consistent with the subject’s medical history, 
AEs in the FIH study (Study IM01400137) were mild to moderate, reversible, and consistent with 
expectations based on nonclinical experience. 
Based upon the mechanism of action of the compound (immunosuppression), BMS has 
implemented additional assessments and risk mitigation approaches (including careful 
consideration of appropriate exclusion criteria and monitoring of subjects during and after dosing) 
in combination with conventional safety monitoring. In Parts A, B, C, and D of the FIH study,37 
there were no dose-related elevations of amylase, lipase, or fasting glucose; no decreases in WBCs 
or Ig levels; and no clinically significant infections; however, this protocol continues to stipulate 
exclusion criteria (eg, assessment for LTBI and chronic viral infections) and clinical and laboratory 
monitoring to reduce the risk of infection. 
Because of the slow return of BTK activity following the discontinuation of branebrutinib dosing 
(based on post-hoc analyses following Study IM014001), BTK occupancy was found to be 
between 10% and 30% with a steep downward trend following treatment with 10 mg branebrutinib 
for 2 weeks), the duration of postdose follow-up of 4 weeks was chosen to account for the time 
needed to recover BTK activity. 
To minimize risk to participating subjects, this protocol has inclusion and exclusion criteria 
appropriate to the populations and proposed treatments, as well as frequent study visits for safety 
assessments. Blinded safety data will be reviewed on an ongoing basis by the BMS Medical 
Monitor and pharmacovigilance group to look for emerging safety trends or issues, and an 
independent external DMC will be in place for the duration of the study. 
In order to provide active study treatment while receiving PBO treatment for a maximum of 
24 weeks, subjects in the pSS sub-protocol will also receive protocol-defined SOC therapy for 
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WKHLU SULPDU\ GLVHDVH $OWKRXJK VXFFHVVIXO &6 WDSHULQJ IRU WKRVH WDNLQJ  10 mg/day will be 
encouraged as appropriate, inability to taper or a requirement to increase the CS dose to protect a 
subject’s safety or well-being will not be prohibited by the protocol. 
The risk for drug-DDIs with branebrutinib has previously been assessed. The potential for 
clinically relevant DDIs of branebrutinib with substrates of a number of enzymes and transporters 
(cytochrome P450 [CYP]1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and organic anion 
transporting polypeptide OATP1B1 and 1B3) is likely to be minimal based on the low projected 
therapeutic concentration (Cmax < 0.20 μM) and high serum protein binding.46 Based on the 
results of Study IM014013 and in vitro studies, branebrutinib may affect the PK of drugs that are 
sensitive substrates of CYP2C8 and P-glycoprotein (P-gp) as a weak inhibitor. Therefore, until 
more knowledge is gained, drugs that are sensitive substrates of CYP2C8 and P-gp may be 
restricted or excluded based on their therapeutic window and metabolism. 
In vivo studies to evaluate the developmental and reproductive effects of branebrutinib have shown 
developmental toxicity in rabbits (at an exposure multiple of 53u relative to the dose of 9 mg 
proposed for this study) that were associated with maternal mortality (IB Section 4.3.512). At the 
NOAEL of 40 mg/kg/day, the safety margin was 16u compared to the human AUC at 10 mg MAD. 
branebrutinib was not associated with maternal or developmental toxicity in pregnant rats at 
exposure multiples up to 437u (versus human AUC at 10 mg MAD). Based on the exposure safety 
multiple, there is minimal risk to WOCBP. However, to ensure safety, the study will require 
WOCBP to use highly effective contraception, and pregnant women will not be enrolled in this 
study. It is not known whether branebrutinib passes into human milk. Therefore, breastfeeding 
women will also not be enrolled in this study. The DDI study with oral contraceptives 
(Study IM014023) demonstrated lack of PK interaction,47 which ensures efficacy of hormonal 
contraception co-administered with branebrutinib. 
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PSS 3 
OBJECTIVES AND ENDPOINTS 
pSS Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
x 
To compare the efficacy of 
branebrutinib with PBO at 
Week 24 in the treatment of 
subjects with pSS 
Proportion of subjects with at least 3 of the following at Week 24: 
x 
'HFUHDVHRISRLQWRUIURPEDVHOLQHLQWKH(6635,7RWDO6FRUH 
x 
'HFUHDVHRISRLQts from baseline in ESSDAI score 
x 
'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRULIQRUPDO
score at baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x 
Improvement in one or more serological markers (RF, IgG, 
complement C3 or C4, cryoglobulin) 
Additional 
x 
To compare the efficacy of 
branebrutinib with PBO at 
Week 24 in the treatment of 
subjects with pSS 
x 
'HFUHDVHRISRLQWRULQWKH(6635,7RWDO6FRUH 
x 
'HFUHDVHRISRLQWVIURPEDVHOLQHLQESSDAI score 
x 
'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRULIQRUPDO
score at baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQ6FKLUPHU¶VWHVWVFRUHRULIQRUPDO
score at baseline no change to abnormal 
x 
,QFUHDVH RI   IURm baseline in TBUT, or if normal score at 
baseline no change to abnormal 
x 
,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x 
Improvement in one or more serological markers (RF, IgG, 
complement C3 or C4, cryoglobulin) 
x 
Change from baseline in autoantibody titers, hsCRP, and ESR 
x 
Change from baseline in DAS28-CRP 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
x 
Changes from baseline in PGA and SGA 
x 
Changes from baseline in NRS for Mouth and Eye Dryness 
Safety 
x 
To compare the safety and 
tolerability of branebrutinib 
with PBO in subjects with pSS 
x 
Number and proportion of subjects experiencing SAEs, AEs, and 
abnormalities in laboratory parameters, vital signs, and ECGs 
Exploratory 
x 
 
 
 
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pSS Table 3 
Objectives and Endpoints 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ADME = absorption, distribution, metabolism, and excretion; 
AE = adverse 
event; 
ANA 
= 
antinuclear 
antibody; 
a
 
 
 
; BTK = Bruton’s tyrosine kinase; 
 
; dsDNA = double-stranded deoxyribonucleic acid; ECG = electrocardiogram; 
EQ-5 D-5 L = Euro Quality of Life Five Dimensions Questionnaire: 5 Level version; ESR = erythrocyte 
sedimentation rate; ESSDAI = European League Against Rheumatism Disease Activity Index; ESSPRI = European 
League 
Against 
Rheumatism 
Patient-reported 
Index; 
hsCRP = high-sensitivity 
C-reactive 
protein; 
 
; Ig = immunoglobulin; IL = interleukin; 
 
; NRS = numeric rating score; PBO = placebo; PGA = Physician Global Assessment; 
PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; pSS = primary 
Sjögren’s syndrome; 
 
; SAE = serious adverse event; 
; SGA = Subject Global 
Assessment; 
 
 
; TBUT = tear break-up time; 
 
 
PSS 4 
STUDY DESIGN 
pSS 4.1 
Overall Design 
x This is a double-blind, PBO-controlled multicenter Phase 2a study to assess the effect of 
branebrutinib treatment concomitant with background disease therapy within protocol-defined 
limits in subjects with moderate to severe pSS. 
x Approximately 45 subjects will be randomized in the pSS sub-protocol. Sample size 
considerations are presented in Section pSS 9.1 Sample Size Determination. 
x For the pSS sub-protocol, there will be a 24-week double-blind PBO-controlled treatment 
period in which subjects will receive branebrutinib 9 mg or PBO QD. 
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x Blinded treatment assignment will be conducted by randomization on Day 1 and managed by 
IRT. Subjects will undergo screening evaluations to determine eligibility within 28 days prior 
to administration of study medication. After successfully meeting entry criteria and completing 
screening assessments, subjects in the pSS sub-protocol will be randomized in a blinded 
manner to receive branebrutinib 9 mg or PBO in a 2:1 ratio. 
x The total duration of participation in the pSS sub-protocol will be approximately 32 weeks and 
will be divided into the following periods: screening (up to 4 weeks [28 days]), double-blind 
PBO-controlled treatment for 24 weeks (Week 0 to Week 24), and follow-up (4 weeks). 
x Efficacy and safety will be assessed throughout the study (see Section pSS 8.1 Efficacy 
Assessments, Section pSS 8.2 Adverse Events, and Section pSS 8.4 Safety for details of 
assessments). Blood samples will be collected for PK and biomarker clinical laboratory 
assessments (see Section pSS 8.5, Section pSS 8.5.1, 
, respectively, for 
details of assessments). 
x An independent DMC will assess study findings on a periodic basis (Section pSS 4.1.1). 
The study design schematic for the pSS sub-protocol is presented in Section pSS 1.2. 
 
DMC and Other External Committees
To ensure the safety of study subjects, across all sub-protocols, an external independent DMC 
consisting of 2 experienced rheumatologists, an infectious disease clinician, and a statistician will 
be established for ongoing evaluation of safety assessments, AEs, and laboratory measurements. 
An independent reporting statistician not involved in the conduct of the study will be designated 
to provide the DMC with essential safety data unblinded to treatment during the study, if required.
The DMC will conduct at regular, prespecified intervals and on an ad hoc basis if warranted, safety 
review meetings throughout the study to ensure that the benefit and risks of study participation 
remain acceptable. Ad hoc meetings may be initiated by the DMC or by the Sponsor based on 
emerging new safety information. Based on the DMC’s assessment, recommendations of protocol 
modifications or other actions may occur, including but not limited to sample size adjustment,
study modification, or discontinuation of the study or one or more of the sub-studies. In addition, 
hold of enrollment, pending more detailed assessment may be requested. 
Blinded SUSARs will be sent to the DMC members on an ongoing basis. SAEs will be sent to the 
DMC on a monthly basis or on an ongoing basis as requested by the DMC. 
The DMC will review safety data including but not limited to SAEs and AEIs. At the request of 
the DMC, designated personnel will provide further information on the medical assessment for a 
specific case. 
The DMC may also consider external data from other branebrutinib studies that may be initiated 
in future or from novel scientific information that may be generated on branebrutinib or other BTK 
inhibitors. 
Further details of DMC responsibilities, specific timing of safety reviews, content, and methods of 
data reports, authorities, processes, and procedures will be specified in the DMC charter. 
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pSS 4.2 
Number of Subjects 
It is expected that approximately 45 subjects will be randomized in the pSS sub-protocol. 
Details regarding sample size determination are provided in Section pSS 9.1. 
pSS 4.3 
End of Study Definition 
The start of the study is defined as the date that the first subject signs the informed consent. The 
end of the pSS sub-protocol is defined as the last visit of the last subject to complete the study or 
the final scheduled procedure shown in the SoA (Section pSS 1.3). Study completion for the pSS 
sub-protocol is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same. The master protocol study will be reported only after the 
last endpoint has been analyzed for all 3 sub-protocols. 
The total duration of study participation for subjects in the pSS sub-protocol is expected to be 
approximately 32 weeks. 
pSS 4.4 
Scientific Rationale for Study Design 
(Please refer to Master Section 1.2 for rationale supporting the choice of a master protocol design 
to evaluate the safety and efficacy of branebrutinib in 3 immune-mediated/autoantibody-related 
diseases.) 
The pathology of pSS involves several signaling events regulated by BTK, as described in 
Section pSS 2.1. It is therefore hypothesized that BTK inhibition will result in clinical benefits in 
subjects with pSS. 
Because there is no currently approved treatment for pSS that targets the underlying mechanism(s) 
of the disease, there is not an appropriate active comparator to use in this study. All subjects will 
continue on their commonly used disease modifiers and symptomatic therapies (including 
hydroxychloroquine, pilocarpine, cevimeline, cyclosporine eye drops, artificial tears/saliva, and 
low-dose oral CS) for the duration of the screening and dosing periods, thus mitigating the impact 
of receiving a PBO. 
A PBO control will be included in the pSS sub-protocol to allow the effects of treatment, both 
desired and adverse, to be appropriately compared against active treatment, with effort to minimize 
treatment period on PBO, as well as to allow continuation of certain background therapy within 
protocol-defined limits. 
pSS 4.5 
Justification for Dose 
The selection of the branebrutinib dose and regimen to be assessed in this study was based on 
findings in the FIH and nonclinical studies. 
In the MAD panels (Part B) of the FIH study (Study IM014001), healthy subjects received 
branebrutinib orally QD for 14 days at 4 dose levels (0.3, 1, 3, and 10 mg; n = 6 per dose).37 
Increases in Cmax and AUC(TAU) were approximately dose proportional within the dose levels 
tested. The mean T-HALF was shorter than 2 hours across the dose range tested, indicating that 
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branebrutinib was rapidly eliminated from the body. Consequently, as expected, accumulation at 
steady-state after multiple daily dosing was negligible. 
The safety profile of branebrutinib 3 mg and 10 mg doses in Study IM014001 demonstrated lack 
of dose effects on safety. The drug was well-tolerated at both dose levels with most AEs also 
observed for the subjects treated with PBO. The AEs mainly included headache and  
upper respiratory tract infection. Based on the AUC in rats at the NOAEL (61,900 QJKP/WKH
safety multiple in humans after multiple doses of 10 mg is > 500×.12 In this study, the dose level 
of branebrutinib will be 9 mg; therefore, the safety margin is sufficient for humans participating 
in the study. 
The dose for branebrutinib was selected based on data from biomarkers obtained in post-hoc 
analysis of Study IM014001. The biomarkers evaluated were BTK occupancy by branebrutinib, 
inhibition of ex vivo stimulated CD69 expression, and plasma CXCL13 levels. The maximum 
RFFXSDQF\UHDFKHGDWEUDQHEUXWLQLEGRVHVRI mg and above (100%; maximum occupancy 
at doses  mg); however, the time to reach maximum occupancy was faster and maintained for 
a longer duration at 3 mg and 10 mg doses (solution formulation). The variability of the effect was 
lower for the higher dose of 10 mg. A similar result was obtained for CD69 inhibition, while the 
largest median inhibition in CD69 expression was observed at the branebrutinib 10 mg dose. The 
highest inhibition of plasma levels of CXCL13 was also obtained at the 10 mg dose level. 
Considering the higher variability and expression of BTK in patients with immune-mediated 
disorders,4 the higher dose is expected to sustain more stable inhibition of BTK for chronic 
treatment of heterogenous patients. 
The comparison of exposure between the branebrutinib 10 mg solution formulation from 
Study IM014001 and the branebrutinib 9 mg capsule formulation (3 × 3 mg) from Day 1 Cycle 2 
in Study IM014023 demonstrated comparable exposure for Cmax and AUC(TAU) with only slight 
delay in Tmax for capsule formulation. Thus, the use of 3 × 3 mg capsules of branebrutinib is 
expected to be equivalent to the 10 mg solution formulation in terms of exposure, safety, and PD 
effects considering the specifics of the patient population. 
The exposure for this dose level is also much lower than the safety limit for exposure identified in 
preclinical studies; as previously mentioned, based on the AUC in rats at the NOAEL, the safety 
multiple in humans after multiple doses of 10 mg is > 500×. 
In summary, the dose to evaluate the PD response with optimal safety and efficacy was chosen to 
be 9 mg branebrutinib administered as 3 × 3 mg capsules (details of treatment administration are 
provided in Section pSS 6.1). 
PSS 5 
STUDY POPULATION 
Eligibility criteria for this sub-protocol have been carefully considered for the safety of the study 
subjects and to ensure that the results of the study can be interpreted. It is imperative that 
randomized subjects meet all eligibility criteria. 
Screening evaluations must be completed and reviewed by the investigator to confirm whether 
potential subjects are eligible. The investigator will maintain a screening log to record details of 
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all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. Subject eligibility will be reviewed and confirmed by the Medical Monitor or 
 
Central Review Services prior to randomization. 
pSS 5.1 
Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
1) Signed Written Informed Consent: pSS Sub-protocol 
a) Willing to participate in the study after completing all informed consent procedures and 
sign the ICF 
b) Willing and able to complete all study-specific procedures and visits 
2) Age and Reproductive Status: pSS Sub-protocol 
a) Not Applicable per Revised Protocol 02 - Male and female patients, aged 18 years (or 
age of majority) to 65 years, inclusive 
b) Not Applicable per Revised Protocol 02 - WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivDOHQW XQLWV RI ȕ-HCG) within 
24 hours prior to the start of study treatment. 
c) Not Applicable per Revised Protocol 02 - Women must not be breastfeeding. 
d) Not Applicable per Revised Protocol 02 - WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) 
branebrutinib or PBO, 30 days before screening and 33 days posttreatment completion or 
longer based on country-specific label for other background therapy. 
e) Not Applicable per Revised Protocol 02 - Male subjects who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception and fetal 
protection (APPENDIX 4) for the duration of treatment with study treatment(s) 
(branebrutinib or PBO) plus 33 days after the final dose of study treatment, or longer based 
on country-specific label for other background therapy. In addition, male subjects must be 
willing to refrain from sperm donation during this time. 
f) Not Applicable per Revised Protocol 02 - WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements, and still must undergo 
pregnancy testing as described in this section. 
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention, the implications of an unexpected pregnancy and the 
potential of fetal toxicity occurring due to transmission of study drug, present in seminal fluid, to 
a developing fetus, even if the participant has undergone a successful vasectomy or if the partner 
is pregnant. 
x The investigator shall evaluate the effectiveness of the contraceptive method in relationship 
to the first dose of study intervention. 
x Local laws and regulations may require the use of alternative and/or additional 
contraception methods. 
g) Not Applicable per Revised Protocol 03 - Female Participants 
h) Not Applicable per Revised Protocol 03 - Male Participants 
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i)  Female Subjects 
i.) Females, ages 18 years or local age of majority to 75 years, inclusive 
ii.) Women who are not of childbearing potential are exempt from contraceptive 
requirements. Women subjects must have documented proof that they are not of 
childbearing potential. 
iii.) WOCBP must have a negative highly sensitive pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study 
treatment. 
1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
iv.) Additional requirements for pregnancy testing during and after study intervention are 
located in Section pSS 1.3, SoA 
v.) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy 
vi.) WOCBP must agree to follow instructions for method(s) of contraception defined in 
APPENDIX 4 and as described below and included in the ICF 
vii.) WOCBP are permitted to use hormonal contraception methods (as described in 
APPENDIX 4) 
viii.) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
1) Is not a WOCBP 
OR 
2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
in APPENDIX 4 during the intervention period, for at least 30 days before 
screening and at least 33 days posttreatment completion or longer based on 
country-specific label for other background therapy and agrees not to donate eggs 
(ova, oocytes) for the purpose of reproduction for the same time period 
j) Male Subjects 
i.) Males, ages 18 years or local age of majority to 75 years, inclusive. 
ii.) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in APPENDIX 4 and as described below. 
iii.) Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP even if the participant has undergone a successful 
vasectomy or if the partner is pregnant. 
iv.) Male subjects will be required to always use a latex or other synthetic condom during 
any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the subjects have 
undergone a successful vasectomy or if their partner is already pregnant or 
breastfeeding. Males should continue to use a condom during the intervention period 
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and for at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
v.) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 
33 days after the last dose of study intervention in the male participant or longer 
based on country-specific label for other background therapy. 
vi.) Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, 
oral) even if the subjects have undergone a successful vasectomy, during the 
intervention period and for at least 33 days after the last dose of study intervention or 
longer based on country-specific label for other background therapy. 
vii.) Male subjects must refrain from donating sperm during the intervention period and for 
at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
viii.) Breastfeeding partners should be advised to consult their healthcare providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms. 
3) Type of Subject and Target Disease Characteristics: pSS Sub-protocol 
a) Diagnosed with pSS  7 years before screening 
b) Subjects diagnosed or classified as having pSS (primary Sjögren’s syndrome is defined as 
Sjögren’s syndrome in the absence of another immune-mediated disease or rheumatologic 
condition) based on the 2016 ACR-EULAR Classification Criteria for pSS, with disease 
duration from time since diagnosis of at least 16 weeks prior to screening with moderate to 
severe activity per ESSDAI 
c) (66'$, VFRUH RI  6, including disease activity (any score > 0) in at least one of the 
following domains: glandular, articular, hematological, biological, lymphadenopathy 
d) Positive anti-Ro/SSA plus at least one of the following at screening, as determined by 
central laboratory: 
o low C3 
o low C4 
o positive for RF 
o positive cryoglobulin test (must be performed at local laboratory) 
o IgG > 16 g/L 
e) Not Applicable per Revised Protocol 03 - A stimulated salivary flow of 
> 0.05 mL/minute at screening and randomization, or unstimulated whole saliva secretion 
> 0.01 mL/minute 
f) A stimulated salivary flow rate > 0.05 mL/minute or unstimulated saliva flow rate 
> 0.01 mL/minute at screening and randomization. 
4) Medications for Target Disease: pSS Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Requirements for subjects who are receiving 
chronic therapy with oral NSAIDs (including marketed cyclooxygenase-2 inhibitors) are 
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as follows; exceptions or changes may be possible with approval by the 
 Medical 
Monitor: 
o The oral NSAID dose must be stable for 14 days before the screening visit and must 
remain stable until randomization and throughout the study. 
o No more than 1 oral NSAID may be used (at a stable dose) during the study and 
may be combined with topical NSAIDs. 
o Use of 1 or more topical NSAID is permitted but must follow a stable regimen 
throughout the study. 
o Oral NSAIDs may not be taken on days of study visits. 
b) Not Applicable per Revised Protocol 03 - 6WDQGDUGRIFDUHLVUHTXLUHGIRU 12 weeks 
before the screening visit and must be at a stable GRVHIRU 8 weeks before the screening 
visit and remain stable until randomization and throughout study participation. Details for 
specific medications are as follows: 
o Antimalarials: -HCQ monotherapy is permitted. Also see exclusion criteria below 
regarding HCQ dose limitation and exclusionary screening HCQ levels. 
o Patients on HCQ must have an ophthalmology assessment within 6 months prior to 
randomization, confirming no findings of HCQ induced retinal toxicity. 
c) Not Applicable per Revised Protocol 03 - CS: 
o 2UDO &6 XVH LV SHUPLWWHG EXW WKH GRVH PXVW EH  10 mg/day prednisone or 
HTXLYDOHQW DQG VWDEOH IRU  28 days before randomization and throughout study 
participation. 
o Topical and inhaled CS use is permitted but must follow a stable regimen 
throughout the study and cannot be used on an as-needed basis. Inhaled CS for 
non-pSS conditions will not count against the maximum CS dose. 
o IM, IA, intrabursal, IV, and modified-release CS are prohibited within 4 weeks 
before randomization or during the study. 
d) Sialogogues, eg cevimeline, pilocarpine, must be held for 48 hours before the screening 
visit saliva flow testing 
e) On study visit days, dried fruit slices, maltose lozenges, xylitol gum or candy, regular, 
sugarless or sugar-free gum or hard candies, or artificial saliva sprays or drops must be 
stopped 2 hours before stimulated/unstimulated salivary flow measurements are taken 
f) Requirements for subjects who are receiving chronic therapy with oral NSAIDs (including 
marketed cyclooxygenase-2 inhibitors) are as follows; exceptions or changes may be 
possible with approval by the 
 Medical Monitor: 
o The oral NSAID dose must be stable for 14 days before the screening visit and must 
remain stable until randomization and throughout the study. 
o No more than 1 oral NSAID may be used (at a stable dose) during the study and 
may be combined with topical NSAIDs. 
o Use of 1 or more topical NSAID is permitted but must follow a stable regimen 
throughout the study. 
o Oral NSAIDs may not be taken on days of study visits until after all study 
assessments have been completed. 
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g) SOC ZLWK+&4LVDOORZHGSURYLGHGWUHDWPHQWVWDUWHG 12 weeks before the screening visit 
DQGPXVWEHDWDVWDEOHGRVHIRU 8 weeks before the screening visit and remain stable until 
randomization and throughout study participation. Details are as follows: 
o Antimalarials: HCQ monotherapy is permitted. Also see exclusion criteria below 
regarding HCQ dose limitation and exclusionary screening HCQ levels. 
o Subjects on HCQ must have an ophthalmology assessment within 6 months prior 
to randomization, confirming no findings of HCQ induced retinal toxicity. 
h) CS: 
o 2UDO &6 XVH LV SHUPLWWHG EXW WKH GRVH PXVW EH  10 mg/day prednisone or 
HTXLYDOHQW DQG VWDEOH IRU  28 days before randomization and throughout study 
participation. 
o Topical and inhaled CS use is permitted but must follow a stable regimen 
throughout the study and cannot be used on an as-needed basis. Inhaled CS for 
non-pSS conditions will not count against the maximum CS dose. 
o IM, IA, intrabursal, IV, and modified-release CS are prohibited within 4 weeks 
before randomization. 
5) Other Inclusion Criteria: pSS Sub-protocol 
a) Subject re-enrollment (rescreening): This study permits the re-enrollment of a subject that 
has discontinued the study as a pretreatment (screening) failure (ie, subject has not been 
randomized/has not been treated). If re-enrolled, the subject must be re-consented. 
pSS 5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in the 
sub-protocol to which the subject is randomized in the study: 
1) General Medical Conditions and History: pSS Sub-protocol 
a) Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, psychiatric) or 
local active infection/infectious illness that, in the investigator’s judgment, will 
substantially increase the risk to the subject if he or she participates in the study 
b) Any major surgery within the last 30 days before the first dose of study treatment, or any 
surgery planned during the course of the study 
c) Cancer or history of cancer or lymphoproliferative disease (other than adequately treated 
cutaneous basal cell or squamous cell carcinoma with no evidence of recurrence within the 
previous 5 years), including pre-lymphoma (pseudolymphoma of the orbit and small 
intestine, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, and 
lymphoid interstitial pneumonitis) 
d) Class III or IV congestive heart failure as defined by the NYHA or any recent onset of 
heart failure resulting in NYHA Class III/IV symptoms 
e) Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or any 
history of significant cerebrovascular disease within 24 weeks before screening 
f) Current or recent (within 3 months before randomization) gastrointestinal disease, 
including gastrointestinal surgery, that could impact the absorption of study treatment 
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g) Inability to tolerate oral medication 
h) Inability to tolerate venipuncture and/or inadequate venous access 
i) Recent (within 6 months before randomization) drug or alcohol abuse as defined by the 
Diagnostic Criteria for Drug and Alcohol Abuse in the Diagnostic and Statistical Manual 5 
(DSM 5) 
j) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator 
k) Subjects with a diagnosis of antiphospholipid antibody syndrome 
l) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks before 
randomization 
m) Not Applicable per Revised Protocol 03 - Subjects with non-pSS concomitant illness (eg, 
asthma) that, in the opinion of the investigator, is likely to require additional systemic 
glucocorticosteroid therapy during the study 
n) Any prior history of atrial fibrillation or flutter. 
o) Subjects with non-pSS concomitant illness (eg, asthma) that, in the opinion of the 
investigator, is likely to require additional systemic CS therapy during the study. 
2) Findings Related to Possible Infection: pSS Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Any of the following TB criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment 
o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) 
during screening as judged by the investigator 
o Any imaging of the chest (eg, chest x-ray, chest CT scan) obtained during the 
screening period, or anytime within 6 months prior to screening with 
documentation, showing evidence of current active or old pulmonary TB 
o LTBI defined as positive IGRA, by QuantiFERON-TB Gold testing at screening, 
in the absence of clinical manifestations Note: Subject may be eligible if (i) there 
are no current signs or symptoms of active TB and (ii) subject has received adequate 
documented treatment for LTBI within 5 years of screening. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB 
must be retested for confirmation. If the second test is again indeterminate the 
subject will be excluded from the study. If the retest is positive, the subject should 
be treated as having LTBI. If the retest is negative, subject may be eligible provided 
no other exclusion criteria for TB are met. 
b) Hepatitis C, hepatitis B, or HIV infection as demonstrated by a positive blood screen for 
anti-HCV confirmed by positive reflex HCV RNA test, HBsAg, HBcAb, or HIV-1 and -2 
antibody. Subjects who have been vaccinated for hepatitis B (HBsAb-positive) are not 
excluded. 
Note: Subjects who are newly found to be HIV-positive should be directed to appropriate 
follow-up care. 
c) History of congenital or acquired immunodeficiency. 
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d) Known active infection, or any major episode of infection requiring hospitalization or 
treatment with parenteral (IM or IV) antimicrobial agents (eg, antibiotics, antiviral, 
antifungal, or antiparasitic agents) within 30 days of randomization, or completion of oral 
antimicrobial agents within 2 weeks of randomization. 
e) Previous history of recurrent herpes zoster (more than 1 episode), disseminated herpes 
simplex, or influenza infection within 12 weeks before randomization or a history of 
disseminated/complicated herpes zoster infection (multidermatomal involvement, 
ophthalmic zoster, CNS involvement, or postherpetic neuralgia). 
f) Chronic infection within 4 weeks of randomization (eg, pneumocystis, CMV, invasive 
bacterial or fungal infections, or atypical mycobacteria). 
g) Any of the following TB criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment 
o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) 
during screening as judged by the investigator 
o Any imaging of the chest (eg, chest x-ray, chest CT scan) obtained during the 
screening period, or anytime within 6 months prior to screening, with 
documentation showing evidence of current active or old pulmonary TB 
o LTBI defined as positive IGRA, by QuantiFERON-TB Gold testing at screening, 
in the absence of clinical manifestations Note: Subject may be eligible if (i) there 
are no current signs or symptoms of active TB and (ii) subject has received adequate 
documented treatment for LTBI within 5 years of screening; this treatment must 
have been completed as defined by local guidance and documented in the subject 
study file. Incomplete or ongoing treatment is unacceptable. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB 
must be retested for confirmation. If the second test is again indeterminate, the 
subject will be excluded from the study, unless there is documentation of a local 
negative TB Spot test result. If the retest is positive, the subject should be treated 
as having LTBI. If the retest is negative, the subject may be eligible provided no 
other exclusion criteria for TB are met. 
h) Subjects hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well as any subjects 
with any sequelae of prior COVID-19 infection at screening, regardless of time since 
infection. 
3) Allergies and Adverse Drug Reaction: pSS Sub-protocol 
a) History of allergy to BTK inhibitors or related compounds 
b) History of any serious condition induced by drug allergy (such as anaphylaxis or 
hepatotoxicity) 
4) Target Disease Exclusions/Exceptions: pSS Sub-protocol 
a) Subjects who have a systemic immune-mediated disease other than pSS, such as RA, SLE, 
mixed connective tissue disease, or systemic sclerosis, that can better explain the majority 
of the symptoms (ie, secondary SS) 
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b) Subjects who have another immune-mediated disease or inflammatory condition that could 
interfere with assessment of response of pSS to therapy (eg, IgG4-related disease, systemic 
sclerosis, inflammatory bowel disease, gout) 
c) Subjects with any other medical condition associated with sicca syndrome (eg, history of 
head and neck radiation treatment, diabetes mellitus, sarcoidosis, chronic graft-versus-host 
disease), subjects with sicca symptoms secondary to ongoing medication use based on the 
investigator’s assessment 
d) Active fibromyalgia with pain symptoms or signs that would interfere with joint 
assessment or requiring adjustment in medication within the 3 months before screening to 
control symptoms; subjects with fibromyalgia that is well controlled on stable treatment 
may otherwise be considered 
e) Severe complications of pSS at the time of screening, including, but not restricted to, the 
following: 
o Vasculitis with renal, digestive, cardiac, pulmonary or CNS involvement 
characterized as severe (note: cutaneous vasculitis is allowed) 
o Active CNS or peripheral nervous system (PNS) involvement requiring high-dose 
steroids (> 10 mg/day) 
o Renal disease including but not limited to the following: 
– Interstitial nephritis 
– Glomerulonephritis 
– Nephrotic syndrome with proteinuria > 3 g/day or UPCR > 339 mg/mmol 
DQGRUVHUXPFUHDWLQLQH 2.0 mg/dL; subjects with interstitial nephritis with 
proteinuria < 1.5 g/day or UPCR < 169.5 mg/mmol and serum creatinine 
< 1.5 mg/dL may be included 
o Severe pulmonary disease based on the investigator’s assessment 
o Active myositis requiring more than the maximum dose of CS 
o Any type of lymphoma 
5) Prior/Concomitant Therapy: pSS Sub-protocol 
a) Inability to comply with restrictions and prohibited treatments as listed in Section pSS 6.7 
Concomitant Therapy; inability to comply with discontinuation requirements 
(Section pSS 7.1) 
b) Not Applicable per Revised Protocol 03 - Previous exposure to BTK inhibitors such as 
ibrutinib, acalabrutinib, or experimental drugs such as tirabrutinib, vecabrutinib, 
zanibrutinib, ARQ-531, GDC-0853, or any others 
c) Exposure to JAK inhibitors such as tofacitinib, baricitinib, filgotinib, or upadacitinib within 
8 weeks before randomization or during the study 
d) Abatacept therapy within 6 months before randomization or during the study 
e) Therapy with other biologics such as tocilizumab and anakinra within 8 weeks before 
randomization or during the study 
f) Other investigational agents must be discontinued at least 12 weeks or 5 half-lives before 
screening, whichever is longer 
g) Not Applicable per Revised Protocol 03 - Required discontinuation periods for 
immunomodulatory drugs (other than HCQ, which is permitted as monotherapy; see 
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exclusion criterion 5u for details of HCQ use), eg, cyclosporine, tacrolimus, etc or biologic 
drugs (including those specifically listed below) are provided in Section pSS 5.2. If a drug 
is not specifically listed, consult the 
 Medical Monitor for guidance. Usual 
discontinuation periods are 4 weeks or 5 half-lives whichever is longer. 
h) Belimumab therapy within 6 months before randomization or during the study 
i) Leflunomide therapy within 36 weeks before screening or during the study 
j) Cyclosporine or tacrolimus therapy within 8 weeks before randomization or during the 
study 
k) Therapy with azathioprine, sulfasalazine, or similar drugs within 8 weeks before 
randomization or during the study 
l) IVIG therapy within 8 weeks before randomization or during the study 
m) Diquafosol or rebamipide therapy within 4 weeks before randomization or during the study 
n) Sialogogues, eg cevimeline, pilocarpine, must be taken on a stable dose regimen for 
8 weeks prior to randomization and remain stable throughout the study, except as specified 
before certain visits when lacrimal and/or salivary gland testing will be performed. 
Sialogogues must be held for 48 hours before screening, Day 1, Week 12, Week 24 and 
Week 28 visits until after tests for tear production (Schirmer’s, ocular staining score, tear 
break-up time) and stimulated/unstimulated salivary flow measurements have been 
performed. If lacrimal gland function (LGF) testing is done on a day other than the rest of 
the study assessments sialogogues must be held for 12 hours before lacrimal testing is 
performed. 
o) Subjects who have a history of refractive eye surgeries (including but not limited to 
laser-assisted in situ keratomileusis, photorefractive keratectomy, and laser epithelial 
keratomileusis) 
p) Subjects who have a history of full-thickness corneal transplantation (penetrating 
keratoplasty); however, subjects who have had endothelial keratoplasty are not excluded. 
q) Subjects who have had cataract surgery within 6 months prior to randomization 
r) Subjects are not permitted to have new installation of lacrimal punctum plugs within 
4 weeks of randomization. Subjects with existing lacrimal punctum plugs are permitted to 
enroll, and have these plugs replaced as necessary during the study. 
s) For oral CS restrictions, see Section pSS 6.7.1. 
t) Other CS: IM, IV, IA, or oral modified-release CS treatment within 4 weeks before 
randomization or during the study 
u) Not Applicable per Revised Protocol 03 - Treatment with DMARDs (excluding HCQ) 
or immunomodulators within 4 weeks before randomization; MTX treatment within 
12 weeks before randomization or during the study. HCQ whole blood concentration 
>2 μg/mL (at screening only) is exclusionary. HCQ dose > 400 mg/day, new initiation, 
or dose increases during treatment are not permitted. 
v) Antimalarial treatment (HCQ is permitted, but must be stable; initiation or change in dose 
during treatment is not permitted. Quinacrine or chloroquine treatment is not permitted 
during the study or within 4 weeks before randomization. For HCQ, see above criterion for 
requirements. 
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w) Current or past approved or investigational biologic DMARD treatments (eg, IL-6 
inhibitors, IL-1 inhibitors, T cell modulators, and anti-CD20 agents [eg, rituximab]), other 
than abatacept treatment, within 12 months before randomization or during the study 
x) Anti-TNF therapy such as adalimumab, certolizumab, etanercept, golimumab, infliximab, 
or biosimilars within 3 months before randomization or during the study 
y) Not applicable per Revised Protocol 03 - Administration of a live vaccine within 90 days 
or an inactivated vaccine within 30 days before randomization; furthermore, live or 
inactivated vaccines should not be used during treatment or within the 14 days following 
the final dose of study treatment 
z) Treatment with tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, 
imipramine, nortriptyline, trimipramine) or quetiapine, within 4 weeks before 
randomization 
aa) Treatment with anticoagulant or antiplatelet therapies, including aspirin for 
cardioprotection, within 2 weeks prior to randomization or during the study 
bb) Previous exposure to BTK inhibitors such as ibrutinib, acalabrutinib, or experimental drugs 
such as tirabrutinib, vecabrutinib, zanubrutinib, ARQ-531, GDC-0853, or any others 
cc) Required discontinuation periods for immunomodulatory drugs (other than HCQ), eg, 
cyclosporine, tacrolimus, etc, or biologic drugs (including those specifically listed below) 
are detailed in pSS Table 6. If a drug is not specifically listed, consult the 
 Medical 
Monitor for guidance. Usual discontinuation periods are 4 weeks or 5 half-lives whichever 
is longer. 
dd) Treatment with DMARDs (excluding HCQ) or immunomodulators beyond required 
washout period before randomization; MTX treatment within 12 weeks before 
randomization or during the study. HCQ whole blood concentration >2 μg/mL (at 
screening only) is exclusionary. HCQ dose > 400 mg/day, new initiation, or dose 
increases during treatment are not permitted. 
ee) Administration of all live vaccines is prohibited within 90 days before randomization. 
Administration of inactivated vaccines and nonlive vaccines, including those for influenza 
and SARS-CoV-2, is prohibited within 30 days before randomization. See 
Section pSS Table 6 for corresponding on-treatment and posttreatment restrictions. 
6) Physical and Laboratory Test Findings: pSS Sub-protocol 
a) Clinically significant abnormalities on chest x-ray or ECG 
b) Clinically significant abnormalities in laboratory tests including the following: 
i. 
Serum ALT > 2× ULN, unless explicitly related to the indication based on the 
investigator’s judgment. 
ii. 
Serum AST > 2× ULN, unless explicitly related to indication based on the 
investigator’s judgment. 
iii. 
Serum total bilirubin > 1.5× ULN (does not apply to subjects with Gilbert’s 
syndrome) 
iv. 
Hemoglobin < 8 g/dL (< 80 g/L) 
v. 
Proteinuria > 3.0 g/day (> 3,000 mg/day) or equivalent level of proteinuria as 
assessed by UPCR (3 mg/mg or 339 mg/mmol) 
vi. 
eGFR < 50 mL/min/1.73 m2 as calculated by the central laboratory 
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vii. 
Serum creatinine > 2.0 mg/dL (> ȝPRO/ 
viii.
Absolute WBC count < 2.5× 103ȝ/ 2.5× 109/L) 
ix. 
Absolute neutrophil count < ȝ/ 1.0× 109/L) 
x. 
Platelet count < 100× 103ȝ/ 100× 109/L) 
c) Any other significant laboratory or procedure abnormalities that, in the opinion of the 
investigator, might pose unacceptable risk to the subject during the study. 
d) BP > Grade 1 hypertension (> 159 mmHg systolic and > 99 mmHg diastolic) according to 
the 2018 ESC/ESH Guidelines for the management of arterial hypertension. 
e) The following exclusionary ECG observations: 
i. 
QTcF: > 480 msec 
ii. 
QRS: > 120 msec 
iii.
Complete heart block 
iv. 
Left bundle branch block 
v. 
Mobitz II second-degree atrioventricular block 
vi. 
Atrial fibrillation or flutter 
7) Other Exclusion Criteria: pSS Sub-protocol 
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances and subject to local law a person who has been imprisoned may be included 
or permitted to continue as a subject. Strict conditions apply and BMS approval is 
required.) 
b) Subjects who are employed by the Sponsor, clinical research organizations, or study site. 
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness. 
d) Inability to comply with the study protocol. 
e) Inability to comply with restrictions as listed in Section pSS 5.3. 
pSS 5.3 
Lifestyle Restrictions 
Study restrictions for contraception use by WOCBP and male subjects who are partners of 
WOCBP (APPENDIX 4) are required for this study. 
 
Meals and Dietary Restrictions 
With the exception of the 8-hour fasting requirement prior to blood sample collection for lipid 
panel and fasting glucose blood testing, no meal or dietary restrictions are required for this study. 
However, subjects are advised to consume in moderation (avoiding more than a single serving a 
day) cruciferous vegetables, such as cabbage, brussels sprouts, watercress, etc, as well as grapefruit 
and Seville oranges. Quinine (tonic water), St. John’s wort and herbal medications are not allowed. 
 
Caffeine, Alcohol, Tobacco, and Cannabinoids 
With the exception of cannabinoids, which are not allowed, and prohibited alcohol abuse as 
defined by the Diagnostic Criteria for Drug and Alcohol Abuse in the DSM 5 within six months 
prior to randomization, and the restrictions described in pSS 5.3.1, there are no restrictions on 
caffeine, alcohol, or tobacco use for this study. However, subjects who use tobacco or alcohol 
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should be counseled for potential contraindications with nonstudy treatments as appropriate, and 
continued study participation should be based on investigator judgment. 
 
Activity 
With the exception of the restrictions surrounding the use of contraceptives during sexual activity 
mentioned above and included in Section pSS 1.3 Schedule of Activities, no activity restrictions 
are required for this study. 
pSS 5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but who are 
not subsequently randomized or entered in the study or included in the analysis population. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects, to meet the CONSORT publishing requirements, as applicable, and to respond to 
queries from regulatory authorities. Minimal information includes date of consent, demography, 
screen failure details, eligibility criteria, and any SAEs. Additional screening data from screen 
failure subjects, such as clinical data for disease assessment, laboratory tests, and other clinically 
relevant data, may be required. 
 
Retesting During Screening Period 
This pSS sub-protocol permits the rescreening of a subject who has been previously failed 
screening. If rescreened, the subject must be re-consented and will be assigned a new identification 
number, and a full screening visit must be performed again. A subject can only be rescreened 
1 time (ie, if the subject fails 1 rescreening attempt, no additional rescreening is allowed). 
Laboratory parameters and/or other assessments that initially do not meet eligibility requirements 
within the screening period may be repeated once in an effort to find all possible well-qualified 
subjects. Consultation with the Medical Monitor may be needed to identify whether repeat testing 
of any particular parameter is clinically relevant. 
The most current result prior to randomization is the value by which study inclusion will be
assessed, as it represents the subject’s most current clinical state. 
PSS 6 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), PBO, or 
medical device intended to be administered to a study subject according to the study randomization 
or treatment allocation. 
Study treatment includes both IP/IMP and non-IP/Non-IMP and is shown in pSS Table 4. 
An IP, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or PBO being tested or used as a reference in a clinical 
study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) differently than the authorized form, or used for an unauthorized 
indication, or when used to gain further information about the authorized form. 
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as noninvestigational 
products. 
pSS Table 4 
Study Treatments for IM014029 
Product 
Description/ 
Class and 
Dosage Form 
Potency 
IP/ 
Non-IP 
Blinded or 
Open-
Label 
Packaging/ 
Appearance 
Storage 
Conditions 
(per label) 
Branebrutinib 
oral capsule 
3 mg dose × 
3 capsules (9 mg 
total dose)a 
IP 
Blinded 
HDPE bottles 
(33 capsules/bottle) with 
child-resistant cap and 
heat-induction seal 
(tamper-evidence and 
moisture barrier); size #0 
hard gelatin capsules 
Store 
refrigerated at 
2° to 8°C (36° 
to 46°F) in 
original 
packaging; 
protected from 
moisture 
PBO matching 
branebrutinib 
oral capsule 
NA 
IP 
Blinded 
HDPE bottles 
(33 capsules/bottle) with 
child-resistant cap and 
heat-induction seal 
(tamper-evidence and 
moisture barrier); size #0 
hard gelatin capsules 
Store 
refrigerated at 
2° to 8°C (36° 
to 46°F) in 
original 
packaging; 
protected from 
moisture 
HDPE = high-density polyethylene; IP = investigational product; NA = not applicable; PBO = placebo. 
a Dosages of 0.5 mg are also available but are not planned for use in this protocol. 
 
pSS 6.1 
Treatments Administered 
The investigator must ensure that the IP will be used only in accordance with the protocol. The 
selection and timing of dose for each subject is shown in pSS Table 5. Study treatment will be 
supplied in bottles (branebrutinib and PBO). If a subject forgets a dose, but remembers within 
12 hours of the expected dose, the dose should be taken. Any dose > 12 hours should be missed, 
and the next expected dose should be taken at the usual time. No dose reductions or modifications 
are allowed. 
pSS Table 5 
Selection and Timing of Dose 
Study Treatment 
Unit Dose Strength 
Dosage Formulation 
Frequency of Administration 
Route of 
Administration 
Branebrutinib 9 mg 
3 mg 
3 active capsules; QD 
Oral 
PBO 
0 mg 
3 PBO capsules; QD 
Oral 
N/A = not applicable; PBO = placebo; QD = once daily 
Note: At all study visits, the study treatment should not be taken at home but should be taken to the site by the subject; 
at the site, the study treatment should be taken only when instructed by the site study staff according to the schedule 
listed below. These requirements also apply to concomitant medications at Day 1 and Week 4 only; at these visits, 
concomitant medications will be administered together with the study treatment. 
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When multiple assessments are conducted at a single visit, the following is the order in which they 
should be performed: 
x Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
x Safety assessments (eg, vitals, AEs) 
x Investigator-administered Assessments (eg, PGA, joint count, etc) 
x Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
x Treatment dosing 
Doses of branebrutinib at 9 mg (3x3 mg capsules) or matching placebo are to be administered 
orally q24h (one time/day) with water and may be taken with or without food. The drug should be 
taken every morning at approximately the same time. 
On Day 1 and at Weeks 4, 8, 16, and 24, study drug will be administered in the morning at the 
study site after blood samples have been collected and questionnaires have been completed. In 
addition, on Day 1 and at Week 4, branebrutinib will be administered together with concomitant 
medications to allow predose sampling for concomitant medication. Branebrutinib and 
concomitant medications are to be taken together with water. 
pSS 6.2 
Method of Treatment Assignment 
Subjects will be centrally randomized according to a computer-generated block randomization 
scheme using IRT to the pSS sub-protocol depending on disease type determined at screening. 
Subjects in this sub-protocol will be randomized in a 2:1 ratio to receive double-blind 
branebrutinib 9 mg or PBO QD from Week 0 to Week 24. 
At the time of the screening visit, after written informed consent is obtained and before any 
study-related procedures are performed, the investigative site will access the enrollment option of 
the IRT system for assignment of a subject number. This number is assigned sequentially by the 
system and will be unique across all sites. If a potential subject is rescreened, a new identification 
number will be used. 
Randomized schedules will be generated by the IRT vendor. 
Randomization will be stratified by HCQ use (yes/no). 
Before the study is initiated, each investigator will receive log-in information and directions on 
how to access the IRT. Study treatment will be dispensed at the study visits as listed in the SoA 
(Section pSS 1.3). 
pSS 6.3 
Blinding 
Blinded treatment assignments will be managed using IRT. All capsules (branebrutinib 3 mg and 
PBO) are identical in appearance. Capsules will be supplied in tamper-evident HDPE bottles with 
each daily dose made up of either active or PBO capsules (as presented in pSS Table 4). 
Investigative site staff, Sponsor and designee personnel, and subjects and their families will remain 
blinded to treatment assignments. 
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Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the IP 
is critical to the subject’s management, the blind for that subject may be broken by the investigator. 
The subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded. 
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the IP, the 
problem may be properly managed by assuming that the subject is receiving active product. It is 
highly desirable that the decision to unblind treatment assignment be discussed with the Medical 
Monitor, but the investigator always has ultimate authority for the decision to unblind. The PI 
should only call in for emergency unblinding AFTER the decision to discontinue the subject has 
been made. 
In case of an emergency, the investigator has unrestricted access to randomization information via 
IRT and is capable of breaking the blind through the IRT system without prior approval from the 
Sponsor. After the unblinding, the investigator shall notify the Medical Monitor and/or study 
director. For information on how to unblind in an emergency, consult the IRT manual. Subject and 
unblinded treatment information and the reason for the blind being broken must be recorded on 
the appropriate study status page of the eCRF. After unblinding via IRT, the investigator shall 
notify the Medical Monitor. 
Any request to unblind a subject for nonemergency purposes should be discussed with the Medical 
Monitor. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. 
Designated staff of BMS Company may be unblinded (obtain the randomization codes) prior to 
database lock to facilitate the bioanalytical analysis of PK samples and immunogenicity. A 
bioanalytical scientist in the Bioanalytical Sciences department of BMS Company (or a designee 
in the external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. 
pSS 6.4 
Dosage Modification 
There is no provision for dose modification of study treatment. If a subject interrupts or 
discontinues temporarily treatment due to an AE, study treatment can be restarted in consultation 
with the Medical Monitor. 
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pSS 6.5 
Preparation/Handling/Storage/Accountability 
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that investigational product is only dispensed to study subjects. The IP 
must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and BMS or designee should be contacted immediately. 
Branebrutinib and PBO should be stored per labeled conditions in tamper-evident HDPE bottles. 
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
Further guidance and information for final disposition of unused study treatment are provided in 
APPENDIX 2. 
 
Retained Samples for Bioavailability/Bioequivalence 
At the time of receipt of the IP by the investigator or designees, BMS will specify the appropriate 
number of containers or units to select for retention, the conditions of sample storage, required 
duration of sample retention, and provisions for returning or disposing of the investigational 
product. When samples are selected, containers or units should be placed in packaging with a 
tamper-evident seal provided by BMS. Package labeling should clearly identify the contents as 
bioavailability/bioequivalence samples and state that the investigational product should be stored 
in the restricted area with limited access. 
pSS 6.6 
Treatment Compliance 
Study treatment compliance will be periodically monitored using standard drug accountability 
procedures (comparing the number of capsules returned to number dispensed, considering the 
expected regimen and any reported missed doses). Drug accountability will be reviewed by the 
site study staff at each visit to confirm treatment compliance. Site staff will discuss discrepancies 
with the subject at each on-treatment study visit and remind the subject of the importance of 
compliance with the assigned regimen. See Section pSS 8.3 for information related to treatment 
overdose. 
pSS 6.7 
Concomitant Therapy 
 
Prohibited and/or Restricted Treatments 
Table 1 in the IM014029 Master Protocol lists exclusions and restrictions for all concomitant 
medications, regardless of indication. pSS Table 6 presents prohibited and/or restricted 
medications taken by subjects with pSS prior to or during study treatment administration with 
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branebrutinib. All prior concomitant medications taken for pSS since diagnosis must be recorded 
on the eCRF. All prior and/or concomitant medications taken for any indication within 4 weeks 
prior to study drug administration must be recorded on the eCRF. The prior use of medications 
after a sufficient washout period prior to study randomization is allowed for some medications, as 
indicated in the table and must be recorded in the eCRF. Details of prohibited (excluded) and/or 
restricted medications are provided in Section pSS 5.2. 
pSS Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
BTK inhibitors 
Marketed drugs, eg, 
ibrutinib, acalabrutinib; 
Experimental drugs, eg, 
tirabrutinib, vecabrutinib, 
zanubrutinib, ARQ-531, 
GDC-0853, and any others 
Prohibited lifetime use 
Not applicable 
JAK inhibitors 
Tofacitinib, baricitinib, 
filgotinib, and upadacitinib 
Prohibited during the study 
8 weeks 
Oral CS 
prednisone 
Stable dose of ч 10 mg/day for 
 28 days before 
randomization; dose must 
remain stable throughout study 
 If not continuing as 
background SOC must 
discontinue 4 weeks 
before randomization. 
Other CS 
IM, IA, intrabursal, IV, 
and oral modified-release 
CS 
Prohibited during the study 
4 weeks 
 
Topical CS 
Stable regimen throughout 
study; may not be used on an 
as-needed basis 
Not applicable 
 
Inhaled CS 
Must follow stable regimen 
throughout the study; cannot 
be used on as-needed basis; 
allowed only for 
nonrheumatologic indications 
Not applicable 
Antimalarial drugs 
Chloroquine and 
quinacrine 
Prohibited during the study 
8 weeks 
 
Hydroxychloroquine 
> 400 mg/day; no initiation or 
dose change during the study; 
whole blood concentration at 
VFUHHQLQJPXVWEH 2 μg/mL 
If not continuing as SOC, 
must discontinue 8 weeks 
before randomization 
Anticoagulant or 
Antiplatelet 
therapies  
Anticoagulant or 
antiplatelet therapies, 
including aspirin for 
cardioprotection  
Treatment with anticoagulant 
or antiplatelet therapies, 
including aspirin for 
cardioprotection, within 2 
weeks prior to randomization 
or during the study 
2 weeks 
Tricyclic 
Antidepressants  
Amitriptyline, 
desipramine, doxepin, 
imipramine, nortriptyline, 
trimipramine) or 
quetiapine 
Treatment with tricyclic 
antidepressants (within 
4 weeks before randomization) 
4 weeks 
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pSS Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
Anti-TNF therapy 
Adalimumab, 
certolizumab, etanercept, 
golimumab, infliximab, 
and TNF biosimilars 
Prohibited during the study 
3 months 
Biologics 
Rituximab 
Prohibited during the study 
12 months 
 
Belimumab 
Prohibited during the study 
6 months 
 
Abatacept 
Prohibited during the study 
6 months 
Other Biologics 
 tocilizumab, anakinra 
Prohibited during the study 
8 weeks 
 
IVIG 
Prohibited during the study 
8 weeks 
DMARD 
MTX 
Prohibited during the study 
12 weeks 
Other DMARDs 
Leflunomide 
Prohibited during the study 
36 weeks before 
screening 
 
Cyclosporine and 
tacrolimus 
Prohibited during the study; 
cyclosporin eye drops are 
permitted 
8 weeks 
 
Cyclophosphamide 
Prohibited during the study 
24 weeks 
 
Azathioprine, 
sulfasalazine, and similar 
Prohibited during the study 
8 weeks 
Sialogogues 
Cevimeline, pilocarpine 
Must be taken on a stable dose 
regimen for 8 weeks prior to 
randomization and remain 
stable throughout the study, 
except as specified here and in 
Section pSS 5.2 
Must be held for 
48 hours before screening, 
Day 1, Week 12, Week 24 
and Week 28 visits until 
after tests for tear 
production and 
stimulated/unstimulated 
salivary flow rate 
measurements have been 
performed. If LGF testing 
is done on a day separate 
from other study 
assessments sialogogues 
must be held for 12 hours 
before lacrimal testing is 
performed 
Saliva stimulants 
Dried fruit slices, maltose 
lozenges, xylitol gum or 
candy, regular, sugarless 
or sugar-free gum or hard 
candies, artificial saliva 
sprays or drops 
 
On study visit days must 
be stopped 2 hours before 
stimulated/unstimulated 
salivary flow rate 
measurements are taken 
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pSS Table 6 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
Antihistamines 
Diphenhydramine, 
hydroxyzine, loratadine 
and similar 
Must be taken on a stable dose 
regimen for 4 weeks prior to 
randomization (if a required 
concomitant medication for 
co-morbid condition) and 
remain stable throughout the 
study except as specified in 
pSS 8.1.1.2 
Must be held for 12 hours 
before screening, Day 1, 
Week 12,  
Week 24 and Week 28 
visits until after tests for 
unstimulated/stimulated 
saliva flow measurements 
have been performed. 
Autologous serum 
eye drops 
Formulated autologous 
serum eye drops 
Prohibited throughout the 
study 
Discontinue at screening 
visit 
NSAIDs (see 
inclusion criterion 4a 
in Section pSS 5.1) 
Ibuprofen, etc 
Only one oral NSAID is 
allowed; may be combined 
ZLWK 1 topical NSAID but 
regimen must be stable 
Not allowed on days of 
study visits until study 
assessments performed. 
Non-narcotic 
analgesics 
Acetaminophen 
Brief course for up to 7 days 
allowed 
Not applicable 
Narcotic analgesics 
Oxycodone and 
hydrocodone  
Prohibited during the study 
Not applicable 
Immunization 
against agents other 
than influenza or 
SARS-CoV-2  
All live vaccines 
 
Nonlive vaccines 
unassociated with 
influenza or SARS-CoV-2 
Prohibited during the study 
90 days before and 
28 days after EOT 
 
30 days before and 
14 days after EOT  
Immunization for 
influenza or 
SARS-CoV-2 
All live vaccines 
 
Nonlive vaccines for 
influenza or SARS-CoV-2 
Prohibited during the study 
 
Not allowed during the 
screening period within 
30 days prior to randomization 
 
During the Treatment and 
Follow-up Periods, vaccine 
doses must be given at least 
5 days before a study visit; 
doses may be given on a study 
day visit once all protocol-
specific procedures are 
complete. 
90 days before and 
28 days after EOT 
 
Inactivated and protein-
based vaccines 
Prohibited during the study 
30 days before 
randomization and 
14 days after EOT 
Other treatments 
Diquafosol, rebamipide 
Prohibited during the study 
4 weeks 
BLQ = below limit of quantitation; BTK = Bruton’s tyrosine kinase; CS = corticosteroid; 
DMARDs = disease-modifying antirheumatic drugs; EOT = end of treatment; IA = intra-articular; 
IM = intramuscular; IV = intravenous; IVIG = intravenous immunoglobulin; JAK = Janus kinase; LGF = lacrimal 
gland function; MTX = methotrexate; NSAIDs = nonsteroidal anti-inflammatory drugs; TNF = tumor necrosis 
factor 
 
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Chronic medications, such as statins and antidepressants, that could be sensitive to modulation of 
CYP2C8/P-gp (and other potentially relevant drug metabolizing enzymes that may lead to 
drug-drug interaction with branebrutinib) and with sufficient representation in the study population 
(eg, > 10% per sub-protocol), are allowed in the study for accompanying conditions. For optional 
measurement of the concentrations of these medications, PK samples will be collected predose 
and 2 hours postdose at Week 0 (Day 1) and Week 4 (Day 29) for potential post-hoc analysis.
These analyses will be based on the totality of information about the frequency of use of the drugs, 
clinical manifestations of possible interactions, availability of validated bioanalytical assays, and 
therapeutic index. When performed, the results of these analyses will be reported separately, along 
with the reasons for the selection. Concentrations of HCQ will also be measured and reported. The 
dosing of allowed chronic medications must be maintained at the same level throughout the study 
unless safety concerns arise. Any changes of dose will be recorded, and additional PK sampling 
may be performed as a result. 
Tobacco use will be allowed in the study. Branebrutinib concentrations will be compared between 
smoking and nonsmoking subgroups to evaluate the effect of smoking on glutathione-s-transferase 
mediated metabolism of branebrutinib. 
No new concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during the study unless they are prescribed for treatment of specific clinical events. Any 
concomitant therapies must be recorded on the eCRF. 
For subjects on any background therapy, the investigator must refer to the label for any potential 
interaction with concomitant medications. 
 
Oral Corticosteroid Rescue 
A maximum of 1 burst of oral CS rescue therapy is permitted in response to increased pSS disease 
activity up to Week 12 during the treatment period at the investigator’s discretion. 
x Rescue therapy must not exceed 20 mg/day prednisone or equivalent and must return within 
7 days to the previous CS dose used before initiation of rescue therapy. 
x Rescue therapy other than prednisone or equivalent is not permitted. 
If a subject requires CS rescue therapy after the first 12 weeks, the subject will be considered a 
nonresponder for analysis purposes but will continue to receive study treatment. 
 
Other Restrictions and Precautions 
No other restrictions and precautions have been identified. 
pSS 6.8 
Treatment After the End of the Study 
At the end of the study, BMS will not continue to provide BMS-supplied study treatment to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate SOC to treat the condition under study. 
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PSS 7 
DISCONTINUATION CRITERIA 
pSS 7.1 
Discontinuation from Study Treatment 
 
Permanent Discontinuation from Study Treatment 
Subjects MUST discontinue study treatment (and non-IP at the discretion of the investigator) for 
any of the following reasons: 
x A subject requests to stop study treatment; subjects who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol-specified follow-up 
procedures. The only exception to this is when a subject specifically withdraws consent for 
any further contact with him/her or persons previously authorized by the subject to provide 
this information. 
x Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject. If treatment is discontinued due to an AE, the AE eCRF must be completed to show 
that the AE caused discontinuation. 
x Termination of the study program by BMS. 
x Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. 
x Unblinding of a subject’s treatment assignment for any reason (emergency or nonemergency). 
x Inability or failure to comply with protocol requirements. 
x Pregnancy. 
Discontinuation of the study treatment for abnormal liver tests indicative of DILI (see 
Section pSS 8.2.8 for definition) should be considered by the investigator when the DILI meets 
one of the conditions necessary to be defined as an SAE outlined in APPENDIX 3 or if the 
investigator believes that it is in the best interest of the subject. 
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the Medical Monitor/designee of this event. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (eg, dose tapering, if necessary, for 
subject safety). Refer to Section pSS 8.2.6. 
All subjects who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in the SoA (Section pSS 1.3). The only exception to this requirement is 
when a subject withdraws consent for all study procedures including posttreatment study follow-up 
or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness). Following the decision to permanently 
discontinue a subject from treatment, an EOT visit should be performed as soon as possible, 
followed by a Safety FU visit approximately 4 weeks later – both according to Table 2 of 
Section pSS 1.3. 
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate eCRF page. 
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Temporary Discontinuation from Study Treatment 
Branebrutinib may be discontinued temporarily at the discretion of the investigator/Medical 
Monitor due to AE, laboratory abnormality or overdose (pSS 8.3). 
Branebrutinib may be discontinued temporarily due to concomitant medication use 
(Master Protocol Table 1), as follows: 
x Digoxin, “For acute use only; exclude at baseline; limit highest dose and monitor trough 
concentrations; stop treatment with branebrutinib during treatment with digoxin and for 3 days 
afterwards.” 
x Posaconazole: “Dose up to 300 mg QD can be used as maintenance dose, for acute infections 
stop using branebrutinib until dosing with posaconazole is discontinued.” 
 
Post-study Treatment Study Follow-up 
Subjects who discontinue study treatment will not be followed beyond the planned Safety FU Visit.
pSS 7.2 
Discontinuation from the Study 
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the subject to provide this information. 
x Subjects should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
x The withdrawal of consent should be explained in detail in the medical records by the 
investigator and entered on the appropriate eCRF page. 
x In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
x If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
The following procedures must be performed upon subject withdrawal: 
x Assessments for the EOT visit must be performed, provided that the subject has not withdrawn 
consent for these activities. 
All required eCRF pages must be completed, including the date of and explanation for the 
withdrawal. 
pSS 7.3 
Lost to Follow-up 
x All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject. 
x Lost to follow-up is defined by the inability to reach the subject after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by subject to 1 registered 
mail letter. All attempts should be documented in the subject’s medical records. 
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x If it is determined that the subject has died, the site will use permissible local methods to obtain 
date and cause of death. 
x If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. 
x The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records. 
PSS 8 
STUDY ASSESSMENTS AND PROCEDURES 
x Study procedures and timing are summarized in the SoA (Section pSS 1.3). 
x Protocol waivers or exemptions are not allowed. 
x All immediate safety concerns must be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue treatment. 
x Adherence to the study design requirements, including those specified in the SoA 
(Section pSS 1.3), is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria before randomization. The investigator will maintain a screening 
log to record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
x Procedures conducted as part of the subject’s routine clinical management (eg, BP, physical 
examination, medical history) and obtained on the day of the screening visit and obtained 
before signing of the informed consent may be used for screening provided the procedure 
meets the protocol-defined criteria and has been performed within the timeframe defined in the 
SoA (Section pSS 1.3). 
pSS 8.1 
Efficacy Assessments 
The PI or sub-investigator, designated by the PI and confirmed by the Sponsor, should perform all 
clinical assessments at a given visit, with the exception of the ocular assessments and salivary flow 
assessments. The sub-investigator may be a Doctor of Medicine or Doctor of Osteopathy, 
Physician’s Assistant, or Nurse Practitioner with experience in the diagnosis and management of 
subjects with pSS. The ocular assessments are to be performed by the Sponsor-approved 
ophthalmologist/optometrist and the salivary flow tests are to be performed by a trained site staff 
member, as designated by the PI. 
All assessments should be performed or administered prior to study drug administration unless 
otherwise indicated. Other conditions include: 
x Every effort must be made to ensure the same investigator performs the assessments for a given 
subject at each visit and throughout the study to minimize inter-observer variation. 
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x If the investigator is unable to complete the assessment at a given visit, the approved back-up 
investigator may complete the assessment. 
x Assessments are to be conducted at approximately the same time of day throughout the 
duration of the study for each subject. 
x Visits should be scheduled with the availability of the specific investigator managing a given 
subject taken into account. 
The requirements above also apply to the ocular assessments. 
 
Investigator-administered Assessments 
 ESSDAI 
The ESSDAI is a systemic activity index designed to measure disease activity in subjects with 
pSS. The ESSDAI includes 12 domains (ie, organ systems: cutaneous, respiratory, renal, articular, 
muscular, CNS, PNS, hematological, glandular, constitutional, lymphadenopathic, biological). 
Each domain is divided into 3 to 4 levels of activity. The definition of each activity level is 
provided by a detailed description of what should be considered in that item. Sites should only use 
the versions of the assessment scale provided by the Sponsor for this study and should ensure that 
all enrolled subjects have a positive score in at least one of these responsive domains: articular, 
biological, glandular, hematological, or lymphadenopathy. Investigators should assess the 
ESSDAI parameters as described by Seror et al.84 The ESSDAI will be completed at the visits 
noted in the SoA (Section pSS 1.3). Results from each assessment will be recorded in site source 
records as well as in the corresponding eCRF. See also Section pSS 1.1 for further details on the 
use of ESSDAI to facilitate enrollment of subjects with moderate to severe disease activity and to 
define the MCII for ESSDAI assessments. (APPENDIX 15) 
 Stimulated/Unstimulated Salivary Flow in pSS 
Evidence of residual salivary function is required for inclusion in the study. A stimulated salivary 
flow rate of > 0.05 mL/minute85 or unstimulated salivary flow rate of > 0.01 mL/minute is required 
for entry and will be assessed at screening and randomization (both tests should be performed at 
screening and randomization, but the minimum flow requirement from only one is needed for 
inclusion). Subjects should refrain from eating, drinking, smoking or chewing gum for at least 
90 minutes prior to the test procedures. Subjects should be instructed to not use 
parasympathomimetic agents, such as pilocarpine and cevimeline for the 48 hours prior to salivary 
assessments (see also Master Protocol 1.5), to withhold antihistamines for 12 hours before the 
assessments and to not use artificial saliva on the day of the assessment. On-study salivary 
assessments will be performed at Week 12, Week 24, and Week 28. The assessments should be 
performed by the same assessor at approximately the same time of day as the baseline salivary 
assessment, if at all possible. Collection procedure requirements are detailed in the pSS Quick 
Reference Guide. Saliva collected for unstimulated salivary flow assessments may also be stored 
for exploratory biomarker analysis. 
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 Lacrimal Gland Function (Tear Break-up Time, Ocular Staining Score, 
Schirmer’s Test) 
The following procedures should be performed at pre-identified visit days by an ophthalmologist 
or optometrist trained in the diagnosis and treatment of patients with Sjögren’s syndrome and 
according to the methods described in Whitcher, et al.86 A visit window of ± 5 days to perform the 
ophthalmologic assessments is acceptable (baseline Day 1 assessment can be performed up to 
5 days prior to dosing only), but all assessments must be performed during the same visit in the 
order outlined below. Subjects should not use cyclosporine eye drops or artificial tears on the day 
of the visit for 12 hours prior to the assessment. Autologous serum eye drops should be 
discontinued at the screening visit and are prohibited throughout the study. The use of alternative 
ocular dyes may be permitted per local standards and/or regulations, after consultation with the 
Medical Monitor. 
x Tear Break-up Time (TBUT): Determined by instilling fluorescein dye and evaluating the 
stability of the pre-corneal tear film. After several blinks, the tear film is examined using a 
broad beam of the slit lamp (biomicroscope) with a cobalt blue filter. The TBUT, defined 
as the time in seconds between the subject’s last blink and the first appearance of a random 
dry spot on the corneal surface, is measured 3 times and recorded. The mean value will be 
calculated programmatically. 
x Ocular Staining Score: The test is performed by instillation of fluorescein dye and either 
Lissamine Green or Rose Bengal dye to stain the cornea and conjunctiva, respectively. 
After instilling the dye, the ocular surface is examined through a slit lamp (biomicroscope) 
the staining pattern is recorded per the method described in Whitcher, et al. 
x Schirmer’s test: To be completed last and at least 15 minutes after completing the Ocular 
Staining Score. The test (without anesthesia) is performed by placing a narrow-calibrated 
filter-paper strip in the inferior cul-de-sac of each eye. Aqueous tear production is 
measured by the length in millimeters that the strip wets during the 5-minute test period. 
Detailed procedure requirements are available in the pSS Quick Reference Guide (QRG). The 
results from each procedure will be recorded in site source records as well as entered into the 
corresponding eCRF. 
 Tender Joint Count 68/Swollen Joint Count 66 (TJC68/SJC66) – pSS 
Sub-protocol 
At specified visits the 66/68 joint count will be used to determine the number of inflamed joints 
(tender and/or swollen) due to pSS activity. The same PI or sub-investigator following the subject 
shall perform this assessment at all visits: 68 joints (34 joints on each side of the subject’s body) 
will be examined for tenderness and/or swelling. They include: 2 temporomandibular joints 
(TMJs), 2 sternoclavicular joints, 2 acromioclavicular joints, 2 shoulder joints, 2 elbow joints, 
2 wrist joints, 10 metacarpophalangeal joints, 2 interphalangeal joints of the thumb, 8 proximal 
interphalangeal joints of the hands, 8 distal interphalangeal joints of the hands, 2 hip joints, 2 knee 
joints, 2 ankle joints, 2 tarsi, 10 metatarsophalangeal joints of the feet, 2 great toes (first proximal 
interphalangeal joint of the feet), and 8 proximal interphalangeal joints of the feet. Joints will be 
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assessed for tenderness by pressure and joint manipulation on physical examination. The subject 
will be asked for pain sensations on these manipulations and watched for spontaneous pain 
reactions. Any positive response on pressure, movement, or both will then be translated into a 
single tender-versus-nontender dichotomy. Swelling is defined as palpable fluctuating synovitis of 
the joint. Only joint tenderness or swelling of an inflammatory origin due to pSS should be scored. 
Arthralgias or synovitis due to other causes such as osteoarthritis, infectious, metabolic, RA, or
other immune-mediated diseases should be excluded. Sixty-six (66) joints (the above 68 excluding 
both hips) will be assessed and classified as swollen or not swollen due to active pSS synovitis. 
Swelling secondary to osteoarthrosis will be assessed as not swollen, unless there is unmistakable 
fluctuation due to active pSS synovitis. 
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
screening visit and will be excluded from evaluation during the study. The locations (or a listing) 
of surgical procedures should be documented in the subject’s source documents/eCRF pages. 
 Disease Activity Score 28-C-Reactive Protein for pSS 
The DAS28-C-reactive protein (DAS28-CRP) is used to assess whether a subject has a significant 
improvement of disease activity compared to baseline. It is a composite index using the number of 
tender joints and swollen joints (specified in the 28 Joint Count), the CRP laboratory result, and 
the subject’s global assessment of health related to pSS on a visual analog scale. The score will be 
calculated programmatically (APPENDIX 16). 
 Physician Global Assessment (PGA) of pSS Disease Activity 
The investigator will rate the overall status of the subject in response to the following statement: 
“How do you assess your patient’s (the subject’s) current Primary Sjogren’s disease activity as 
compared to the activity and Physician Global Assessment at the last visit?” (APPENDIX 17). 
 
Patient-reported Assessments 
Patient-reported assessments used in pSS studies have included questionnaires about the subject’s 
general health, rheumatology, and pSS disease, and the subjects responses to these health outcomes 
instruments are to be recorded electronically on eCOA devices provided by the Sponsor or 
designee to the sites. 
 ESSPRI 
The ESSPRI was developed as 3-question symptom index for dryness, fatigue, and pain in subjects 
with pSS. Dryness, pain, somatic and mental fatigue were identified as the main symptoms in 
patients with pSS in studies conducted during the development of the Profile of Fatigue and 
Discomfort (PROFAD) and Sicca Symptoms Inventory. The ESSPRI performed satisfactorily for 
evaluation of patients’ symptoms and has the advantage that it is easy to use. It was hypothesized 
that a single 0 to 10 numerical scale for each domain was sufficient to assess these symptoms 
(APPENDIX 18). 
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 Numeric Rating Scale (NRS) for Mouth and Eye Dryness 
NRS scales for mouth and eye dryness will be used to assess a subject’s perception of change in 
these specific symptoms using the same wording found in the EULAR ESSPRI instrument for 
dryness referencing the specific organs. 
 Subject Global Assessment (SGA) of Disease Activity 
SGA is an NRS used by the subject to make an overall assessment of the subject’s Sjogren’s 
disease in the past week (APPENDIX 19). 
 PROMIS-Fatigue Instrument, Form 6 a 
The PROMIS™ Form 6 a, provides item banks that offer the potential for PRO measurement that 
is efficient (minimizes item number without compromising reliability), flexible (enables optional 
use of interchangeable items), and precise (has minimal error in estimate) measurement of 
commonly studied PROs.78, 79, 80, 81 In the health outcomes measurement perspective, for example, 
fatigue is divided conceptually into the experience of fatigue (such as its intensity, frequency, and 
duration), and the impact of fatigue upon physical, mental, and social activities. The fatigue item 
bank consists of 95 items assessing the intensity, frequency, and impact of fatigue. Most PROMIS 
items employ response scales with 5 options (see APPENDIX 12). 
 Euro Quality of Life Five Dimensions Questionnaire: 5-Level Version 
(EQ-5 D-5 L) 
The EQ-5 D-5 L consists of 2 parts – the EQ-5 D-5 L descriptive system and the EQ VAS. The 
descriptive system comprises the same 5 dimensions as the EQ-5 D-3 L (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems; slight 
problems; moderate problems; severe problems; and extreme problems. The respondent indicates 
his/her health state by ticking in the box against the most appropriate statement in each of the 
5 dimensions. The resulting 1-digit number expresses the level selected for that dimension. The 
digits for all 5 dimensions can then be combined in a number describing the respondent’s health 
state. 
The numbers 1 through 5 have no arithmetic properties and should not be used as a cardinal score. 
During the development of the EQ-5 D-5 L, the opportunity was also taken to improve some of 
the wording in the dimensions to enhance consistency and facilitate understanding. For example, 
the old wording of “confined to bed” to indicate the upper extreme in the EQ-5 D-3 L has been 
replaced with “I am unable to walk about” which is more consistent with the wording within the 
Mobility dimension and with the extreme levels on other dimensions. 
The EQ VAS records the respondent’s self-rated health on a 20-cm vertical VAS with endpoints 
labeled “the best health you can imagine” and “the worst health you can imagine.” This 
information can be used as a quantitative measure of health as judged by the individual 
respondents. The instructions for the EQ VAS task have also been simplified (APPENDIX 13). 
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Salivary Gland Ultrasonography 
Salivary gland ultrasonography (SG-US) is a noninvasive tool that has been proven effective for 
identifying structural abnormalities of the salivary glands and diagnosing pSS.87 
Each subject in the pSS sub-protocol will have 3 SG-US examinations at screening, Week 12 and 
Week 24 (pSS 1.3). The parotid and submandibular glands will be scanned on both sides (4 main 
salivary glands). Screening visit scans may be repeated to ensure quality baseline data. 
At screening, the SG-US should be performed approximately 14 days prior to randomization to 
allow review and to repeat, if required. 
Week 12 and Week 24 SG-US examinations are to be performed within 7 days of both scheduled 
Week 12 visit and Week 24 visits. Subjects who terminate the study early require a SG-US 
H[DPLQDWLRQDWWKH(27YLVLWRQO\LIWKDWYLVLWLVZHHNVIURPWKHGDWHRf randomization or 
 4 weeks from Week 12 and should have the EOT SG-US examination NO MORE than 7 days 
from the EOT visit. 
Each site will be trained for the acquisition of SG-US examinations by an imaging core laboratory 
to maximize the quality and the consistency of the imaging data. Each investigator will assess the 
SG-US data according to local procedures. The results will not be reported in the study’s eCRFs, 
although any incidental findings detected with the SG-US evaluation must be recorded in the 
study’s eCRF and followed-up by an investigator as appropriate. 
The SG-US data will be centrally evaluated at an imaging core laboratory by independent readers 
blinded to the study arms, clinical information, and the chronology of SG-US acquisitions. Two 
readers will independently evaluate the data and a consensus evaluation will be performed in case 
of discrepancy. 
The following scale will be used to evaluate the SG-US data. The echostructure of each gland will 
be graded on a scale of 0 to 3 as an exploratory assessment: 
x Grade 0: normal parenchyma; 
x Grade 1: minimal change - mild inhomogeneity without anechoic/hypoechoic areas; 
x Grade 2: moderate change - moderate inhomogeneity with focal anechoic/hypoechoic areas; 
x Grade 3: severe change - diffuse inhomogeneity with anechoic/hypoechoic areas occupying 
the entire gland surface. 
Details about the procedures involved in the conduct of SG-US assessments will be provided in 
the Imaging Charter. 
Because the salivary gland ultrasonography in pSS is a fast-evolving research field and given the 
exploratory nature of these assessments, additional scoring and analysis methodologies may be 
implemented. 
 
 
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pSS 8.2 
Adverse Events 
The definitions of an AE or SAE can be found in APPENDIX 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver or surrogate). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the subject to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in APPENDIX 3. 
 
AEs of Interest 
AEIs are AEs for a particular product or class of products that a Sponsor may wish to monitor 
carefully. AEIs may be serious or nonserious. Such events may require further investigation to 
better characterize and understand them. In the branebrutinib clinical development program, 
infection AEs have been identified as potential AEIs; however, there has been no definitive 
assessment on the causal relationship between these events and treatment with branebrutinib. 
Therefore, additional information about infection AEs may be collected on the eCRF in order to 
better characterize and understand them. 
 
Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 
discharge, at the timepoints specified in the SoA (Section pSS 1.3). Nonserious AE information 
should also be collected from the start of a PBO lead-in period or other observational period 
intended to establish a baseline status for the subjects. The Reference Safety Information in 
Sections 5.6.1 and 5.6.2 of the IB12 should be used to determine the expectedness of SAEs for 
expedited reporting. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing or 
subject’s participation in the study if the last scheduled visit occurs at a later time. 
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The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
x Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the designated eCRF. 
x All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in APPENDIX 3. 
x The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study treatment 
or study participation, the investigator must promptly notify the Sponsor. 
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in APPENDIX 3. 
 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) Nonserious pSS-related AEs 
will be collected solely on the disease assessment instruments and will not be reported as AEs 
unless characterized as an SAE 
 
Follow-up of AEs and SAEs 
x Nonserious AEs should be followed to resolution, stabilization, or reported as SAEs if they 
become serious (see APPENDIX 3). 
x Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
x All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the eCRF. Completion of supplemental eCRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study. 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and nonserious AEIs (as defined in Section pSS 8.2.1) will 
be followed until resolution, until the condition stabilizes, until the event is otherwise explained, 
or until the subject is lost to follow-up (as defined in Section pSS 7.3). 
Further information on follow-up procedures is provided in APPENDIX 3. 
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Regulatory Reporting Requirements for SAEs 
x Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of subjects and the safety of a product 
under clinical investigation are met.
x An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations (CFR) 21 CFR, Parts 312 and 320. A SUSAR is a subset of SAEs and will be 
reported to the appropriate regulatory authorities and investigators following local and global 
guidelines and requirements. 
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify 
 Drug 
Safety of this event and complete and forward a Pregnancy Surveillance Form to 
Drug Safety 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in APPENDIX 3. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study subject should be reported to 
 
Drug Safety. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the AE eCRF page. 
x Any laboratory test result that is clinically significant or meets the definition of an AE or SAE
x Any laboratory test result abnormality that required the subject to have study treatment 
discontinued or interrupted 
x Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy 
If a laboratory test result meets the definition of an AE or SAE, the laboratory test result should be 
reported as an AE or SAE and submitted to 
 Drug Safety, as specified in APPENDIX 3. 
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It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value). 
 
Potential DILI 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (see Section pSS 8.2 and APPENDIX 3 for reporting 
details). 
Potential DILI is defined as: 
1) ALT or AST elevation > 3× ULN 
AND 
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, preexisting chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
Other Safety Considerations 
Any significant worsening of a preexisting medical condition noted during interim or final physical 
examination, electrocardiogram (ECG), x-ray filming, or any other potential safety assessment 
required or not required by protocol should also be recorded as a nonserious AE or SAE, as 
appropriate, and reported accordingly. 
pSS 8.3 
Overdose 
For this study, any dose of branebrutinib greater than 2 daily doses of study treatment within a 
24-hour time period will be considered an overdose. See APPENDIX 3 for AE assessment and 
reporting procedures regarding suspected overdose and intentional overdose. 
Based on the IB, there has been no clinical experience with overdose of branebrutinib.12 There is 
no known specific antidote for overdose with branebrutinib. 
In the event of an overdose, the investigator should: 
1) Contact the Medical Monitor immediately. 
2) Closely monitor the subject for AEs/SAEs and laboratory abnormalities. 
3) Obtain a plasma sample for PK analysis within 4 hours of the overdose if requested by the 
Medical Monitor (determined on a case-by-case basis). 
4) Document the quantity of the excess dose as well as the duration of the overdosing in the source 
documentation. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 
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pSS 8.4 
Safety 
Planned time points for all safety assessments are listed in the SoA (Section pSS 1.3). 
 
Physical Examinations 
A complete physical examination will include general appearance, vital signs, eyes, ears, nose, 
mouth, throat, neck, respiratory, cardiovascular, respiratory, gastrointestinal/abdomen, lymphatic, 
musculoskeletal, skin, psychiatric, and neurologic exams. A targeted physical examination will 
include any organ system associated with an AE, a laboratory abnormality, or a pSS activity not 
captured elsewhere. 
 
Vital Signs 
Refer to SoA (Section pSS 1.3). 
 
Electrocardiograms 
A 12-lead ECG will be performed at the visits indicated in the SoA (Section pSS 1.3). The subject 
will remain supine for 5 to 10 minutes prior to the ECG and must have lab work done after the 
tracing so that the ECG results remain as accurate as possible. The ECG results will be read by the 
primary study investigator or a designee. 
 
TB Screening and Chest Imaging 
A subject must not have active signs or symptoms of TB, as judged by the investigator, to be 
eligible for the study. 
In addition to a complete physical examination and medical history to evaluate exposure to TB, all 
subjects will have a screening test, an IGRA (eg, QuantiFERON®-TB Gold) performed centrally. 
A subject with an indeterminate IGRA test result from the central laboratory must be retested for 
confirmation. If the second result is again indeterminate, the subject will be excluded from the 
study, unless there is documentation of a local negative TB Spot test result. If the second result 
from the central laboratory is positive, the subject should be considered as having LTBI provided 
there are no signs or symptoms of active TB. If the second result is negative, the subject may be 
eligible provided no other exclusion criteria for TB are met. A chest x-ray is also required if one 
has not been performed within 6 months of screening; a copy of the radiology report must be on 
file and reviewed by the investigator. If unable to obtain central laboratory results, an IGRA test 
could be obtained locally, after consultation with the 
 Medical Monitor. 
 
Clinical Safety Laboratory Assessments 
A central laboratory will perform assessments of safety laboratory assessments (except urine 
pregnancy tests, cryoglobulin, and ESR) and provide reference ranges and laboratory reports. 
Investigators must document their reviews of each laboratory safety report. Any laboratory test 
result that the investigator considers clinically relevant is to be recorded on the appropriate AE 
page of the eCRF (Section pSS 8.2.7). Additional safety assessments may be performed at local 
laboratories at the investigator’s discretion. The laboratory parameters to be assessed are included 
in pSS Table 7. 
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In addition, serum or urine pregnancy testing will be performed for WOCBP. 
pSS Table 7 
Clinical Safety Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including manual differential 
Platelet count 
Red blood cell count 
Prothrombin time/INR 
PTT 
aPTT 
Serum Chemistry 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyltransferase 
hsCRP 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Lactate dehydrogenase 
Creatinine 
Blood urea nitrogen 
Uric acid 
Fasting glucose (nonfasting at screening only) 
Creatinine clearance – screening only 
Estimated glomerular filtration rate 
Total Protein 
Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphorus 
Magnesium 
Creatine kinasea 
Fasting lipid panel (total cholesterol, high-density 
lipoprotein, low-density lipoprotein, and triglycerides; 
nonfasting at screening only) 
Urinalysis 
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH 
Microscopic examination of sediment  
Urine chemistry – Spot urine for urine protein:creatinine ratio (UPCR) 
Infectious Serologies 
Anti-HCV antibodies with reflex testing of HCV RNA if positive 
HBsAg 
Anti-HBsAb 
Anti-HBcAb 
Anti-HIV-1 and anti-HIV-2 antibody 
Other Analyses 
Serum will be collected at baseline (Week 0) and at the EOT (Week 24) for optional measurements of anti-SARS-
CoV-2 immunoglobulins. 
Tuberculosis test (QuantiFERON®-TB Gold) at screening only 
Direct Coomb’s test (only if clinically indicated) 
Whole blood HCQ level (in subjects taking HCQ) 
3UHJQDQF\7HVWIRU:2&%3VHUXPRUXULQHȕ-HCG test every 4 weeks) 
Follicle-stimulating hormone if needed to confirm menopausal status (see APPENDIX 4), at screening 
HbA1c 
Thyroid-stimulating hormone (if above normal reference range, test free T4; if below normal range, test free T4 
and T3) 
 
Erythrocyte sedimentation rate 
 
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pSS Table 7 
Clinical Safety Laboratory Assessments 
 
 
T cells, B cells, natural killer cells 
Beta-2-microglobulin 
Cryoglobulin 
 aPTT = activated partial 
WKURPERSODVWLQWLPHȕ-HCG = beta-human chorionic gonadotropin; 
; DNA = 
deoxyribonucleic acid; dsDNA = double-stranded DNA; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B 
surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; hsCRP = hjgh-sensitivity C-reactive protein; Ig = immunoglobulin; 
INR = international normalization ratio; PTT = partial thromboplastin time; RNA = ribonucleic acid; 
; Sm = Smith; SSA = Sjögren’s syndrome antigen A; SSB = Sjögren’s syndrome antigen B; 
T3 = tri-iodothyronine; T4 = thyroxine; TB = tuberculosis; ULN = upper limit of normal; WOCBP = women of 
childbearing potential 
a If the creatine kinase is > 2.5× ULN, reflex testing of creatine kinase-MB and troponin I will be required. 
 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance on chest x-ray or any additional imaging 
performed that is not directly associated with the objectives of the protocol should be evaluated 
and handled by the study investigator as per standard medical/clinical judgment. Images may be 
requested for submission to the assigned imaging core lab for central analysis. 
pSS 8.5 
PK of Branebrutinib 
The PK sampling schedule for branebrutinib, its metabolites, and concomitant medications will be 
harmonized among all treatments and sub-protocols where applicable. 
For the predose and postdose PK assessments of branebrutinib and metabolites, samples will be 
collected from 2 groups of subjects—all study subjects will comprise one group; and subjects at 
preselected clinical sites only and who will also have extended PK sampling comprise the second 
group (pSS Table 8). 
Samples collected from all study subjects who receive branebrutinib will be analyzed for 
branebrutinib PK only, including samples drawn on days scheduled solely for predose samples. 
Samples collected from subjects at the preselected clinical sites will be analyzed for both 
branebrutinib and metabolites as indicated in pSS Table 8 and will be divided into 2 collection 
tubes, one tube for branebrutinib and one tube for metabolites analyses. 
In general, predose (trough) concentrations will be assessed to evaluate the attainment of 
steady-state and accumulation. It is expected that steady-state will be achieved for all analytes at 
Week 4 after 28 days of continuous dosing. 
Pharmacokinetic samples may also be used in correlation analyses for evaluation of PK/PD and 
the effect of pharmacogenomics (PGx), and may be used for other correlation analyses as well. 
The sampling schedule is based on available information on branebrutinib and its metabolites. 
(Samples for PK analysis collected from subjects receiving PBO will not be analyzed for 
branebrutinib or metabolites.) 
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Branebrutinib and Metabolites Analysis: 
Branebrutinib PK samples will be analyzed by a vendor using a validated assay. Plasma samples 
for metabolites will be analyzed by the BMS bioanalytical laboratory. These analyses will be 
reported separately. The BMS laboratory will be unblinded before the end of the study and will 
not communicate unblinded information to the BMS 
 study teams. Where the data allow, 
individual subject PK parameter values for branebrutinib and its metabolites will be derived from 
plasma concentration data versus time by noncompartmental methods with a validated PK analysis 
program. Actual times will be used for the analyses. 
For all study subjects, the branebrutinib PK parameters listed below will be calculated and 
summarized with data up to 4 hours postdose. Accumulation ratios for Cmax and AUC0-4 will 
also be calculated. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
Ctrough 
Trough observed plasma concentration 
AUC(0-4) 
Area under the plasma concentration-time curve from time zero to the 4-hour 
dosing period 
 
For subjects at preselected sites with extended sampling, separate plasma concentrations of 
branebrutinib and select metabolites at all timepoints will be summarized by time point. The 
branebrutinib and metabolites PK parameters listed below will be calculated and summarized. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
AUC(0-T) 
Area under the plasma concentration-time curve from time zero to time of 
last quantified concentration 
AUC(TAU) 
Area under the concentration-time curve to the end of the dosing period 
Ctrough 
Trough observed plasma concentration 
 
pSS Table 8 lists the complete sampling schedule for assessment of the PK of branebrutinib, 
metabolites, and concomitant medications in subjects with pSS. 
To assess steady-state concentrations of branebrutinib, a total of 5 predose PK samples 
(approximately 4 mL each) will be drawn from all study subjects at Week 0 (Day 1), Week 4 
(Day 29), Week 8 (Day 57), Week 16 (Day 113), and Week 24 (Day 169). (Note that these samples 
will be drawn within a 1-hour window before the next dose is administered.) For subjects at 
preselected sites with extended sampling, predose PK samples collected at Week 8 (Day 57) will 
also be aliquoted to assess metabolite concentrations. 
For postdose sampling, all study subjects will have branebrutinib PK samples drawn at Week 0 
(Day 1), Week 8 (Day 57), and Week 24 (Day 169) at the 0.5, 1, 2, and 4-hour time points, a total 
of 14 samples. (Note that these samples will be drawn within ±15 min from the given time points.) 
For subjects at preselected sites with extended sampling, postdose PK samples will be aliquoted 
to assess metabolite concentrations at these time points. 
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In addition, for subjects at preselected sites with extended sampling, a total of 7 postdose PK 
samples will be drawn and assessed for both branebrutinib and metabolite concentrations at 
Week 0 (Day 1) and Week 8 (Day 57) at approximately 06:00 hours, and from 08:00 to 
10:00 hours (flexible window), and from 10:00 to 12:00 hours (flexible window). Samples will 
also be collected at Week 0 (Day 2) at approximately 24:00 hours postdose (predose of 
branebrutinib on Day 2). Efforts should be made to collect the samples within these windows; 
however, any sample drawn outside the prespecified window will not be considered a protocol 
deviation. Both planned and actual time points at which the blood samples will be taken will be 
recorded and used in analysis and modeling. 
Concomitant Medications 
Concentrations of concomitant medications that are sensitive substrates of CYP2C8 and other 
potentially relevant drug metabolizing enzymes that may have a drug-drug interaction with 
branebrutinib and P-gp transporter may be measured (post-hoc) in subjects receiving PBO and 
active treatment. Samples for the PK assessment of the relevant concomitant medications will be 
collected at Week 0 and Week 4 from all study subjects. Samples for PK analysis collected from 
subjects receiving branebrutinib or PBO will be analyzed for HCQ and other relevant concomitant 
comedications provided that these subjects are receiving HCQ and other relevant concomitant 
comedications. 
Detailed instructions for the collection, labeling, processing, storage, shipping, and disposition of 
all PK blood samples are provided in the Laboratory Manual. 
pSS Table 8 PK Sampling for Branebrutinib, Metabolites, and Concomitant Medications 
Study 
Day 
Study 
Week 
Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Medsa,b,c 
Comments 
1 
0 
Predose 
00:00 
X 
 
Xa,b,c 
Predose PK samples will be 
collected from all study subjects 
to assess branebrutinib and 
relevant concomitant 
medications; 
 )RU VXEMHFWV RQ +&4 ZKROH
blood samples will be collected 
for HCQ level assessment. 
1 
0 
Postdose 
00:30 
X 
X 
 
Postdose PK samples collected 
from all study subjects at these 
time points will be assessed for 
branebrutinib; 
3RVWGRVH3.VDPSOHVFROOHFWHG
at these time points from subjects 
at preselected clinical sites will 
also be assessed for metabolites; 
3RVWGRVH3.VDPSOHVFROOHFWHG
at 2 hours after dosing, will be 
assessed 
for 
relevant 
1 
0 
Postdose 
01:00 
X 
X 
 
1 
0 
Postdose 
02:00 
X 
X 
Xa,b,c 
1 
0 
Postdose 
04:00 
X 
X 
 
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pSS Table 8 PK Sampling for Branebrutinib, Metabolites, and Concomitant Medications 
Study 
Day 
Study 
Week 
Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Medsa,b,c 
Comments 
concomitant 
medications; 
 For subjects on HCQ, whole 
blood samples will be collected 
for HCQ level assessment. 
1 
0 
Postdose 
06:00 
X 
X 
 
Postdose PK samples collected 
from subjects at preselected 
clinical 
sites 
only 
will 
be 
assessed for branebrutinib and 
metabolites at these time points. 
1 
0 
Postdose 
08:00-10:00 
X 
X 
 
1 
0 
Postdose 
10:00-12:00 
X 
X 
 
2 
0 
Postdosed  24:00 
X 
X 
 
29 
4 
Predose 
00:00 
X 
 
Xa,b,c 
Predose PK samples will be 
collected from all study subjects 
for assessment of branebrutinib 
and concomitant medications; 
 )RU VXEMHFWV RQ +&4 ZKROH
blood samples will be collected 
for HCQ level assessment. 
29 
4 
Postdose 
02:00 
 
 
Xa,b,c 

3ODVPD
VDPSOHV
ZLOO
EH
collected from all study subjects 
at 2 hours after dosing for 
assessment 
of 
relevant 
concomitant medications; 
 )RU VXEMHFWV RQ +&4 ZKROH
blood samples will be collected 
in addition for HCQ level 
assessment. 
57 
8 
Predose 
00:00 
X 
X 
 
 3UHGRVH and postdose PK 
samples collected at these time 
points from all study subjects 
will be assessed for branebrutinib 
only. 
 3UHGRVH and postdose PK 
samples collected at these time 
points 
from 
subjects 
at 
preselected clinical sites will also 
be assessed for metabolites. 
57 
8 
Postdose 
00:30 
X 
X 
 
57 
8 
Postdose 
01:00 
X 
X 
 
57 
8 
Postdose 
02:00 
X 
X 
 
57 
8 
Postdose 
04:00 
X 
X 
 
57 
8 
Postdose 
06:00 
X 
X 
 
Postdose PK samples collected 
at preselected clinical sites only 
will be assessed at these time 
points for branebrutinib and 
metabolites. 
57 
8 
Postdose 
08:00-10:00 
X 
X 
 
57 
8 
Postdose 
10:00-12:00 
X 
X 
 
113 
16 
Predose 
00:00 
X 
 
 
3UHGRVH3.VDPSOHVWDNHQIURP
all study subjects will be assessed 
for branebrutinib only. 
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pSS Table 8 PK Sampling for Branebrutinib, Metabolites, and Concomitant Medications 
Study 
Day 
Study 
Week 
Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Medsa,b,c 
Comments 
169 
24 
Predose 
00:00 
X 
 
 
3UHGRVH3.VDPSOHVWDNHQIURP
all study subjects will be assessed 
for branebrutinib only. 
169 
24 
Postdose 
00:30 
X 
 
 
3RVWGRVH3.6DPSOHVWDNHQat 
these time points from all study 
subjects will be assessed for 
branebrutinib only. 
169 
24 
Postdose 
01:00 
X 
 
 
169 
24 
Postdose 
02:00 
X 
 
 
169 
24 
Postdose 
04:00 
X 
 
 
NA = not applicable; PK = pharmacokinetic; Concom Meds = concomitant medications; HCQ = hydroxychloroquine. 
a Concentrations of concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant 
drug metabolizing enzymes that may have a drug-drug interaction with branebrutinib and P-gp transporter may be 
evaluated post-hoc for subjects receiving PBO and active treatment at predose of branebrutinib on Day 1 and Day 29 
(see Section pSS 8.5.1). 
b For subjects taking HCQ on-study, whole blood samples will be taken at predose and 2 hours after dosing with the 
IP on Day 1 (Week 0) and Day 29 (Week 4) (see Section pSS 8.5.1). 
c Subjects who are on HCQ will be informed to bring HCQ to the clinic on Day 1 and Day 29 for simultaneous dosing 
with branebrutinib and not to take it at home on those 2 days. Similarly, subjects who are on other prescription 
concomitant medications will also be informed to bring them to the clinic on Day 1 and Day 29 for simultaneous 
dosing with branebrutinib, but only when it is safe for subjects and operationally feasible. This should be based on 
the investigator’s discretion with consideration that the medications which should not be delayed until the time of 
dosing in the clinic should be taken at home. The self-reported time for all prescription medications taken at home 
should be recorded as accurately as possible. 
d PK sample must be drawn before the IP dose is administered on Day 2. 
 
PK of Potential Concomitant Medications 
Concentrations of Concomitant medications that are sensitive substrates of CYP2C8 and other 
potentially relevant drug metabolizing enzymes and P-gp transporter may be evaluated for subjects 
receiving PBO and active treatment with the bioanalytical analysis as part of a retrospective 
analysis. HCQ will be among the concomitant medications. The retrospective analysis will be 
conducted after review of the enrollment records, reported concomitant medication use within the 
enrolled population and on the incidence threshold and relevance to drug interaction with 
branebrutinib based on preclinical and clinical data. Other confounding factors will be evaluated 
as part of the analysis to avoid inclusion of bias or artifact results. 
Subjects who are on HCQ will be informed to bring HCQ to the clinic on Day 1 and Day 29 for 
simultaneous dosing with branebrutinib and not to take it at home on those 2 days. Similarly, 
subjects who are on other prescription concomitant medications will also be informed to bring 
them to the clinic on Day 1 and Day 29 for simultaneous dosing with branebrutinib, but only when 
it is safe for subjects and operationally feasible. This should be based on the investigator’s 
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discretion with consideration that the medications which should not be delayed until the time of 
dosing in the clinic should be taken at home. The self-reported time for all prescription medications 
taken at home should be recorded as accurately as possible. 
The concentrations of relevant concomitant medications will be measured, post-hoc, using samples 
collected predose of branebrutinib or placebo on both Day 1 and Day 29 (Week 4; at which point 
accumulation of branebrutinib and its metabolites is expected to achieve steady-state). In addition 
to predose samples on Day 1 and Day 29, samples will also be collected at 2 hours after dosing 
with branebrutinib or placebo to evaluate the concentration of relevant concomitant medications, 
including HCQ. Bioanalytical analysis of all relevant concomitant medications will be conducted 
post-hoc. The doses of the concomitant drugs and the time they are taken, will be carefully 
recorded at all times (including Day 1 on Week 0 and on Day 29 on Week 4). Actual and dose-
normalized concentrations will be listed, summarized, and compared between posttreatment and 
pretreatment of branebrutinib and PBO separately; other covariates such as MTX use, gender, etc. 
can be added to the comparison as needed. 
Detailed instructions for PK sample collection for the relevant concomitant medications, labeling, 
processing, storage, shipping, and disposition are provided in the Laboratory Manual. While blood 
samples will be used for the analysis of HCQ, plasma samples will be analyzed for the other 
relevant concomitant medications by available validated assays. The results of these post hoc 
analyses will not be recorded in the CSR. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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pSS 8.7 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
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PSS 9 
STATISTICAL CONSIDERATIONS 
pSS 9.1 
Sample Size Determination 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the pSS sub-protocol 
is pSS composite response at Week 24. 
Estimates for response rates were obtained from the published literature.82, 83 Sample size 
justification is provided below: 
Assuming a total sample size of 45 subjects randomized in a blinded fashion at a 2:1 ratio to 
branebrutinib (30 subjects) or PBO (15 subjects) and a treatment difference of 30% with a PBO 
response of 20% for the pSS composite response at Week 24, the 95% CI is expected to exclude 0 
(expected 95% CI based on a z-test = 3%, 57%). 
pSS 9.2 
Populations for Analyses 
The following analysis sets will be used in the summary and analysis of study data: 
Population 
Description 
Enrolled Set 
All subjects who sign informed consent. 
FAS 
All subjects who are randomized. Following the intent-to-treat principle, 
subjects will be analyzed according to the treatment assigned at 
randomization. The FAS will be the primary efficacy analysis population. 
This is the same as the intent-to-treat population. 
PPS 
A subset of the FAS who are compliant with study treatment and who do 
not have any statistically relevant protocol deviations that may impact the 
primary efficacy endpoint assessments. The PPS will be analyzed according 
to the treatment assigned at randomization. The PPS will be a supportive 
efficacy analysis population. 
Safety Analysis 
Set 
All randomized subjects who receive at least 1 dose of double-blind study 
treatment. Subjects will be analyzed according to treatment received. In 
case subjects take the incorrect treatment, the following scenario will be 
considered: 
x For subjects who should be receiving branebrutinib treatment, if the 
subject took any placebo dose, the subject will still be counted in 
branebrutinib treatment group for safety analysis set unless the subject 
took placebo throughout the entire course. 
For subjects who should be receiving placebo treatment, if the subject took 
any branebrutinib dose, the subject will be counted in the branebrutinib 
treatment group for safety analysis set.  
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Population 
Description 
PK 
All randomized subjects who receive at least 1 dose of branebrutinib and 
have any available branebrutinib concentration data. Subjects will be 
analyzed according to treatment received during the PK collection. 
Biomarker 
All randomized subjects who receive at least 1 dose of double-blinded study 
treatment and have at least 1 posttreatment biomarker measurement. 
pSS 9.3 
Endpoints 
The following sections outline the efficacy endpoints for this study. 
 
Primary Endpoint 
Proportion of subjects with at least 3 of the following at Week 24: 
x 'HFUHDVHRISRLQWRUIURPEDVHOLQHLQWKH(6635,7RWDO6FRUH 
x 'HFUHDVHRISRLQWVIURPEDVHOLQHLQ(66'$,VFRUH 
x 'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRULIQRUPDOVFRUHDWEDVHOine no 
change to abnormal 
x ,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x Improvement in one or more serological markers (RF, IgG, complement C3 or C4, 
cryoglobulin) 
 
Additional Endpoints 
The following are the additional efficacy endpoints as defined at Week 24: 
Proportion of subjects with the following at Week 24: 
x 'HFUHDVHRISRLQWRULQWKH(6635,7RWDO6FRUH 
x 'HFUHDVHRISRLQWVIURPEDVHOLQHLQ(66'$,VFRUH 
x 'HFUHDVHRIIURPEDVHOLQHLQRFXODUVWDLQLQJVFRUHRUif normal score at baseline no 
change to abnormal 
x ,QFUHDVHRIIURPEDVHOLQHLQ6FKLUPHU¶VWHVWVFRUHRULIQRUPDOVFRUHDWEDVHOLQHQR
change to abnormal 
x ,QFUHDVHRIIURPEDVHOLQHLQTBUT or, if normal score at baseline no change to abnormal
x ,QFUHDVHRIIURPEDVHOLQHLQVWLPXODWHGVDOLYDU\IORZ 
x Improvement in one or more serological markers (RF, IgG, complement C3 or C4, 
cryoglobulin) 
Change from baseline in: 
x Autoantibody titers, hsCRP, and ESR at Week 24 
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x DAS28-CRP 
x EQ-5 D-5 L scores at Week 24 
x PROMIS Fatigue 6 a 
x PGA and SGA 
x NRS for Mouth and Eye Dryness 
 
PK Endpoints 
x Concentration values and PK parameters of branebrutinib and metabolites of clinical interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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pSS 9.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock. Section pSS 9.4.1 provides a 
summary of planned statistical analyses of the primary and secondary efficacy endpoints. 
Additional and exploratory endpoints will be summarized in a descriptive manner. 
 
Efficacy Analyses 
Efficacy data will be summarized using the FAS. Data will be summarized using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum), unless otherwise 
specified, for continuous variables and frequency distributions (counts and percentages) for 
categorical variables. Efficacy data will be summarized separately for each sub-protocol and with 
each sub-protocol combined for variables that are similar among the sub-protocols. 
For the pSS sub-protocol, data will be presented for the following treatments:
x Branebrutinib 
x PBO 
Endpoint 
Statistical Analysis Methods 
Primary 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for binary endpoints 
(responder/nonresponder) will be analyzed using a CMH test stratified by HCQ 
use. The 95% CI for each treatment group response rate and the difference in 
response rate for branebrutinib compared to PBO will be provided. If expected 
cell counts are not sufficient, then Fisher’s exact test will be used. Since this sub-
protocol is not powered to determine statistical significance, P-values will be 
added descriptively. 
Imputation Method 
Nonresponder imputation will be used for binary endpoints for subjects who 
discontinue study treatment early, start a protocol-prohibited medication/therapy 
prior to the specified timepoint, or otherwise have missing endpoint data for the 
specified timepoint. 
Other imputation methods may be considered for sensitivity analyses and will be 
described in the SAP if used. 
Additional 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for binary endpoints 
(responder/nonresponder) will be analyzed using a CMH test stratified by HCQ 
use. The 95% CI for each treatment group response rate and the difference in 
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Endpoint 
Statistical Analysis Methods 
response rate for branebrutinib compared to PBO will be provided. If expected 
cell counts are not sufficient, then Fisher’s exact test will be used. 
Continuous endpoints (change from baseline values) will be analyzed using 
analysis of covariance. The baseline value of the endpoint being tested will be 
added into the model as a covariate and HCQ use and treatment as fixed effects. 
Treatment differences based on least-squares means and corresponding 2-sided 
95% CIs will be provided for the difference between branebrutinib and PBO. 
Supportive Analyses 
Supportive analyses for continuous endpoints may be performed using MMRM to 
investigate response over time. Bayesian borrowing to utilize historical controls 
may also be performed as supportive analyses. Details will be provided in the SAP 
if needed. 
Imputation Method 
Nonresponder imputation will be used for binary endpoints for subjects who 
discontinue study treatment early, start a protocol-prohibited medication/therapy 
prior to the specified timepoint, or otherwise have missing endpoint data for the 
specified timepoint. 
Other imputation methods may be considered for sensitivity analyses and will be 
described in the SAP if used. 
Testing Strategy for Additional Endpoints 
There will be no alpha level adjustment for multiple endpoint testing. 
 Subgroup Analyses 
Subgroup analyses will be conducted for the primary and secondary efficacy endpoints on the FAS 
population. Subgroups that may be evaluated include the following: 
x Gender 
x Race 
x Tobacco use 
Additional subgroups defined for descriptive summaries may be specified in the SAP. 
 
Safety Analyses 
Safety data will be descriptive in nature and will be summarized using the Safety Analysis Set. 
Data will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum), unless otherwise specified, for continuous variables and frequency 
distributions (counts and percentages) for categorical variables. Safety data will be summarized 
separately for each sub-protocol and with all sub-protocols combined. 
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Data will be presented for the following treatments: 
x Branebrutinib 
x PBO 
 Adverse Events 
TEAEs are defined as AEs that occur after the subject received first dose of study treatment or if 
a preexisting condition worsens in severity or becomes serious after receiving the first dose of 
study treatment up to 30 days after the last dose of study treatment. All reported TEAEs, SAEs, 
deaths, AEs leading to study treatment discontinuation, and target AEIs will be summarized by 
MedDRA system organ class and preferred term. 
 Clinical Laboratory Tests 
Laboratory parameters will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities summarized by visit and shift tables will also be provided. For clinical 
laboratory test results, marked abnormalities will be defined in the SAP. 
 Vital Signs and ECGs 
Vital signs and ECGs will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities will be summarized by visit as well. For vital signs and ECGs, marked 
abnormalities will be defined in the SAP. 
 
Other Analyses 
The PK, PD, and exploratory biomarker analyses will be described in the SAP finalized before 
database lock. Any population pharmacokinetics analysis and PD analyses will be presented 
separately from the main CSR. 
 
Analysis and Reporting 
After all subjects in the pSS sub-protocol have finished the study and the data have been locked 
for the sub-protocol, analyses of the efficacy and safety data for the sub-protocol will be performed
in order to aid in planning for subsequent clinical development. Details of these analyses will be 
described in the SAP. The study team responsible for managing the study, including Medical 
Monitors, will remain blinded to treatment assignment and the results of safety analysis until full 
database lock and treatment unblinding has occurred. The data will be reported only after 
completion of all 3 sub-protocols. 
 
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Page: 193 
 
Protocol Number: IM014029 
 
IND Number: 142401 
 
EX-US Non-IND 
 
EUDRACT Number: 2019-002205-22 
Date: 01-Jul-2019 
Revised Date: 01-Dec-2021 
 
Clinical Protocol IM014029: 
RA SUB-PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Assess the Efficacy and 
Safety of Branebrutinib Treatment in Subjects with Active Systemic Lupus Erythematosus or 
Primary Sjögren’s Syndrome, or Branebrutinib Treatment Followed by Open-label Abatacept 
Treatment in Subjects with Active Rheumatoid Arthritis 
Protocol Amendment 04 RA 
Study Director 
Medical Monitor 
 
 
Bristol Myers Squibb Company 
556 Morris Avenue, Building S5 
Summit, NJ 07901 
 
Telephone (office): 
 
Email: 
 
Medical Monitoring Support Center 
Telephone (office): 
 
Mobile: 
 
 
Fax: 
 
 
Email: 
 
 
24-hr Emergency Telephone Number 
USA: 
 
International: 
 
 
Bristol Myers Squibb Company 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
 
Avenue de Finlande 4 
B-1420 Braine-l’Alleud, Belgium 
 
 
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RA TABLE OF CONTENTS 
RA 1 
SUB-PROTOCOL SUMMARY ..............................................................................198 
RA 1.1 
Synopsis ....................................................................................................................198 
RA 1.2 
Schema ......................................................................................................................204 
RA 1.3 
Schedule of Activities ...............................................................................................205 
RA 2 
INTRODUCTION ....................................................................................................220 
RA 2.1 
Background and Research Hypothesis .....................................................................220 
RA 2.1.1 
Study Hypotheses ......................................................................................................221 
RA 2.2 
Benefit/Risk Assessment ..........................................................................................221 
RA 2.2.1 
Branebrutinib ............................................................................................................221 
RA 2.2.2 
Open-label Therapy with Abatacept .........................................................................222 
RA 3 
OBJECTIVES AND ENDPOINTS ..........................................................................224 
RA 4 
STUDY DESIGN .....................................................................................................226 
RA 4.1 
Overall Design ..........................................................................................................226 
RA 4.1.1 
DMC and Other External Committees .....................................................................227 
RA 4.2 
Number of Subjects ..................................................................................................228 
RA 4.3 
End of Study Definition ............................................................................................228 
RA 4.4 
Scientific Rationale for Study Design ......................................................................228 
RA 4.5 
Justification for Dose ................................................................................................228 
RA 5 
STUDY POPULATION ...........................................................................................230 
RA 5.1 
Inclusion Criteria ......................................................................................................230 
RA 5.2 
Exclusion Criteria .....................................................................................................234 
RA 5.3 
Lifestyle Restrictions ................................................................................................239 
RA 5.3.1 
Meals and Dietary Restrictions ................................................................................239 
RA 5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoids .......................................................239 
RA 5.3.3 
Activity ......................................................................................................................240 
RA 5.4 
Screen Failures ..........................................................................................................240 
RA 5.4.1 
Rescreening and Retesting During Screening Period ..............................................240 
RA 6 
TREATMENT ..........................................................................................................240 
RA 6.1 
Treatments Administered ..........................................................................................243 
RA 6.2 
Method of Treatment Assignment ............................................................................244 
RA 6.3 
Blinding ....................................................................................................................244 
RA 6.4 
Dosage Modification ................................................................................................245 
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RA 6.5 
Preparation/Handling/Storage/Accountability ..........................................................245 
RA 6.5.1 
Retained Samples for Bioavailability/Bioequivalence ..............................................246 
RA 6.6 
Treatment Compliance ..............................................................................................246 
RA 6.7 
Concomitant Therapy ...............................................................................................246 
RA 6.7.1 
Prohibited and Restricted Treatments ......................................................................246 
RA 6.7.2 
Rescue Medications ..................................................................................................249 
RA 6.7.3 
Other Restrictions and Precautions ..........................................................................249 
RA 6.8 
Treatment After the End of the Study .......................................................................250 
RA 7 
DISCONTINUATION CRITERIA ..........................................................................250 
RA 7.1 
Discontinuation from Study Treatment ....................................................................250 
RA 7.1.1 
Permanent Discontinuation from Study Treatment ..................................................250 
RA 7.1.2 
Temporary Discontinuation from Study Treatment ..................................................251 
RA 7.1.3 
Post-study Treatment Study Follow-up ....................................................................251 
RA 7.2 
Discontinuation from the Study ................................................................................251 
RA 7.3 
Lost to Follow-up .....................................................................................................252 
RA 8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................252 
RA 8.1 
Efficacy Assessments ...............................................................................................253 
RA 8.1.1 
Patient-reported Outcomes .......................................................................................253 
RA 8.1.2 
Clinical Assessments .................................................................................................254 
RA 8.1.3 
Composite-Assessments of Disease Activity in Rheumatoid Arthritis (RA) ..............256 
RA 8.2 
Adverse Events .........................................................................................................257 
RA 8.2.1 
AEs of Interest ...........................................................................................................257 
RA 8.2.2 
Time Period and Frequency for Collecting AE and SAE Information .....................258 
RA 8.2.3 
Method of Detecting AEs and SAEs ..........................................................................258 
RA 8.2.4 
Follow-up of AEs and SAEs ......................................................................................259 
RA 8.2.5 
Regulatory Reporting Requirements for SAEs .........................................................259 
RA 8.2.6 
Pregnancy .................................................................................................................259 
RA 8.2.7 
Laboratory Test Result Abnormalities ......................................................................260 
RA 8.2.8 
Potential DILI ...........................................................................................................260 
RA 8.2.9 
Management of Possible Hypersensitivity Reactions to Abatacept ..........................260 
RA 8.2.10 Other Safety Considerations .....................................................................................261 
RA 8.3 
Overdose ...................................................................................................................261 
RA 8.4 
Safety ........................................................................................................................262 
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RA 8.4.1 
Physical Examinations ..............................................................................................262 
RA 8.4.2 
Vital Signs .................................................................................................................262 
RA 8.4.3 
Electrocardiograms ..................................................................................................262 
RA 8.4.4 
TB Screening and Chest Imaging .............................................................................262 
RA 8.4.5 
Clinical Safety Laboratory Assessments ...................................................................262 
RA 8.4.6 
Imaging Safety Assessment .......................................................................................264 
RA 8.5 
PK of Branebrutinib ..................................................................................................264 
RA 8.5.1 
PK and Immunogenicity of Abatacept (Weeks 12 and Later) ...................................269 
RA 8.5.2 
PK of Potential Concomitant Medications ...............................................................270 
 
270 
 
273 
 
274 
RA 8.7 
Health Economics OR Medical Resource Utilization and Health Economics .........274 
RA 9 
STATISTICAL CONSIDERATIONS .....................................................................275 
RA 9.1 
Sample Size Determination ......................................................................................275 
RA 9.2 
Populations for Analyses ..........................................................................................275 
RA 9.3 
Endpoints ..................................................................................................................276 
RA 9.3.1 
Primary Endpoint .....................................................................................................276 
RA 9.3.2 
Secondary Endpoints ................................................................................................276 
RA 9.3.3 
Additional Endpoints ................................................................................................276 
RA 9.3.4 
PK Endpoints ............................................................................................................278 
RA 9.3.5 
Exploratory Endpoints ..............................................................................................278 
RA 9.4 
Statistical Analyses ...................................................................................................278 
RA 9.4.1 
Efficacy Analyses ......................................................................................................278 
RA 9.4.2 
Safety Analyses .........................................................................................................280 
RA 9.4.3 
Other Analyses ..........................................................................................................281 
RA 9.4.4 
Analysis and Reporting .............................................................................................281 
 
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RA LIST OF TABLES 
RA Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 ...............205 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to 
Week 12) ..................................................................................................209 
RA Table 3 
Procedural Outline Branebrutinib Study IM014029: Open-label 
Abatacept Therapy (Week 14 to Week 28) ..............................................215 
RA Table 4 
Objectives and Endpoints ........................................................................224 
RA Table 5 
Study Treatments for IM014029 ..............................................................242 
RA Table 6 
Selection and Timing of Dose ..................................................................243 
RA Table 7 
Prohibited and Restricted Medications ....................................................246 
RA Table 8 
Clinical Safety Laboratory Assessments .................................................263 
RA Table 9 
PK Sampling Schedule for Branebrutinib, Metabolites, and 
Concomitant Medications ........................................................................266 
RA Table 10 
PK and Immunogenicity Sampling Schedule for Abatacept ...................269 
 
272 
 
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RA 1 SUB-PROTOCOL SUMMARY 
RA 1.1 
Synopsis 
Protocol Title: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to 
Assess the Efficacy and Safety of Branebrutinib Treatment in Subjects with Active Systemic 
Lupus Erythematosus or Primary Sjögren’s Syndrome, or Branebrutinib Treatment 
Followed by Open-label Abatacept Treatment in Subjects with Active Rheumatoid Arthritis 
Short Title: 
Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Branebrutinib 
Treatment Followed by Abatacept Treatment in Subjects with Rheumatoid Arthritis: RA 
Sub-protocol 
Study Phase: 
Phase 2a 
RA Sub-protocol Rationale: 
The Study IM014029 RA sub-protocol is designed to evaluate the efficacy and safety of 
branebrutinib, an oral, highly selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK) in 
the treatment of moderate to severe adult-onset RA. The RA sub-protocol will also evaluate the 
safety and efficacy of switching to 12 weeks of treatment with abatacept after 12 weeks of 
treatment with branebrutinib or placebo. 
BTK inhibition is expected to (1) inhibit antigen-dependent B cell signaling and function without 
depleting B cells,2 (2) lead to decreases IC-mediated production of pro-inflammatory cytokines, 
(3) reduce IgG-containing IC signaling in monocytic cells, and (4) reduce IgE-containing signaling 
in mast cells and basophils.8, 9, 10, 11 These processes are key pathogenic molecular mechanisms of 
immune-mediated diseases. Therefore, branebrutinib will be tested for efficacy in RA. 
A PBO control is included in the RA sub-protocol of this study to allow the effects of treatment, 
both desired and adverse, to be appropriately attributed to the treatment received. 
Despite recent progress in RA with a number of medications approved in the US and Europe,12 
unmet medical needs remain.24 First, many agents approved for RA treatment have significant 
safety concerns, including the risk of serious or chronic infections, malignancies, and 
gastrointestinal perforation. Second, many patients respond only partially to currently available 
therapies, and only a minority of patients (< 10%) achieve true remission. Treatments that reduce 
osteoclasts and bone resorption may help to address some of these unmet medical needs.25 
The IM014029 RA sub-protocol is designed to help determine if branebrutinib is biologically 
active and effective in the treatment of RA (see Section RA 4.4). The RA sub-protocol will also 
evaluate the safety and efficacy of switching to 12 weeks of treatment with abatacept after 
12 weeks of treatment with branebrutinib or placebo. 
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RA Sub-protocol Study Population: 
The study population will consist of male and female subjects aged 18 years (or age of majority) 
to 75 years inclusive at screening with moderate to severe adult-onset RA. 
RA Sub-protocol Key Inclusion/Exclusion Criteria: 
a) Documented diagnosis of adult-onset RA as defined by American College of Rheumatology 
(ACR)/European League Against Rheumatism (EULAR) 2010 standard criteria < 4 years 
before screening 
b) ACR global functional status Class I to III 
c) MTX inadequate response (MTX-IR) based on investigator’s judgment 
d) Minimum of 6 swollen and 6 tender joints on a 66/68 joint count at the screening and baseline 
visit 
e) Evidence of swelling in at least 1 joint of the hand or wrist by clinical examination at the 
screening and baseline visit 
f) &HQWUDO ODERUDWRU\ UHVXOWV IRU KV&53  0.6 mg/dL (6 mg/L) or site laboratory results for 
ESR  28 mm/h at the screening visit. These may be retested 1 time during screening period, 
if initial screening results are not within inclusion level. 
g) Anti-FLWUXOOLQDWHGSURWHLQSHSWLGHDQWLERGLHV$&3$SRVLWLYH 30 U/mL (with a positive cut-
off value of 10 U/mL for the central laboratory) 
h) Subjects with juvenile idiopathic arthritis diagnosis or idiopathic arthritis onset before age 16 
are excluded. 
i) Subjects with documented Felty’s syndrome are excluded. 
j) Subjects with psoriatic arthritis are excluded. 
k) Subjects with active fibromyalgia with pain symptoms or signs that would interfere with joint 
assessment or requiring adjustment in medication within the 3 months before screening to 
control symptoms are excluded. Subjects with fibromyalgia that is well controlled on stable 
treatment may otherwise be considered. 
l) Subjects hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well as any subjects 
with any sequelae of prior COVID-19 infection at screening, regardless of time since infection, 
are excluded. 
RA Sub-protocol Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
x 
To 
compare 
the 
efficacy 
of 
branebrutinib with PBO at Week 12 in 
the 
treatment 
of 
subjects 
with 
moderate to severe RA on a stable 
background of MTX who have had an 
inadequate response to MTX 
x 
ACR50 response compared to baseline 
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RA Sub-protocol Objectives and Endpoints: 
Objectives 
Endpoints 
Secondary/Additional 
Branebrutinib therapy: Day 1 to Week 12 
x 
To compare the efficacy of 
branebrutinib with PBO at Week 12 
in the treatment of subjects with 
moderate to severe RA on a stable 
background of MTX who have had 
an inadequate response to MTX 
Secondary: 
x 
Changes in efficacy measures, including DAS with 28 joint 
count and CRP or ESR [DAS28-CRP and DAS28-ESR], 
SDAI, and CDAI 
x 
ACR20 and ACR70 response compared to baseline 
Additional: 
x 
Change from baseline in autoantibody titers, change from 
baseline in BTK occupancy 
x 
Change from baseline in ACR component assessments: 
- 
Tender/Painful Joint Count (68) 
- 
Swollen Joint Count (66) 
- 
PGA of Arthritis 
- 
Subject Global Assessment of Disease Activity 
- 
hsCRP 
- 
HAQ-DI 
x 
Change from baseline in RAMRIS scores of synovitis, osteitis 
(bone marrow edema), bone erosion, and cartilage loss (joint-
space narrowing) 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
Additional 
Open-label abatacept therapy: Week 12 to Week 24 
x 
To evaluate the efficacy at Week 24 
of switching from branebrutinib or 
PBO to abatacept at Week 12 in the 
treatment of subjects with moderate 
to severe RA on a stable background 
of MTX who have had an inadequate 
response to MTX 
Additional: 
x 
Changes from Week 12 at Week 24 in efficacy measures, 
including DAS28-CRP and DAS28-ESR, SDAI, and CDAI 
x 
ACR20, ACR50, and ACR70 response at Week 24 based on 
activity at Week 12 after pretreatment with branebrutinib or 
PBO (treatment effect of abatacept following treatment with 
branebrutinib versus PBO) 
x 
Change from Week 12 to Week 24 in autoantibody titers, 
change from Week 12 to Week 24 in BTK occupancy 
x 
Change from Week 12 to Week 24 in ACR component 
assessments: 
 
Tender/Painful Joint Count (68) 
 
Swollen Joint Count (66) 
 
PGA of Arthritis 
 
Subject Global Assessment of Disease Activity 
 
hsCRP 
 
HAQ-DI 
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RA Sub-protocol Objectives and Endpoints: 
Objectives 
Endpoints 
x 
Change from Week 12 to Week 24 in RAMRIS scores of 
synovitis, osteitis (bone marrow edema), bone erosion, and 
cartilage loss (joint-space narrowing) 
x 
Change from Week 12 to Week 24 in the  
EQ-5 D-5 L score 
x 
Change from Week 12 to Week 24 in PROMIS Fatigue 6 a 
Additional 
Branebrutinib followed by open-label abatacept therapy: Day 1 to Week 24 
x 
To evaluate the efficacy at Week 24 
of branebrutinib or PBO treatment 
followed by abatacept treatment in 
subjects with moderate to severe RA 
on a stable background of MTX who 
have had an inadequate response to 
MTX 
x 
Changes from baseline at Week 24 in efficacy measures, 
including DAS28-CRP, DAS28-ESR, SDAI, and CDAI 
x 
ACR20, ACR50, and ACR70 response at Week 24 compared to 
baseline 
x 
Change from baseline at Week 24 in PROMIS Fatigue 6 a 
Safety 
x 
To evaluate the safety and 
tolerability at Week 24 of switching 
at Week 12 from branebrutinib or 
PBO to abatacept in subjects with 
RA 
x 
Number and proportion of subjects experiencing SAEs, AEs, 
and abnormalities in laboratory parameters, vital signs, and 
ECGs 
Exploratory 
x 
Evaluate the PK of branebrutinib and metabolites of clinical interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ACR = American College of Rheumatology; 
ADME = absorption, distribution, metabolism, and excretion; AE = adverse event; ANA = antinuclear antibodies; 
; 
 
; 
BTK = Bruton’s tyrosine kinase; C = complement; CDAI = Clinical Disease Activity Index; CRP = C-reactive protein; 
CS = corticosteroid;
 DAS28 = Disease Activity Score 28; 
; ECG = electrocardiogram; EQ-5 D-5 L = Euro Quality of Life Five 
Dimensions Questionnaire: 5 Level version; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment 
2.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
202 
Questionnaire-Disease Index; hsCRP = high-sensitivity C-reactive protein; 
 
; Ig = immunoglobulin; IL; = interleukin; MTX = methotrexate; PBO = placebo; PGA = physician 
global assessment; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; 
RA = rheumatoid arthritis; 
; RNA = ribonucleic acid; 
 SAE = serious adverse event; 
 
 SDAI = Simplified Disease Activity Index; 
 
 
RA Sub-protocol Design: 
x This is a double-blind, PBO-controlled Phase 2a study sub-protocol to evaluate the effect of 
branebrutinib (BMS-986195) in subjects with RA. All subjects will receive background 
therapy for their primary disease as appropriate. 
x Subjects will receive double-blind branebrutinib 9 mg administered orally once daily (QD) or 
branebrutinib PBO for 12 weeks (Week 0 to Week 12). Note: the last day of dosing of 
branebrutinib or PBO in the RA sub-protocol should be the day prior to the Week 12/Day 85 
visit. 
x All subjects will receive an additional 12 weeks of treatment (Week 12 to Week 24) with open-
label abatacept. 
x Treatment assignment will be randomized. Subjects will undergo screening evaluations to 
determine eligibility within 28 days prior to administration of study medication. Following the 
screening process, if eligible for study participation, subjects will be randomized in the study 
to the RA sub-protocol in a 3:1 ratio for study treatment and PBO. No stratification will be 
imposed at randomization in this sub-protocol. 
RA Sub-protocol Number of Subjects: 
It is expected that 80 subjects will be randomized in the RA sub-protocol. 
RA Sub-protocol Duration: 
The total duration of participation in the RA sub-protocol is approximately 32 weeks and will be 
divided into the following periods: screening (up to 4 weeks), double-blind, PBO-controlled 
branebrutinib treatment for 12 weeks (Week 0 to Week 12), open-label treatment with abatacept 
for an additional 12 weeks (Week 12 to Week 24), and follow-up (4 weeks). 
RA Sub-protocol Study Treatment: 
Study Drug for IM014029 
Medication 
Potency 
IP/Non-IP 
Branebrutinib 
9 mg QD, oral 
IP 
Branebrutinib PBO 
QD, oral 
IP 
Abatacept 
125 mg QW, SC 
IP 
IP = investigational product; PBO = placebo; QD = once daily; QW = once weekly; SC = subcutaneous 
 
2.0
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930168072
2.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
203 
RA Sub-protocol Statistical Methods: 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the RA sub-protocol 
is: 
x ACR50 response at Week 12 
Estimates for PBO response rates, treatment differences, and common standard deviations were 
obtained from the published literature. Sample size justification is provided below for the 
RA sub-protocol: 
Assuming a total sample size of 80 subjects randomized in a blinded fashion at a 3:1 ratio to 
branebrutinib (60 subjects) or PBO (20 subjects), there will be 82% power to detect a treatment 
difference of 30% assuming the PBO response rate is 15% in ACR50 at Week 12 given a 1 sided, 
two-group test of a difference in binomial proportions with a 5% level of significance. 
Categorical data will be summarized by treatment group as frequency counts and percentages. 
Continuous data will be summarized by treatment group using n, mean, standard deviation, 
median, minimum, and maximum unless otherwise specified. Efficacy data will be summarized 
separately for each sub-protocol and with each sub-protocol combined for variables that are similar 
among the sub-protocols. Primary analysis for each sub-protocol will be performed after all 
subjects finish the study within a sub-protocol. There will be no alpha level adjustment for multiple 
endpoint testing. 
Response rates of branebrutinib compared to PBO for binary endpoints (responder/nonresponder) 
will be analyzed using a Chi-square test. The 95% CIs for each treatment group response rate and 
the difference in response rate for branebrutinib compared to PBO will be provided. If expected 
cell counts are not sufficient, then Fisher’s exact test will be used. 
Logistic regression models may be used in supportive analyses to incorporate additional covariates 
of interest. 
Continuous endpoints (change from baseline values) will be analyzed using analysis of covariance. 
The baseline value of the endpoint being tested will be added into the model as a covariate. 
Treatment differences based on least-squares means and corresponding 2-sided 95% CIs will be 
provided for the difference between branebrutinib and PBO. Bayesian borrowing to utilize 
historical controls may also be performed as supportive analyses. Details will be provided in the 
SAP if needed. 
Nonresponder imputation will be used for binary endpoints for subjects who discontinue study 
treatment early, start a protocol-prohibited medication/therapy prior to the specified timepoint, or 
otherwise have missing endpoint data for the specified timepoint. 
Supportive analyses for continuous endpoints may be performed using MMRM to investigate 
response over time with treatment, visit, treatment-by-visit interaction as the fixed effects and the 
baseline value of the endpoint as a covariate. 
2.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
204 
TEAEs and SAEs will be summarized using counts and percentages of subjects experiencing the 
event as well as the number of events by system organ class, preferred term, and treatment group. 
Physical examinations findings, vital signs, clinical laboratory test results, and ECG test results 
will be summarized using descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) for continuous variables and frequency distributions (counts and percentages) for 
categorical variables. Safety data will be summarized separately for each sub-protocol and with all 
sub-protocols combined. 
RA 1.2 
Schema 
ACPA = anti-citrullinated protein/peptide antibody; ACR = American College of Rheumatology; CRP = C-reactive 
protein; IR = inadequate response; QD = once daily; QW = once weekly; RA = rheumatoid arthritis; 
SC = subcutaneous; SJC = swollen joint count; TJC = tender joint count; w = week 
For the RA sub-protocol, abatacept 125 mg will be administered SC QW from Week 12 to 
Week 24. 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
205 
RA 1.3 
Schedule of Activities 
RA Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Eligibility Assessments 
 
 
Informed Consent 
X 
A subject is considered enrolled only when a protocol-specific ICF is signed; this includes subjects at preselected 
clinical sites consenting to participate in extended PK sampling in addition to the sampling scheduled for all 
study subjects. 
Enroll subject in the IRT 
system 
X 
 
Inclusion/Exclusion Criteria 
X 
Includes: 
Documented RA diagnosis (< 4 years before screening) as defined by ACR/EULAR 2010 standard criteria. 
ACR global functional status Class I to III. 
MTX-IR based on investigator’s judgment. 
RA History; RA-related 
Treatment 
X 
 
General Medical History 
X 
 
History of Tobacco Use 
X 
Nonsmoker, light or heavy smoker. 
Patient-reported Outcomes 
 
 
SGA of Disease Activity  
X 
Collected on eCOA device (refer to Section RA 8.1.1.4). 
HAQ-DI 
X 
Collected on eCOA device (includes pain VAS for ACR calculation; refer to RA 8.1.1.1). 
EQ-5 D-5 L 
X 
Collected on eCOA device (refer to Section RA 8.1.1.3). 
PROMIS-Fatigue 6 a 
X 
Collected on eCOA device (refer to Section RA 8.1.1.2). 
Safety Assessments 
 
 
Physical Examination 
X 
Complete physical examination. 
Physical Assessments  
X 
 
Vital Signs 
X 
Includes height (screening only) and weight, body temperature (ear or oral), respiratory rate, seated BP, and 
seated heart rate. BP and heart rate should be measured after the subject has been resting quietly for at least 
5 minutes. 
ECG 
X 
ECGs should be recorded after the subject has been supine for at least 5 minutes. 
2.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
206 
RA Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
Chest Imaging (eg, Chest 
X-ray) 
X 
 Chest imaging is required if not performed within 6 months of screening visit; copy of radiology report must be 
on file and reviewed by the investigator. 
Prior and Concomitant 
Medication Use 
X 
Includes prescription, over-the-counter medications, and herbal supplements. All concomitant medications to be 
reviewed by the Medical Monitor and clinical pharmacology asset lead. 
SAE Assessment 
X 
All SAEs must be collected from the time of signing the consent, including those thought to be associated with 
protocol-specified procedures and within 30 days of discontinuation of dosing or subject’s participation in the 
study if the last scheduled visit occurs at a later time. 
Clinical Assessments 
 
 
Tender/Swollen Joint Count 
(68/66) 
X 
Performed by independent joint count assessor. Collected on eCOA device (refer to Section RA 8.1.2.1). 
PGA 
X 
Performed by investigator. Collected on eCOA device (refer to Section RA 8.1.2.2). 
MRI of the hand/wrist that is 
clinically most swollen at 
screening will be imaged 
using a whole-body MRI 
system (RAMRIS) a 
X 
Perform approximately 14 days prior to randomization to allow review by imaging core lab and perform repeat, if 
required. MRI results obtained as part of the first screening instance may be used for rescreening, if the MRI 
performance date is within 30 days of randomization. (Refer to Section RA 8.1.2.3). 
Composite Assessments of 
Disease Activity 
 
 
CDAI 
X 
Composite score calculated programmatically (Refer to Section RA 8.1.3). 
SDAI 
X 
Composite score calculated programmatically (Refer to Section RA 8.1.3). 
DAS28-CRP, DAS28-ESR 
X 
Composite score calculated programmatically (Refer to Section RA 8.1.3). 
Laboratory Tests 
 
Includes blood and urine samples. 
Hematology 
X 
CBC with differential. 
Serum Chemistry Panel 
X 
Includes liver function testing. 
Lipid Panel 
X 
Nonfasting. 
Urinalysis 
X 
 
HbA1c 
X 
,I+E$FFRQVXOW0HGLFDO0RQLWRU. 
TSH 
X 
If out of normal range (high or low), consult the Medical Monitor. 
2.0
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930168072
2.0
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Approved
1.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
207 
RA Table 1 
Screening Procedural Outline Branebrutinib Study IM014029 
Procedure 
Screening 
(V1) 
Notes 
UPCR 
X 
 
eGFR 
X 
 
ESR b 
X 
Performed at site. 
ACPA 
X 
$&3$ U/mL (with a cut-off value of 10 U/mL for the central laboratory) as inclusion criterion. 
RF 
X 
 
hsCRP 
X 
Collected as central laboratory assessment. 
Serology 
X 
Includes HCV antibody, HBsAg, HbsAb, HbcAb, and HIV antibodies. 
TB Test (IGRA; eg, 
QuantiFERON®-TB Gold) 
X 
 
Pregnancy Test  
(serum or urine) 
X 
WOCBP only. Must have negative pregnancy test within 24 hours prior to the start of treatment. 
FSH 
X 
For select women only, serum FSH level will be determined to confirm menopausal status. See APPENDIX 4 for 
definition and Section RA 5.1 for reproductive status inclusion criteria. 
Biomarker Assessments 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 ACR = American College of Rheumatology; 
 BP = blood pressure; 
CBC = complete blood count; CDAI = Clinical Disease Activity Index; CRP = C-reactive protein; 
; DAS = Disease 
Activity Score; ECG = electrocardiogram; eCOA = Electronic Clinical Outcome Assessment; eGFR = estimated glomerular filtration rate; EQ-5 D-5 L = Euro 
Quality of Life 5 Dimensions Questionnaire: 5-Level version; ESR = erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; 
FSH = follicle-stimulating hormone; HAQ-DI = Health Assessment Questionnaire – Disability Index; HbcAb = hepatitis B core antibody; HbsAb = hepatitis B 
surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
hsCRP = high-sensitivity C-reactive protein; ICF = informed consent form; IGRA = interferon gamma-release assay; 
; IRT = interactive response 
technology; MRI = magnetic resonance imaging; MTX-IR = methotrexate-inadequate response; PA = posterior-anterior; PGA = Physician Global Assessment; 
PK = pharmacokinetic; PROMIS = Patient-reported Outcomes Measurement Information System; RA = rheumatoid arthritis; RAMRIS = Rheumatoid Arthritis 
Magnetic Resonance Imaging Scoring System; 
; RF = rheumatoid factor; RNA = ribonucleic acid; 
2.0
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930168072
2.0
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
208 
; SAE = serious adverse event; SDAI = Simplified Disease Activity Index; SGA = Subject Global Assessment; TB = 
tuberculosis; 
 VAS = visual analog scale; WOCBP = women of childbearing potential 
a The MRI conducted at screening is considered the baseline MRI for the study. If a subject requires rescreening, the MRI results obtained as part of the first 
screening instance may be used for the rescreening as long as the MRI performance date is within 30 days of randomization (scoring is done by a central imaging 
vendor). 
b ESR laboratory samples should be collected and recorded by an unblinded staff member who does not perform/have access to other subject procedures, including 
joint counts. All ESR laboratory samples after screening should be collected and recorded in a blinded fashion. (Refer to RA 8.4.5). 
 
 
 
 
 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1. Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
209 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 12) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
(EOT) a 
Notes 
Patient-reported 
Outcomes 
 
 
 
 
 
 
SGA of Disease Activity 
X 
X 
X 
X 
X 
Collected on eCOA device (refer to Section RA 8.1.1.4). 
HAQ-DI 
X 
X 
X 
X 
X 
Collected on eCOA device (includes pain VAS for ACR calculation; 
refer to Section RA 8.1.1.1). 
EQ-5 D-5 L 
X 
 
 
 
X 
Collected on eCOA device (refer to Section RA 8.1.1.3). 
PROMIS-Fatigue 6 a 
X 
 
 
 
X 
Collected on eCOA device (refer to Section RA 8.1.1.2). 
Safety Assessments 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
X 
 
Targeted Physical 
Examination 
 
X 
X 
X 
 
 
Body Weight 
X 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
Temperature (ear or oral), respiratory rate, seated BP, and seated heart 
rate; BP and heart rate should be measured after the subject has been 
resting quietly for at least 5 minutes. 
ECG 
X 
X 
X 
X 
X 
ECGs should be recorded after the subject has been supine for at least 
5 minutes. 
Concomitant Medication 
Use 
X 
X 
X 
X 
X 
 
AE and SAE Assessment 
X 
X 
X 
X 
X 
Nonserious AEs must be collected from the time of the first dose of 
the study drug through the date of the follow-up or last visit. 
Clinical Assessments 
 
 
 
 
 
 
Tender/Swollen/Painful 
Joint Count (68/66) 
X 
X 
X 
X 
X 
Performed by independent joint count assessor. Collected on eCOA 
device (Refer to Section RA 8.1.2.1). 
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930168072
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
210 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 12) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
(EOT) a 
Notes 
PGA 
X 
X 
X 
X 
X 
Performed by investigator. Collected on eCOA device (Refer to 
Section RA 8.1.2.2). 
MRI of the hand/wrist that 
is clinically most swollen 
at screening will be imaged 
using a whole-body MRI 
system (RAMRIS) b 
 
 
 
 
X 
Perform within 7 days of scheduled visit (Refer to Section RA 
8.1.2.3). 
Composite Assessments 
of Disease Activity 
 
 
 
 
 
 
CDAI 
X 
X 
X 
X 
X 
Composite score calculated programmatically (Refer to Section RA 
8.1.3). 
SDAI 
X 
X 
X 
X 
X 
Composite score calculated programmatically (Refer to Section RA 
8.1.3). 
DAS28-CRP, DAS28-ESR 
X 
X 
X 
X 
X 
Composite score calculated programmatically (Refer to Section RA 
8.1.3). 
ACR 20/50/70 
X 
X 
X 
X 
X 
Composite score calculated programmatically (Refer to Section RA 
8.1.3). 
Laboratory Tests 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
Serum Chemistry Panel 
X 
X 
X 
X 
X 
 
Lipid Panel (Fasting) 
X 
 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
 
eGFR 
X 
X 
X 
X 
X 
 
Beta-2-microglobulin 
X 
X 
X 
X 
X 
 
ESR c 
X 
X 
X 
X 
X 
Performed at site. 
 
 
 
 
 
 
 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
211 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 12) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
(EOT) a 
Notes 
 
 
 
 
 
 
 
 
RF 
X 
 
X 
X 
X 
 
hsCRP 
X 
X 
X 
X 
X 
Collected as central laboratory assessment. 
Pregnancy Test (serum or 
urine) 
X 
 
X 
X 
X 
WOCBP only. Must have negative pregnancy test within 24 hours 
prior to the start of treatment. 
TBNK 
X 
X 
X 
 
X 
 
Serum IgM, IgG, IgA, IgE, 
free Kappa/Lambda light 
chains 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
PK Assessments 
 
 
 
 
 
 
Standard blood samples for 
the PK assessment of 
branebrutinib d 
X 
 
X 
X 
 
Refer to Section RA 8.5, RA Table 9 for details. 
Blood samples at 
preselected sites for the PK 
assessment of 
branebrutinib and 
metabolites e 
X 
 
 
X 
 
Refer to Section RA 8.5, RA Table 9 for details. 
Blood samples for the PK 
assessment of concomitant 
medications f 
X 
 
X 
 
 
Refer to Section RA 8.5, RA Table 9 for details. 
Blood sample for the PK 
assessment of abatacept g 
 
 
 
 
X 
Predose only (sample is not required, if Week 12 is a subject’s EOT 
visit). 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
212 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 12) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
(EOT) a 
Notes 
Biomarkers 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
Randomize 
X 
 
 
 
 
 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
213 
RA Table 2 
Procedural Outline Branebrutinib Study IM014029 (Week 0 to Week 12) 
Procedure 
W0 
D1 
V2 
W2 
D15 
(± 3 d) 
V3 
W4 
D29 
(± 3 d) 
V4 
W8 
D57 
(± 3 d) 
V5 
W12 
D85 
(± 3 d) 
V6 
(EOT) a 
Notes 
Dispense/Administer Study 
Treatment 
X 
X 
X 
X 
X j, k 
Note: At Week 2 the subject is requested to bring IP to the site visit 
and IP is administered at the site; no new kit is dispensed at this visit. 
Study Treatment 
Compliance 
 
X 
X 
X 
X 
 
 ACR = American College of Rheumatology; AE = adverse event; 
; BP = blood 
pressure; BTK = Bruton’s tyrosine kinase; CDAI = Clinical Disease Activity Index; 
 DAS28-CRP = Disease Activity 
Score 28-C-reactive protein; DAS28-ESR = DAS28-erythrocyte sedimentation rate; DNA = deoxyribonucleic acid; dsDNA = double-stranded deoxyribonucleic 
acid; ECG = electrocardiogram; eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; EOT = end of treatment; EQ-5D-5L = Euro 
Quality of Life 5 Dimensions Questionnaire: 5-Level version; ESR = erythrocyte sedimentation rate; FU = follow-up; HAQ-DI = Health Assessment Questionnaire 
Disability Index; hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; 
; IP = investigational product; MRI = magnetic resonance 
imaging; PBO = placebo; PGA = Physician Global Assessment; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; 
RAMRIS = Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System; 
; 
RF = rheumatoid factor; RNA = ribonucleic acid; SAE = serious adverse event; SDAI = Simplified Disease Activity Index; SGA = Subject Global Assessment; 
; TBNK = T cells, B cells, natural killer cells; 
 V = visit; 
WOCBP = women of childbearing potential 
a  If the decision has been made for a subject to permanently discontinue treatment before the planned Week 12 visit (Section RA 7.1.1), the subject should undergo 
a Week 12 EOT visit, as specified in the Week 12 column of this table (RA Table 2) followed by a Week 28 Safety FU visit, 4 weeks (±3 days) later, as specified 
in the Week 28 column (RA Table 3). The appropriate eCRF pages for the EOT and Safety FU visits should be completed accordingly. 
b  Same hand/wrist imaged aWVFUHHQLQJVXEMHFWVZKRWHUPLQDWHWKHVWXG\HDUO\UHTXLUHDQ05,DWWKH(27YLVLWRQO\LIWKDWYLVLWLV 4 weeks from the date of 
UDQGRPL]DWLRQRU 4 weeks from Week 12 and should have the EOT MRI no more than 7 days from the EOT visit. 
c ESR laboratory samples should be collected and recorded by an unblinded staff member who does not perform/have access to other subject procedures, including 
joint counts. All samples after screening should be collected and recorded in a blinded fashion. (Refer to Section RA 8.4.5). 
d Blood samples for the PK assessment of branebrutinib concentrations will be taken predose in all study subjects on Week 0 (Day 1), and Week 8 (Day 57) and 
postdose at Week 8 (Day 57) at approximately 0.5, 1, 2, and 4 hours after dosing. At Week 4 (Day 29), samples will be taken predose only for the assessment 
of steady-state trough concentration of branebrutinib. 
e At preselected clinical sites with extended sampling: blood samples will be taken from subjects at Week 0 (Day 1) and Week 8 (Day 57) at 0 hours (predose), 
and postdose at approximately 0.5, 1, 2, 4, and at 6 hours and from 8-10 hours (flexible window), 10-12 hours (flexible window), and at Week 0 (Day 2) at 24 
hours after dosing (predose of branebrutinib on Day 2); collected blood samples will be divided into 2 tubes at each time point for the PK assessment of 
branebrutinib and its metabolites concentrations. 
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Clinical Protocol 
IM014029 - RA 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
214 
f Blood samples for PK assessment of relevant concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant drug metabolizing 
enzymes and P-gp transporter may be measured (post-hoc); as such, the levels of exposure for subjects receiving PBO and active treatment will be collected at 
Week 0 (Day 1) and Week 4 (Day 29) predose and 2 hours postdose. 
g Blood sample for PK of abatacept not required if this is subject’s EOT visit. 
  
 
 
 
 
 
j The last day of dosing of branebrutinib or PBO in the RA sub-protocol should be the day prior to the Week 12/Day 85 visit. 
k First dose of abatacept is to be administered at the Week 12 visit. 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1. Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
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RA Table 3 
Procedural Outline Branebrutinib Study IM014029: Open-label Abatacept Therapy (Week 14 to 
Week 28) 
Procedure 
Week 14 
D99 
(± 3 d) 
V7 
Week 16 
D113 
(± 3 d) 
V8 
Week 20 
D141 
(± 3 d) 
V9 
Week 24 
D169 
(± 3 d) 
V10 
(EOT) a 
Week 28 
D197 (±3 d) 
V11 
Safety FU 
Notes 
Patient-reported Outcomes 
SGA of Disease Activity  
X 
X 
X 
X 
X 
Collected on eCOA device (refer to 
Section RA 8.1.1.4). 
HAQ-DI 
X 
X 
X 
X 
X 
Collected on eCOA device (includes 
pain VAS for ACR calculation; refer to 
Section RA 8.1.1.1). 
EQ-5 D-5 L 
 
 
 
X 
X 
Collected on eCOA device (refer to 
Section RA 8.1.1.3). 
PROMIS-Fatigue 6 a 
 
 
 
X 
X 
Collected on eCOA device (refer to 
Section RA 8.1.1.2). 
Safety Assessments 
Complete Physical Examination 
 
 
 
 
X 
 
Targeted Physical Examination 
X 
X 
X 
X 
 
 
Body Weight 
 
X 
 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
Temperature (ear or oral), respiratory 
rate, seated BP, and seated heart rate; 
BP and heart rate should be measured 
after the subject has been resting 
quietly for at least 5 minutes. 
ECG 
X 
X 
X 
X 
X 
ECGs should be recorded after the 
subject has been supine for at least 
5 minutes. 
Concomitant Medication Use 
X 
X 
X 
X 
X 
 
AE and SAE Assessment 
X 
X 
X 
X 
X 
Nonserious AEs must be collected 
from the time of the first dose of the 
study drug through the date of the 
follow-up or last visit. 
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RA Table 3 
Procedural Outline Branebrutinib Study IM014029: Open-label Abatacept Therapy (Week 14 to 
Week 28) 
Procedure 
Week 14 
D99 
(± 3 d) 
V7 
Week 16 
D113 
(± 3 d) 
V8 
Week 20 
D141 
(± 3 d) 
V9 
Week 24 
D169 
(± 3 d) 
V10 
(EOT) a 
Week 28 
D197 (±3 d) 
V11 
Safety FU 
Notes 
Clinical Assessments 
Tender/Swollen Joint Count (68/66) 
X 
X 
X 
X 
X 
Performed by independent joint count 
assessor. Collected on eCOA device 
(Refer to Section RA 8.1.2.1). 
PGA 
X 
X 
X 
X 
X 
Performed by investigator. Collected 
on eCOA device (Refer to 
Section RA 8.1.2.2). 
MRI of the hand/wrist that is clinically 
most swollen at screening will be 
imaged using a whole-body MRI 
system. (RAMRIS) b 
 
 
 
X 
 
Perform within 7 days of scheduled 
visit (Refer to Section RA 8.1.2.3). 
Composite-Assessments of Disease Activity 
CDAI  
 
X 
 
X 
X 
Composite score calculated 
programmatically (Refer to 
Section RA 8.1.2.1). 
SDAI 
X 
X 
X 
X 
X 
Composite score calculated 
programmatically (Refer to 
Section RA 8.1.2.1). 
DAS28-CRP, DAS28-ESR 
X 
X 
X 
X 
X 
Composite score calculated 
programmatically (Refer to 
Section RA 8.1.2.1). 
ACR 20/50/70 
X 
X 
X 
X 
X 
Composite score calculated 
programmatically (Refer to 
Section RA 8.1.2.1). 
Laboratory Tests  
Hematology 
X 
X 
X 
X 
X 
 
Serum Chemistry Panel 
X 
X 
X 
X 
X 
 
Lipid Panel (Fasting) 
 
X 
 
X 
X 
 
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RA Table 3 
Procedural Outline Branebrutinib Study IM014029: Open-label Abatacept Therapy (Week 14 to 
Week 28) 
Procedure 
Week 14 
D99 
(± 3 d) 
V7 
Week 16 
D113 
(± 3 d) 
V8 
Week 20 
D141 
(± 3 d) 
V9 
Week 24 
D169 
(± 3 d) 
V10 
(EOT) a 
Week 28 
D197 (±3 d) 
V11 
Safety FU 
Notes 
Urinalysis 
X 
X 
X 
X 
X 
 
HbA1c 
 
 
 
X 
X 
 
eGFR 
X 
X 
X 
X 
X 
 
ESR c 
X 
X 
X 
X 
X 
Performed at site. 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
RF 
 
X 
X 
X 
X 
 
hsCRP 
X 
X 
X 
X 
X 
Collected as central laboratory 
assessment. 
TBNK 
X 
X 
 
X 
X 
 
Serum IgM, IgG, IgA, IgE, free 
Kappa/Lambda light chains 
 
X  
  
X 
X 
 
Pregnancy Test (serum or urine) 
 
X 
X 
X 
X 
WOCBP. 
Immunogenicity (abatacept) 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
PK Assessments 
Blood samples for the PK assessment 
of abatacept  
X 
X 
X 
X 
X 
Refer to Section RA 8.5, RA Table 10 
Biomarker Sampling 
  
 
 
 
 
 
 
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RA Table 3 
Procedural Outline Branebrutinib Study IM014029: Open-label Abatacept Therapy (Week 14 to 
Week 28) 
Procedure 
Week 14 
D99 
(± 3 d) 
V7 
Week 16 
D113 
(± 3 d) 
V8 
Week 20 
D141 
(± 3 d) 
V9 
Week 24 
D169 
(± 3 d) 
V10 
(EOT) a 
Week 28 
D197 (±3 d) 
V11 
Safety FU 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
Dispense/Administer Study Treatment 
X 
X 
X 
 
 
At Week 14 the subject is requested to 
bring IP to the site visit and IP is 
administered at the site; no new kit is 
dispensed at this visit. No IP 
administered or dispensed at Week 24. 
Study Treatment Compliance 
X 
X 
X 
X 
X f 
 
; ACR = American College of Rheumatology; AE = adverse event; 
 
 CDAI = Clinical Disease Activity Index; 
; DAS28 = Disease Activity Score 28; 
DNA = deoxyribonucleic acid; 
 ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
EQ-5D-5L = Euro Quality of Life 5 Dimensions Questionnaire: 5-Level version; ESR = erythrocyte sedimentation rate; ET = early termination; FU = follow-up; 
HAQ-DI = Health Assessment Questionnaire Disability Index; hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; 
; 
IP = investigational product; MRI = magnetic resonance imaging; PGA = Physician Global Assessment; PK = pharmacokinetic; PROMIS = Patient-Reported 
Outcomes Measurement Information System; RAMRIS = Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System; 
 
 RF = rheumatoid factor; RNA = ribonucleic acid; SAE = serious adverse event; SDAI = Simplified Disease Activity Index; 
SGA = Subject Global Assessment; 
 TBNK = T cells, B cells, natural killer cells; 
V = visit; WOCBP = women of childbearing potential. 
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a If the decision has been made for a subject to permanently discontinue (Section RA 7.1.1) treatment with abatacept before the planned Week 24 visit, the subject 
should undergo a Week 24 EOT visit as specified in the Week 24 column of this table followed by a Week 28 Safety FU visit, 4 weeks (±3 d) later, as specified 
in the Week 28 column of this table. The appropriate eCRF pages for the EOT and Safety FU visits should be completed accordingly. 
b  Same hand/wrist imaged at screening. Subjects who terminate the study early should have the ET MRI no more than 7 days from the EOT visit. 
c ESR laboratory samples should be collected and recorded by an unblinded staff member who does not perform/have access to other subject procedures, including 
joint counts. All ESR laboratory samples after screening should be collected and recorded in a blinded fashion. (Refer to RA 8.4.5). 
 
 
 
 
 
 
f Study treatment compliance is to be performed at Week 28 only if the subject’s study participation has completed and the subject failed to return study drug at 
the prior visit. 
 
When multiple assessments are conducted at a single visit, the following is the order in which they should be performed: 
1. Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
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RA 2 
INTRODUCTION 
An overall introduction to this protocol employing a master protocol design for 3 separate 
immune-mediated indications is provided in Section Master 1.2. 
RA 2.1 
Background and Research Hypothesis 
The Study IM014029 RA sub-protocol is designed to evaluate the efficacy and safety of 
branebrutinib in addition to background disease therapy in the treatment of subjects with moderate 
to severe adult-onset RA (see Section RA 4.4). The RA sub-protocol will also evaluate the safety 
and efficacy of switching to 12 weeks of treatment with abatacept after 12 weeks of treatment with 
branebrutinib or placebo. 
RA is a systemic immune-mediated disease affecting 0.5 to 1.0% of the population that targets the 
joints (large and small), which develop synovial inflammation, leading to swelling, pain, stiffness, 
and dysfunction.22 Constitutional symptoms such as fatigue, fever, and malaise are not uncommon 
and contribute to reduced quality of life. Additionally, patients with RA have a high risk for 
cardiovascular morbidity and reduced life span that correlates with disease severity, including an 
increased risk of cardiovascular disease.23 
Despite recent progress in RA with a number of medications approved in the US and Europe,12 
unmet medical needs remain.24 First, many agents approved for RA treatment have significant 
safety concerns, including the risk of serious or chronic infections, malignancies, and 
gastrointestinal perforation. Second, many patients respond only partially to currently available 
therapies, not many patients ever experience the end of RA destructive processes, and only a 
minority of patients (< 10%) achieve true remission. Treatments that reduce osteoclasts and bone 
resorption may help to address some of these unmet medical needs.25 
BTK inhibition is expected to inhibit antigen-dependent B cell signaling and function without 
depleting B cells,2 leading to reduction of IgG-containing ICs signaling in monocytic cells, and 
decreases in IC-mediated production of pro-inflammatory cytokines. Some evidence suggests that 
this may also reduce IgE-containing signaling in mast cells and basophils.8, 9, 10, 11 These processes 
include key pathogenic mechanisms of immune-mediated diseases. 
In RA, ICs are present in the joints and act on synovial macrophages to drive the production of 
cytokines, chemokines, and MMPs mediating disease pathology. Expression of Ig receptors 
)FȖ5,,DDQG)FȖ5,,,DLVLQFUHDVHGLQPRQRF\WHVPDFURSKDJHVIUom RA patients,26, 27, 28 and these 
FHOOVSURGXFHKLJKHUOHYHOVRI71)ĮDQG003VWKDQLQKHDOWK\FRQWUROV26 6LJQDOLQJWKURXJK)FȖ
receptors is important in the activation of monocyte-derived dendritic cells.29 Genome-wide 
association studies have identiILHG )FȖ5,,,D WR EH DVVRFLDWHG ZLWK 5$ VXVFHSWLELOLW\30 
Additionally, murine models of RA such as the CIA model have suggested a critical role of 
DFWLYDWLQJ)FȖUHFHSWRUVLQGLVHDVHSDWKRJHQHVLV31, 32 BTK is expressed in high levels in myeloid 
lineages and regulates the signaling pathways leading to expression of pro-inflammatory 
cytokines, chemokines, and cell adhesion molecules that are induced through IC binding to 
)FȖ5,,,D DQG )FȖ5,,D %7. KDV DOVR EHHQ LPSOLFDWHG LQ )FȖ5, VLJQDOLQJ LQ PDVW FHOOV DQG
basophils.5, 6, 7, 33, 34 
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Mast cells may contribute to the pathobiology of RA. The IgE ACPAs are present in patients with 
RA,10 and the number of activated mast cells are increased in synovial tissue and correlate with 
disease activity.8, 9, 11 Thus, inhibition of BTK will be tested to determine whether it has therapeutic 
benefit in RA. 
BTK inhibition may also have a direct effect on bone damage in RA through its role on 
osteoclastogenesis. The differentiation of osteoclasts, which mediate bone destruction in RA, is 
regulated by RANKL acting through the RANK receptor on osteoclast precursors, and BTK has 
been shown to regulate RANK-dependent osteoclastogenesis.35, 36 
In summary, this study will test whether effects of BTK inhibition on antigen-specific 
BCR-mediated B cell functions, IgG-FRQWDLQLQJ,&VLJQDOLQJWKURXJK)FȖUHFHSWRUVLQPRQRF\WLF
cells, IgE-containing signaling through the BTK-GHSHQGHQW UHFHSWRU )Fİ5, LQ PDVW FHlls and 
basophils, as well as RANK-dependent osteoclastogenesis, could provide benefit in the treatment 
of RA. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of branebrutinib is 
provided in the IB.12 
The RA sub-protocol will also evaluate the safety and efficacy of switching to 12 weeks of 
treatment with abatacept after 12 weeks of treatment with branebrutinib or placebo. A PBO control 
for branebrutinib is included in the RA sub-protocol to allow the effects of treatment, both desired 
and adverse, to be appropriately attributed to the treatment received. Safety monitoring, including 
laboratory monitoring, will be ongoing throughout the study, for subjects in all treatment arms, 
along with an independent DMC. 
RA 2.1.1 Study Hypotheses 
BTK plays a role in the pathology of RA. The first hypothesis to be tested is that BTK inhibition 
provides benefit in the treatment of moderate to severe adult-onset RA. The second hypothesis to 
be tested is to assess the safety and efficacy after switching from branebrutinib to abatacept. 
RA 2.2 
Benefit/Risk Assessment 
RA 2.2.1 Branebrutinib 
At this early stage in the development of branebrutinib for the treatment of immune-mediated 
disorders, assessments of benefit and risk rely on nonclinical data and data from completed Phase 1 
studies in healthy volunteer subjects. The proposed 9 mg QD dosing regimen reflects 
implementation of appropriate safety margins (> 500× based on the AUC in rats and dogs at the 
NOAEL [20 mg/kg/day and 15 mg/kg/day in rats and dogs, respectively]) and is within the range 
of doses tested in the FIH study (Study IM01400137). 
The effects of BTK inhibition by branebrutinib have been documented in pharmacology studies, 
and the potential for benefit has been demonstrated by nonclinical studies using mouse models of 
RA (see details of nonclinical toxicology findings and potential clinical benefits of branebrutinib 
in Section 1.5.1 Master Protocol: Benefit/Risk Assessment). 
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With the exception of an unrelated SAE that was consistent with the subject’s medical history, 
AEs in the FIH study (Study IM01400137) were mild to moderate, reversible, and consistent with 
expectations based on nonclinical experience. 
Based upon nonclinical toxicology findings and the mechanism of action of the compound 
(immunosuppression), BMS has also proactively implemented additional assessments, frequent 
study visits for safety assessments, risk mitigation approaches, and blinded safety reviews by BMS 
and an independent external DMC (see details in Section 1.5.1 Master Protocol: Benefit/Risk 
Assessment). 
All subjects in the RA sub-protocol will receive either branebrutinib or PBO treatment for a 
maximum of 12 weeks while receiving protocol-defined SOC therapy for their RA. All subjects in 
the RA sub-protocol will also receive open-label abatacept from Week 12 to Week 24. 
The risk for DDIs of branebrutinib with substrates of a number of enzymes and transporters are 
expected to be minimal, with the exception of drugs that are sensitive substrates of CYP2C8 and 
P-gp as a weak inhibitor (which may be restricted or excluded based on their therapeutic window 
and metabolism), as are developmental and reproductive effects of the study treatment in WOCBP 
(see details in Section 1.5 Master Protocol: Benefit/Risk Assessment). 
RA 2.2.2 Open-label Therapy with Abatacept 
Abatacept, a soluble fusion protein that consists of the extracellular domain of human CTLA-4 
linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human IgG1, is a selective 
co-stimulation modulator that inhibits T cell activation by binding to CD80 and CD86 molecules 
on antigen-presenting cells, thereby inhibiting interaction with CD28. 
Abatacept is a biologic compound approved for the treatment of patients with active RA (see the 
abatacept IB48 for properties and mechanisms of action of abatacept). 
In clinical studies, abatacept demonstrated clear, consistent, and medically important benefit in the 
treatment of signs and symptoms of RA, improving physical function, reducing the progression of 
structural damage, and improving the quality of life in subjects with moderate to severe RA who 
were MTX-naïve, or were inadequate responders to MTX or anti-TNF therapies.49 
With over 27,754 patient-years of abatacept exposure, clinical studies of abatacept provide 
extensive experience characterizing the safety and efficacy/effectiveness of abatacept.49 Review 
of safety data from the ongoing long-term extensions of the clinical studies reveals a consistent 
safety profile for abatacept over time. However, there are inherent limitations to the assessment of 
infrequent AEs in clinical programs. Abatacept was first approved in 2005. Since that time, there 
have been an estimated 648,974 patient-years of exposure to abatacept in the marketplace. 
Postmarketing reports have not altered the favorable benefit-risk profile for abatacept and its safety 
profile remains generally similar to that established during the clinical studies. There remains 
limited information in patients with hepatic and renal impairment, and use in elderly subjects. 
Based on the clinical study experience in adults, the identified risks associated with the use of 
abatacept include infections (some of which may be serious or fatal), infusion-related reactions 
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(IV only), and systemic injection reactions (SC only).49 The main potential risks include the 
development of malignancies and immune-mediated disorders, but an increased risk of these types 
of events has not been observed. The rate of immunogenicity has generally been low, and there 
has not been an apparent effect on safety, efficacy, or PK. 
With regard to the developmental and reproductive effects of abatacept, the study treatment has 
been shown to have no effects on male or female fertility in rats, no teratogenic effects in rats and 
rabbits at doses up to 200 mg/kg daily (29-fold higher than the human 10 mg/kg dose based on 
AUC in rats and rabbits), and no adverse effects in offspring of rats treated with abatacept during 
early gestation and throughout the lactation period at doses up to 45 mg/kg (threefold higher than 
the human 10 mg/kg dose based on AUC). Abatacept has also been shown to cross the placenta in 
rats and rabbits. Because animal reproduction studies are not always predictive of human response, 
and because there are no adequate and well-controlled studies of abatacept use in pregnant women, 
pregnant and breastfeeding women will not be enrolled in this study and WOCBP will use 
protocol-specified highly effective contraceptive methods (APPENDIX 4). Further details of 
developmental/reproductive/toxicity effects of abatacept are provided in Section 1.5.2 
Master Protocol: Benefit/Risk Assessment and in the Abatacept Development Safety Update 
Report50. 
Detailed information about the known and expected benefits and risks and reasonably anticipated 
AEs of branebrutinib and abatacept are provided in the branebrutinib IB12 and the abatacept IB48, 
respectively. 
In summary, nonclinical data and clinical experience with branebrutinib in healthy subjects, and 
clinical experience with abatacept in subjects with RA, taken together with the design and study 
treatment dose selected for the current Phase 2a study indicate an overall favorable benefit/risk 
assessment for investigating branebrutinib treatment, and treatment of branebrutinib followed by 
abatacept, in subjects with RA. 
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RA 3 
OBJECTIVES AND ENDPOINTS 
RA Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
x 
To compare the efficacy of branebrutinib with PBO 
at Week 12 in the treatment of subjects with 
moderate to severe RA on a stable background of 
MTX who have had an inadequate response to MTX 
x 
ACR50 response compared to baseline 
Secondary/Additional 
Branebrutinib therapy: Day 1 to Week 12 
x 
To compare the efficacy of branebrutinib with PBO 
at Week 12 in the treatment of subjects with 
moderate to severe RA on a stable background of 
MTX who have had an inadequate response to MTX 
Secondary: 
x 
Changes in efficacy measures, including 
DAS28-CRP and DAS28-ESR, SDAI, and 
CDAI 
x 
ACR20 and ACR70 response compared to 
baseline 
Additional: 
x 
Change from baseline in autoantibody titers, 
change from baseline in BTK occupancy 
x 
Change from baseline in ACR component 
assessments: 
 
Tender/Painful Joint Count (68) 
 
Swollen Joint Count (66) 
 
PGA of Arthritis 
 
Subject Global Assessment of Disease 
activity 
 
hsCRP 
 
HAQ-DI 
x 
Change from baseline in RAMRIS scores of 
synovitis, osteitis (bone marrow edema), bone 
erosion, and cartilage loss (joint-space 
narrowing) 
x 
Change from baseline in the EQ-5 D-5 L score 
x 
Change from baseline in PROMIS Fatigue 6 a 
Additional 
Open-label abatacept therapy: Week 12 to Week 24 
x 
To evaluate the efficacy at Week 24 of switching 
from branebrutinib or PBO to abatacept at Week 12 
in the treatment of subjects with moderate to severe 
RA on a stable background of MTX who have had 
an inadequate response to MTX 
Additional: 
x 
Changes from Week 12 at Week 24 in efficacy 
measures, including DAS28-CRP, DAS28-ESR, 
SDAI, and CDAI 
x 
ACR20, ACR50, and ACR70 response at 
Week 24 based on activity at Week 12 after 
pretreatment with branebrutinib or PBO 
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RA Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
(treatment effect of abatacept following 
treatment with branebrutinib versus PBO) 
x 
Change from Week 12 to Week 24 in 
autoantibody titers, change from Week 12 to 
Week 24 in BTK occupancy 
x 
Change from Week 12 to Week 24 in ACR 
component assessments: 
 
Tender/Painful Joint Count (68) 
 
Swollen Joint Count (66) 
 
PGA of Arthritis 
 
Subject Global Assessment of Disease 
Activity 
 
hsCRP 
 
HAQ-DI 
x 
Change from Week 12 to Week 24 in RAMRIS 
scores of synovitis, osteitis (bone marrow 
edema), bone erosion, and cartilage loss 
(joint-space narrowing) 
x 
Change from Week 12 to Week 24 in the 
EQ-5 D-5 L score 
x 
Change from Week 12 to Week 24 in PROMIS 
Fatigue 6 a 
Additional 
Branebrutinib followed by open-label abatacept therapy: Day 1 to Week 24 
x 
To evaluate the efficacy at Week 24 of branebrutinib 
or PBO treatment followed by abatacept treatment in 
subjects with moderate to severe RA on a stable 
background of MTX who have had an inadequate 
response to MTX 
Additional: 
x 
Changes from baseline at Week 24 in efficacy 
measures, including DAS28 CRP, DAS28-ESR, 
SDAI, and CDAI 
x 
ACR20, ACR50, and ACR70 response at 
Week 24 compared to baseline 
x 
Change from baseline at Week 24 in 
PROMIS Fatigue 6 a 
Safety 
x 
To evaluate the safety and tolerability of switching 
from branebrutinib or PBO to abatacept in subjects 
with RA 
x 
Number and proportion of subjects experiencing 
SAEs, AEs, and abnormalities in laboratory 
parameters, vital signs, and ECGs 
Exploratory 
x 
Evaluate the PK of branebrutinib and metabolites of clinical interest 
 
 
 
 
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RA Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ACR = American College of Rheumatology; 
ADME = absorption, distribution, metabolism, and excretion; AE = adverse event; 
; 
 
r; 
BTK = Bruton’s tyrosine kinase; C = complement; CDAI = Clinical Disease Activity Index; CRP = C-reactive protein; 
CS = corticosteroid; CXCL13
 DAS28 = Disease Activity Score 28; 
; ECG = electrocardiogram; EQ-5 D-5 L = Euro Quality of Life Five 
Dimensions Questionnaire: 5 Level version; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment 
Questionnaire-Disease Index; hsCRP = high-sensitivity C-reactive protein; 
 
 Ig = immunoglobulin; IL; = interleukin; MTX = methotrexate; PBO = placebo; PGA = physician 
global assessment; PK = pharmacokinetic; PROMIS = Patient-Reported Outcomes Measurement Information System; 
RA = rheumatoid arthritis; 
; RNA = ribonucleic acid; 
 SAE = serious adverse event; 
 
; 
 SDAI = Simplified Disease Activity Index; 
 ; 
 
 
RA 4 
STUDY DESIGN 
RA 4.1 
Overall Design 
This is a double-blind, PBO-controlled multicenter study to assess the effect of branebrutinib 
treatment and branebrutinib followed by abatacept (also named BMS-188667 and Orencia™) 
125 mg SC QW in subjects with moderate to severe adult-onset RA. 
x The RA study population will consist of male and female subjects aged 18 years (or age of 
majority) to 75 years inclusive at screening with moderate to severe adult-onset RA. 
x Approximately 80 subjects will be randomized to the RA sub-protocol. Sample size 
considerations are presented in Section RA 9.1 Sample Size Determination. 
x For all subjects there will be a 12-week double-blind PBO-controlled treatment period in which 
subjects will receive branebrutinib 9 mg or branebrutinib PBO. Note: the last day of dosing of 
branebrutinib or PBO in the RA sub-protocol should be the day prior to the Week 12/Day 85 
visit. 
x Blinded treatment assignment will be conducted by randomization on Day 1 and managed by 
IRT. Subjects will undergo screening evaluations to determine eligibility within 28 days prior 
to administration of study medication. After successfully meeting entry criteria and completing 
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screening assessments, subjects will be randomized (3:1 ratio) in a blinded manner to 
branebrutinib 9 mg or PBO QD. 
x No stratification will be imposed at randomization in this sub-protocol. 
x The total duration of participation in the RA sub-protocol will be approximately 32 weeks and 
will be divided into the following periods: screening (up to 4 weeks), double-blind 
PBO-controlled treatment with branebrutinib for 12 weeks (Week 0 to Week 12), open-label 
abatacept treatment for an additional 12 weeks (Week 12 to Week 24), and follow-up 
(4 weeks). 
x Efficacy and safety will be assessed throughout the study (see Section RA 8.1 Efficacy 
Assessments, Section RA 8.2 Adverse Events, and Section RA 8.4 Safety for details of 
assessments). Blood samples will be collected for PK and biomarker clinical laboratory 
assessments (see Section RA 8.5 and Section RA 8.6, respectively, for details of assessments). 
x An independent DMC will assess study findings on a periodic basis (Section RA 4.1.1). 
The RA study design schematic is found in Section RA 1.2. 
RA 4.1.1 DMC and Other External Committees 
To ensure the safety of study subjects, across all sub-protocols, an external independent DMC 
consisting of 2 experienced rheumatologists, an infectious disease clinician, and a statistician will 
be established for ongoing evaluation of safety assessments, AEs, and laboratory measurements. 
An independent reporting statistician not involved in the conduct of the study will be designated 
to provide the DMC with essential safety data unblinded to treatment during the study, if required. 
The DMC will conduct at regular, prespecified intervals and on an ad hoc basis if warranted, safety 
review meetings throughout the study to ensure that the benefit and risks of study participation 
remain acceptable. Ad hoc meetings may be initiated by the DMC or by the Sponsor based on 
emerging new safety information. Based on the DMC’s assessment, recommendations of protocol 
modifications or other actions may occur, including but not limited to sample size adjustment, 
study modification, or discontinuation of the study or one or more of the sub-studies. In addition, 
hold of enrollment, pending more detailed assessment may be requested. 
Blinded SUSARs will be sent to the DMC members on an ongoing basis. SAEs will be sent to the 
DMC on a monthly basis or on an ongoing basis as requested by the DMC. 
The DMC will review safety data including but not limited to SAEs and AEIs. At the request of 
the DMC, designated personnel will provide further information on the medical assessment for a 
specific case. 
The DMC may also consider external data from other branebrutinib studies that may be initiated 
in future or from novel scientific information that may be generated on branebrutinib or other BTK 
inhibitors. 
Further details of DMC responsibilities, specific timing of safety reviews, content, and methods of 
data reports, authorities, processes, and procedures will be specified in the DMC charter. 
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RA 4.2 
Number of Subjects 
It is expected that approximately 80 subjects will be randomized in the RA sub-protocol. 
Further details regarding sample size determination are provided in Section RA 9.1. 
RA 4.3 
End of Study Definition 
The start of the study is defined as the date that the first subject signs the informed consent. The 
end of the RA sub-protocol is defined as the last visit of the last subject to complete the study or 
the final scheduled procedure shown in the SoA (Section RA 1.3). Study completion for the RA 
sub-protocol is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same. The master protocol study will be reported only after the 
last endpoint has been analyzed for all 3 sub-protocols. 
The total duration of study participation for subjects in the RA sub-protocol is expected to be 
approximately 32 weeks. 
RA 4.4 
Scientific Rationale for Study Design 
(Please refer to Master Section 1.2 for rationale supporting the choice of a master protocol design 
to evaluate the safety and efficacy of branebrutinib in 3 immune-mediated/autoantibody-related 
diseases.) 
In the RA sub-protocol, for ethical reasons, the branebrutinib PBO treatment arm will be limited 
to 12 weeks to limit duration of treatment without active treatment, beyond background therapy, 
in subjects with active disease. This design is aligned with regulatory guidance on PBO arms in 
studies with subjects with active RA.88 All subjects in the RA sub-protocol, including the 
branebrutinib PBO arm, will also continue receiving background MTX during the study. 
The standard approved dose of abatacept (125 mg SC QW) was selected for open-label treatment 
for all subjects from Week 12 to Week 24., given the acceptable safety profile of abatacept at this 
approved dose for RA, Safety monitoring, including laboratory monitoring, will be ongoing 
throughout the study for subjects in this sub-protocol, along with an independent DMC. 
Complete details of the study design are provided in Section RA 4.1. 
RA 4.5 
Justification for Dose 
The selection of the branebrutinib dose and regimen to be assessed in this study was based on 
findings in the FIH and nonclinical studies. 
In the MAD panels (Part B) of the FIH study (Study IM014001), healthy subjects received 
branebrutinib solution QD for 14 days at 4 dose levels (0.3, 1, 3, and 10 mg; n = 6 per dose).37 
Increases in Cmax and AUC(TAU) were approximately dose proportional within the dose levels 
tested. The mean T-HALF was shorter than 2 hours across the dose range tested, indicating that 
branebrutinib was rapidly eliminated from the body. Consequently, as expected, accumulation at 
steady-state after multiple daily dosing was negligible. 
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The safety between branebrutinib 3 mg and 10 mg doses in Study IM014001 demonstrated lack of 
dose effects on safety profile. The drug was well-tolerated at both dose levels with most AEs also 
observed for the subjects treated with PBO. The AEs mainly included headache and upper 
respiratory tract infection. Based on the AUC in rats at the NOAEL (61,900 QJKP/WKHVDIHW\
multiple in humans after multiple doses of 10 mg is > 500×.12 In this study, the dose level of 
branebrutinib will be 9 mg; therefore, the safety margin is sufficient for humans participating in 
the study. 
The dose for branebrutinib was selected based on the totality of data from multiple biomarkers 
obtained through post-hoc analysis from Study IM014001. The biomarkers evaluated were BTK 
occupancy by branebrutinib, inhibition of ex vivo stimulated CD69 expression, and plasma 
&;&/OHYHOV7KHPD[LPXPRFFXSDQF\UHDFKHGDWEUDQHEUXWLQLEGRVHVRI mg and 
above (1 PD[LPXP RFFXSDQF\ DW GRVHV   mg); however, the time to reach maximum 
occupancy was faster and maintained for a longer duration at 3 mg and 10 mg doses (solution 
formulation). The variability of the effect was lower for the higher dose of 10 mg. A similar result 
was obtained for CD69 inhibition, while the largest median inhibition in CD69 expression was 
observed at the branebrutinib 10 mg dose. The highest inhibition of plasma levels of CXCL13 was 
also obtained at the 10 mg dose level. Considering the higher variability and expression of BTK 
in patients with RA and other immune-mediated disorders,4 the higher dose is expected to sustain 
more stable inhibition of BTK for chronic treatment of patients. 
The comparison of exposure between the branebrutinib 10 mg solution formulation from 
Study IM014001 and the branebrutinib 9 mg capsule formulation (3 × 3 mg) from Day 1 Cycle 2 
in Study IM014023 demonstrated comparable exposure for Cmax and AUC(TAU) with only slight 
delay in Tmax for capsule formulation. Thus, the use of 3 × 3 mg capsules of branebrutinib is 
expected to be equivalent to the 10 mg solution formulation in terms of exposure, safety, and PD 
effects considering the specifics of the patient population. 
The exposure for this dose level is also much lower than the safety limit for exposure identified in 
preclinical studies; as previously mentioned, based on the AUC in rats at the NOAEL, the safety 
multiple in humans after multiple doses of 10 mg is > 500×. 
In summary, the dose to evaluate the PD response with high-level, safe exposure and achieve 
optimal efficacy was chosen to be 9 mg branebrutinib administered as 3 × 3 mg capsules (details 
of treatment administration are provided in Section RA 6.1). 
With regard to use of abatacept, it is proposed that this study be conducted using the abatacept SC 
125 mg prefilled syringe with weekly administration in subjects with RA; the same dose and 
dosing regimen used in patients with RA in Study IM101174,38 as well as the approved dose of 
this biologic used in the treatment of active RA. Study IM101174 clearly established that the 
weekly 125 mg SC and monthly ~10 mg/kg IV dosing were therapeutically equivalent in RA, with 
both dosing regimens consistently delivering abatacept Cminss of 10 μg/mL and above, the 
exposure associated with near-maximal efficacy response in RA, in patients across all body 
weights. 
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RA 5 
STUDY POPULATION 
Eligibility criteria for this sub-protocol have been carefully considered for the safety of the study 
subjects and to ensure that the results of the study can be interpreted. It is imperative that 
randomized subjects meet all eligibility criteria. 
Screening evaluations must be completed and reviewed to confirm whether potential subjects are 
eligible. The investigator will maintain a screening log to record details of all subjects screened 
and to confirm eligibility or record reasons for screening failure, as applicable. 
RA 5.1 
Inclusion Criteria 
To be eligible to participate in the RA sub-protocol for this study, an individual must meet all of 
the following criteria: 
1) Signed Written Informed Consent: RA Sub-protocol 
a) Willing to participate in the study after completing all informed consent procedures and 
sign the ICF 
b) Willing and able to complete all study-specific procedures and visits 
2) Age and Reproductive Status: RA Sub-protocol 
a) Not Applicable per Revised Protocol 02 - Male and female patients, aged 18 years (or 
age of majority) to 65 years, inclusive 
b) Not Applicable per Revised Protocol 02 - WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/ RU HTXLYDOHQW XQLWV RI ȕ-HCG) within 
24 hours prior to the start of study treatment. 
c) Not Applicable per Revised Protocol 02 - Women must not be breastfeeding. 
d) Not Applicable per Revised Protocol 02 - WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) 
branebrutinib or PBO, 30 days before screening and 33 days posttreatment completion or 
longer based on country-specific label for other background therapy. After Week 12, due 
to the use of abatacept study treatment, the subject must agree to follow instructions for 
contraception for 70 days after the final dose of study treatment, or longer based on 
country-specific label for other background therapy. 
e) Not Applicable per Revised Protocol 02 - Male subjects who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception and fetal 
protection (APPENDIX 4) for the duration of treatment with study treatment(s) plus 
33 days after the final dose of study treatment, or longer based on country-specific label 
for other background therapy. In addition, male subjects must be willing to refrain from 
sperm donation during this time. 
f) Not Applicable per Revised Protocol 02 - WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements, and still must undergo 
pregnancy testing as described in this section. 
g) This criterion does not exist. Letter g) was omitted in error in Revised Protocol 02. 
h) This criterion does not exist. Letter h) was omitted in error in Revised Protocol 02. 
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i) This criterion does not exist. Letter i) was omitted in error in Revised Protocol 02. 
j) This criterion does not exist. Letter j) was omitted in error in Revised Protocol 02. 
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention, the implications of an unexpected pregnancy and the 
potential of fetal toxicity occurring due to transmission of study drug, present in seminal fluid, to 
a developing fetus, even if the participant has undergone a successful vasectomy or if the partner 
is pregnant. 
x The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention. 
x Local laws and regulations may require the use of alternative and/or additional contraception 
methods. 
k) Not Applicable per Revised Protocol 03 - Female Participants 
l)  Not Applicable per Revised Protocol 03 - Male Participants 
m) Female Subjects 
i. 
Females, ages 18 years or local age of majority to 75 years, inclusive 
ii. 
Women subjects must have documented proof that they are not of childbearing 
potential. Women who are not of childbearing potential are exempt from 
contraceptive requirements 
iii. 
WOCBP must have a negative highly sensitive pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study 
treatment. 
1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive 
iv. 
Additional requirements for pregnancy testing during and after study intervention are 
located in Section RA 1.3, SoA 
v. 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy 
vi. 
WOCBP must agree to follow instructions for method(s) of contraception defined in 
APPENDIX 4 and as described below and included in the ICF. 
vii. 
WOCBP are permitted to use hormonal contraception methods (as described in 
APPENDIX 4) 
viii. 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
1) Is not a WOCBP 
OR 
2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described in 
APPENDIX 4 during the intervention period, for at least 30 days before screening 
and at least 33 days posttreatment completion or longer based on country-specific 
label for other background therapy and agrees not to donate eggs (ova, oocytes) for 
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the purpose of reproduction for the same time period. After Week 12, due to the 
use of abatacept study treatment, the participant must agree to use a contraceptive 
method that is highly effective for 14 weeks posttreatment completion or longer 
based on country-specific label for other background therapy and must agree not to 
donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. 
n) Male Subjects 
i. 
Males, ages 18 years or local age of majority to 75 years, inclusive 
ii. 
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in APPENDIX 4 and as described below. 
iii. 
Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP even if the participant has undergone a 
successful vasectomy or if the partner is pregnant. 
iv. 
Male subjects will be required to always use a latex or other synthetic condom during 
any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the subjects have 
undergone a successful vasectomy or if their partner is already pregnant or 
breastfeeding. Males should continue to use a condom during the intervention period 
and for at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
v. 
Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 
33 days after the last dose of study intervention in the male participant or longer based 
on country-specific label for other background therapy. 
vi. 
Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, 
anal, oral) even if the subjects have undergone a successful vasectomy, during the 
intervention period and for at least 33 days after the last dose of study intervention or 
longer based on country-specific label for other background therapy. 
vii. 
Male subjects must refrain from donating sperm during the intervention period and 
at least 33 days after the last dose of study intervention or longer based on 
country-specific label for other background therapy. 
viii. 
Breastfeeding partners should be advised to consult their healthcare providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms. 
3) Type of Subject and Target Disease Characteristics: RA Sub-protocol 
a) Not Applicable per Revised Protocol 03 - Documented diagnosis of adult-onset RA as 
defined by American College of Rheumatology (ACR)/EULAR 2010 standard criteria 
< 2 years before screening 
b) ACR global functional status Class I to III 
c) Not Applicable per Revised Protocol 03 - MTX-IR based on investigator’s judgment; 
MTX requirements are as follows: 
i. 
Subjects must have been taking MTX for at least 3 months at a minimal weekly dose 
of 15 mg (maximum 25 mg/week) and at a stable dose and administration route for 
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4 weeks before randomization. A lower dose of MTX is permitted if documented that 
a dose of 15 mg weekly was not possible due to toxicity or intolerance and the dose 
is at least 10 mg MTX at the screening visit. 
ii. 
In Canada, and any other applicable country, a minimum dose of 7.5 mg per week is 
permitted. 
iii. 
Subjects using IM or SC MTX for administration of their weekly dose are eligible. 
d)  Minimum of 6 swollen and 6 tender joints on a 66/68 joint count at the screening and 
baseline visit. 
e) Evidence of swelling in at least 1 joint of the hand or wrist by clinical examination at the 
screening and baseline visit. 
f) &HQWUDOODERUDWRU\UHVXOWVIRUKV&53 0.6 mg/dL (6 mg/L) or site laboratory results for 
(65 28 mm/hour at the screening visit. These may be retested 1 time during screening 
period, if initial screening results are not within inclusion level. 
g) $&3$ SRVLWLYH  30 U/mL (with a positive cut-off value of 10 U/mL for the central 
laboratory). 
h) Documented diagnosis of adult-onset RA as defined by American College of 
Rheumatology (ACR)/EULAR 2010 standard criteria < 4 years before screening. 
i) MTX-IR based on investigator’s judgment; MTX requirements are as follows: 
i. 
6XEMHFWVPXVWKDYHEHHQWDNLQJ07;IRUZHHNVDWDPLQLPDOZHHNO\GRVHRI
15 mg (maximum 25 mg/week) and at a stable dose and administration route for 
12 weeks before randomization. A lower dose of MTX is permitted if documented 
that a dose of 15 mg weekly was not possible due to toxicity or intolerance and the 
dose is at least 10 mg MTX at the screening visit. 
ii. 
In Canada, and any other applicable country, a minimum dose of 7.5 mg per week is 
permitted. 
iii. 
Subjects using IM or SC MTX for administration of their weekly dose are eligible. 
4) Medications for Target Disease: RA Sub-protocol 
a) Requirements for subjects who are receiving chronic therapy with NSAIDs (including 
marketed cyclooxygenase-2 inhibitors) are as follows; exceptions or changes may be 
possible with approval by the 
 Medical Monitor: 
i. 
The NSAID dose must be stable for 14 days before the screening visit and must remain 
stable until randomization and throughout the study. 
ii. 
No more than 1 oral NSAID may be used (at a stable dose) during the study and may 
be combined with topical NSAIDs. 
iii. 
Use of 1 or more topical NSAID is permitted, but must follow a stable regimen 
throughout the study. 
b) Not Applicable per Revised Protocol 03 - 6WDQGDUGRIFDUHLVUHTXLUHGIRU 12 weeks 
EHIRUHWKHVFUHHQLQJYLVLWDQGPXVWEHDWDVWDEOHGRVHIRU 8 weeks before the screening 
visit and remain stable until randomization and throughout study participation. Details for 
specific medications are as follows: 
i. 
MTX: Subjects must have been taking MTX for at least 12 weeks at a minimal 
weekly dose of 15 mg (maximum 25 mg/week) and at a stable dose and 
administration route for 4 weeks before randomization. A lower dose of MTX is 
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permitted if documented that a dose of 15 mg weekly was not possible due to toxicity 
or intolerance and the dose is at least 10 mg MTX at the screening visit. 
ii. 
Oral CS use is SHUPLWWHGEXWWKHGRVHPXVWEH 10 mg/day prednisone or equivalent 
DQGVWDEOHIRU 28 days before randomization and throughout study participation. 
Further specifications are as follows: 
1) Topical and inhaled CS use is permitted but must follow a stable regimen 
throughout the study and cannot be used on an as-needed basis. Inhaled CS for 
non-RA conditions will not count against the maximum CS dose. 
2) IM, IA, intrabursal, IV, and modified-release CS use is prohibited within 
4 weeks before screening 
c) SOC is UHTXLUHGIRU 12 weeks before the screening visit and must be at a stable dose for 
 8 weeks before the screening visit and remain stable until randomization and throughout 
study participation. Details for specific medications are as follows: 
i. 
MTX: SubjectVPXVWKDYHEHHQWDNLQJ07;IRUZHHNVDWDPLQLPDOZHHNO\
dose of 15 mg (maximum 25 mg/week) and at a stable dose and administration route 
for 12 weeks before randomization. A lower dose of MTX is permitted if documented 
that a dose of 15 mg weekly was not possible due to toxicity or intolerance and the 
dose is at least 10 mg MTX at the screening visit. 
ii. 
2UDO&6XVHLVSHUPLWWHGEXWWKHGRVHPXVWEH 10 mg/day prednisone or equivalent 
DQGVWDEOHIRU 28 days before randomization and throughout study participation. 
Further specifications are as follows: 
1) Topical and inhaled CS use is permitted but must follow a stable regimen 
throughout the study and cannot be used on an as-needed basis. Inhaled CS for 
non-RA conditions will not count against the maximum CS dose. 
2) IM, IA, intrabursal, IV, and modified-release CS use is prohibited within 
4 weeks before screening. 
5) Other Inclusion Criteria: RA Sub-protocol 
a) Subject re-enrollment (rescreening): This study permits the re-enrollment of a subject that 
has discontinued the study as a pretreatment (screening) failure (ie, subject has not been 
randomized/has not been treated). If re-enrolled, the subject must be re-consented. 
RA 5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in the 
RA sub-protocol: 
1) General Medical Conditions and History: RA Sub-protocol 
a) Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, psychiatric) or 
local active infection/infectious illness that, in the investigator’s judgment, will 
substantially increase the risk to the subject if he or she participates in the study 
b) Any major surgery within the last 30 days before the first dose of study treatment, or any 
surgery planned during the course of the study 
c) Cancer or history of cancer or lymphoproliferative disease (other than adequately treated 
cutaneous basal cell or squamous cell carcinoma with no evidence of recurrence within the 
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previous 5 years), including pre-lymphoma (pseudolymphoma of the orbit and small 
intestine, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, and 
lymphoid interstitial pneumonitis) 
d) Class III or IV congestive heart failure as defined by the NYHA or any recent onset of 
heart failure resulting in NYHA Class III/IV symptoms 
e) Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or any 
history of significant cerebrovascular disease within 24 weeks before screening 
f) Current or recent (within 3 months before randomization) gastrointestinal disease, 
including gastrointestinal surgery, that could impact the absorption of study treatment 
g) Not Applicable per Revised Protocol 03 - Subjects with non-RA concomitant illness that, 
in the opinion of the investigator, is likely to require additional systemic 
glucocorticosteroid therapy during the study (eg, asthma) 
h) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks before 
randomization 
i) Inability to tolerate oral medication 
j) Inability to tolerate venipuncture and/or inadequate venous access 
k) Recent (within 6 months before randomization) drug or alcohol abuse as defined by the 
Diagnostic Criteria for Drug and Alcohol Abuse in the DSM 5 
l) Subjects with a diagnosis of antiphospholipid antibody syndrome 
m) Contraindication to magnetic resonance imaging (MRI); eg, magnetizable metallic 
parts/devices including cardiac pacemakers on and in the body, severe claustrophobia, 
body size incompatible with the scanner, sensitivity to gadolinium, severe renal 
insufficiency (ie, glomerular filtration rate (GFR) < 30 mL/min/1.73 m2), and metallic 
tattoos. Complete contraindications are provided in the site MRI manual; however, the 
ultimate decision about subject appropriateness for MRI will be made by the radiologist 
and investigator in accordance with local standards and ethics committees. 
n) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator 
o) Any prior history of atrial fibrillation or flutter 
p) Subjects with non-RA concomitant illness that, in the opinion of the investigator, is likely 
to require additional systemic CS therapy during the study (eg, asthma) 
2) Findings Related to Possible Infection: RA Sub-protocol 
a) Not applicable per Revised Protocol 03 - Any of the following TB criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment 
o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) during 
screening as judged by the investigator 
o Any imaging of the chest (eg, chest x-ray, chest CT scan) obtained during the screening 
period, or anytime within 6 months prior to screening with documentation, showing 
evidence of current active or old pulmonary TB 
o LTBI defined as positive IGRA, by QuantiFERON-TB Gold testing at screening, in the 
absence of clinical manifestations Note: Subject may be eligible if (i) there are no 
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current signs or symptoms of active TB and (ii) subject has received adequate 
documented treatment for LTBI within 5 years of screening. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB must 
be retested for confirmation. If the second test is again indeterminate the subject will 
be excluded from the study. If the retest is positive, the subject should be treated as 
having LTBI. If the retest is negative, subject may be eligible provided no other 
exclusion criteria for TB are met. 
b) Not Applicable per Revised Protocol 03 - Hepatitis C, hepatitis B, or HIV infection as 
demonstrated by a positive blood screen for anti-HCV confirmed by positive reflex HCV 
RNA test, HBsAg, HbcAb, or HIV-1 and -2 antibody. Subjects who have been vaccinated 
for hepatitis B (hepatitis B surface antibody [HbsAb]-positive) are not excluded. 
c) Not Applicable per Revised Protocol 03 - Note: Subjects who are newly found to be 
HIV-positive should be directed to appropriate follow-up care. 
d) History of congenital or acquired immunodeficiency 
e) Known active infection, or any major episode of infection requiring hospitalization or 
treatment with parenteral (IM or IV) antimicrobial agents (eg, antibiotics, antiviral, 
antifungal, or antiparasitic agents) within 30 days of randomization, or completion of oral 
antimicrobial agents within 2 weeks of randomization 
f) Previous history of recurrent herpes zoster (more than 1 episode), disseminated herpes 
simplex, or influenza infection within 12 weeks before randomization or a history of 
disseminated/complicated herpes zoster infection (multidermatomal involvement, 
ophthalmic zoster, CNS involvement, or postherpetic neuralgia) 
g) Chronic infection within 4 weeks of randomization (eg, pneumocystis, CMV, invasive 
bacterial or fungal infections, or atypical mycobacteria) 
h) Hospitalized with PCR-proven or suspected COVID-19 infection (unless for 
quarantine/observation) within the 3 months prior to randomization, as well any sequelae 
of prior COVID-19 infection at screening, regardless of time since infection. 
i) Any of the following criteria: 
o History of active TB prior to screening visit, regardless of completion of adequate 
treatment 
o Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) during 
screening as judged by the investigator 
- Any imaging of the chest (eg, chest x-ray, chest CT scan) obtained during the 
screening period, or anytime within 6 months prior to screening, with 
documentation showing evidence of current active or old pulmonary TB. 
o LTBI defined as positive IGRA, by QuantiFERON-TB Gold testing at screening, in the 
absence of clinical manifestations Note: Subject may be eligible if (i) there are no 
current signs or symptoms of active TB and (ii) subject has received adequate 
documented treatment for LTBI within 5 years of screening; this treatment must have 
been completed as defined by local guidance and documented in the subject study file. 
Incomplete or ongoing treatment is unacceptable. 
Note: An IGRA test that is indeterminate with no signs or symptoms of active TB must 
be retested for confirmation. If the second test is again indeterminate, the subject will 
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be excluded from the study, unless there is documentation of a local negative TB Spot 
test result. If the retest is positive, the subject should be treated as having LTBI. If the 
retest is negative, the subject may be eligible provided no other exclusion criteria for 
TB are met. 
j) Hepatitis C, hepatitis B, or HIV infection as demonstrated by a positive blood screen for 
anti-HCV confirmed by positive reflex HCV RNA test, HBsAg, HbcAb, or HIV-1 and 2 
antibody. Subjects who have been vaccinated for hepatitis B (hepatitis B surface antibody 
[HbsAb]-positive) are not excluded. 
Note: Subjects who are newly found to be HIV-positive should be directed to appropriate 
follow-up care. 
3) Allergies and Adverse Drug Reaction: RA Sub-protocol 
a) History of allergy to BTK inhibitors or related compounds 
b) History of any serious condition induced by drug allergy (such as anaphylaxis or 
hepatotoxicity) 
4) Target Disease Exclusions/Exceptions: RA Sub-protocol 
a) Subjects with juvenile arthritis diagnosis or idiopathic arthritis onset before age 16 are 
excluded. 
b) Subjects with documented Felty’s syndrome are excluded. 
c) Subjects with psoriatic arthritis are excluded. 
d) Subjects with active fibromyalgia with pain symptoms or signs that would interfere with 
joint assessment or requiring adjustment in medication within the 3 months before 
screening to control symptoms are excluded. Subjects with fibromyalgia that is well 
controlled on stable treatment may otherwise be considered. 
5) Prior/Concomitant Therapy: RA Sub-protocol 
a) Inability to comply with restrictions and prohibited treatments as listed in Section RA 6.7 
Concomitant Therapy; inability to comply with discontinuation requirements 
(Section RA 7.1). 
b) Prior exposure to BTK inhibitors 
c) Other investigational agents must be discontinued at least 12 weeks or 5 half-lives before 
screening, whichever is longer. 
d) Previous exposure to JAK inhibitors such as tofacitinib, baricitinib, filgotinib, or 
upadacitinib. 
e) Required discontinuation periods for immunomodulatory drugs (eg, cyclosporine, 
tacrolimus, etc.) or biologic drugs (including those specifically listed below) are provided 
in RA Table 7. If a drug is not specifically listed, consult the 
 Medical Monitor for 
guidance. Usual discontinuation periods are 4 weeks or 5 half-lives whichever is longer. 
f) Current or past use of rituximab. 
g) Current or past use of belimumab. 
h) Subjects who have taken leflunomide within 36 weeks prior to screening and during the 
study. 
i) Subjects who have taken IVIG within 8 weeks of randomization and during the study. 
j) For oral CS restrictions, see Section RA 5.1. 
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k) IM, IV, IA, intrabursal, or modified-release CS treatment 4 weeks before randomization 
and during the study. 
l) Treatment with DMARDs (including hydroxychloroquine) or immunomodulators other 
than MTX 4 weeks before randRPL]DWLRQWKH07;GRVHPXVWEHVWDEOHIRU 12 weeks; 
new initiation or dose changes during treatment are not permitted. Hydroxychloroquine use 
is also prohibited during the study. 
m) Not Applicable per Revised Protocol 03 - Use of antimalarial drugs (chloroquine and 
quinacrine) is prohibited within 4 weeks before randomization and during the study. 
n) Not applicable per Revised Protocol 03 - Current or past approved or investigational 
biologic DMARD treatments (eg, TNF-inhibitors, IL-6 inhibitors, IL-1 inhibitors, T cell 
modulators, and anti-CD20 agents) are prohibited at any time prior to the study or during 
WKH VWXG\ ZLWK WKH H[FHSWLRQ RI 07; GRVH PXVW EH VWDEOH IRU  12 weeks before 
randomization and new initiation or dose changes during treatment are not permitted). 
Abatacept therapy is prohibited at any time prior to the study. 
o) Subjects who have taken denosumab within 6 months before randomization and during the 
study; bisphosphonates are permitted 
p) Not Applicable per Revised Protocol 03 - Administration of a live vaccine within 90 days 
or an inactivated vaccine within 30 days before randomization; furthermore, live and 
inactivated vaccines should not be used during treatment and should not be used within the 
90 days or 14 days following last dose, respectively. 
q) Treatment with anticoagulant or antiplatelet therapies, including aspirin for 
cardioprotection, within 2 weeks prior to randomization or during the study. 
r) Diquafosol or rebamipide therapy within 4 weeks before randomization or during the 
study. 
s) Use of antimalarial drugs (HCQ, chloroquine and quinacrine) is prohibited within 12 weeks 
before randomization and during the study. 
t) Current or past approved or investigational biologic DMARD treatments (eg, 
TNF-inhibitors, IL-6 inhibitors, IL-1 inhibitors, T cell modulators, and anti-CD20 agents) 
are prohibited at any time prior to the study or during the study. Abatacept therapy is 
prohibited at any time prior to the study. 
u) Administration of all live vaccines is prohibited within 90 days before randomization. 
Administration of inactivated vaccines and nonlive vaccines, including those for influenza 
and SARS-CoV-2, is prohibited within 30 days before randomization. See RA Table 7 for 
corresponding on-treatment and posttreatment restrictions. 
6) Physical and Laboratory Test Findings: RA Sub-protocol 
a) Clinically significant abnormalities on chest x-ray or ECG 
b) Clinically significant abnormalities in laboratory tests including the following: 
i. 
Serum ALT > 1.5× ULN. 
ii. 
Serum AST > 1.5× ULN. 
iii. 
Serum total bilirubin > 1.5× ULN (does not apply to subjects with Gilbert’s 
syndrome). 
iv. 
Hemoglobin < 8 g/dL (< 80 g/L). 
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v. 
eGFR < 50 mL/min/1.73 m2 as calculated by the central laboratory; follow MTX 
usage guidelines with eGFR < 60 mL/min/1.73 m2. 
vi. 
Serum creatinine > 2.0 mg/dL (> 177 ȝPRO/ 
vii. 
Absolute WBC count < 3.0× 103ȝ/ 3.0× 109/L). 
viii. 
Neutrophil count < 1000/ȝ/ 1.0× 109/L). 
ix. 
Platelet count < 100× 103ȝ/ 100× 109/L). 
c) Any other significant laboratory or procedure abnormalities that, in the opinion of the 
investigator, might pose unacceptable risk to the subject during the study. 
d) BP > Grade 1 hypertension (> 159 mmHg systolic and > 99 mmHg diastolic) according to 
the 2018 ESC/ESH Guidelines for the management of arterial hypertension 
e) The following exclusionary ECG observations: 
i. 
QTcF: > 480 msec 
ii. 
QRS: > 120 msec 
iii. 
Complete heart block 
iv. 
Left bundle branch block 
v. 
Mobitz II second-degree atrioventricular block 
vi. 
Atrial fibrillation or flutter 
7) Other Exclusion Criteria: RA Sub-protocol 
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances and subject to local law a person who has been imprisoned may be included 
or permitted to continue as a subject. Strict conditions apply and BMS approval is 
required.) 
b) Subjects who are employed by the Sponsor, clinical research organizations, or study site 
c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
d) Inability to comply with the study protocol 
e) Inability to comply with restrictions as listed in Section RA 5.3 
RA 5.3 
Lifestyle Restrictions 
Study restrictions for contraception use by WOCBP and male subjects who are partners of 
WOCBP (APPENDIX 4) are required for this study. 
RA 5.3.1 Meals and Dietary Restrictions 
With the exception of the 8-hour fasting requirement prior to blood sample collection for lipid 
panel and fasting glucose blood testing, no meal or dietary restrictions are required for this study. 
However, subjects are advised to consume in moderation (avoiding more than a single serving a 
day) cruciferous vegetables, such as cabbage, brussels sprouts, watercress, etc, as well as grapefruit 
and Seville oranges. Quinine (tonic water), St. John’s wort and herbal medications are not allowed. 
RA 5.3.2 Caffeine, Alcohol, Tobacco, and Cannabinoids 
With the exception of cannabinoids, which are not allowed, prohibited alcohol abuse as defined 
by the Diagnostic Criteria for Drug and Alcohol Abuse in the DSM 5 within six months prior to 
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randomization, and prohibited alcohol use in subjects receiving MTX therapy (see 
Section RA 5.2), there are no restrictions on caffeine, alcohol, or tobacco use for this study. 
However, subjects who use tobacco or alcohol should be counseled for potential contraindications 
with nonstudy treatments as appropriate, and continued study participation should be based on 
investigator judgment. 
RA 5.3.3 Activity 
With the exception of the restrictions surrounding the use of contraceptives during sexual activity 
mentioned above and included in Section RA 1.3 Schedule of Activities, no activity restrictions 
are required for this study. 
RA 5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but who are 
not subsequently randomized or entered in the study or included in the analysis population. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure subjects, to meet the CONSORT publishing requirements, as applicable, and to respond to 
queries from regulatory authorities. Minimal information includes date of consent, demography, 
screen failure details, eligibility criteria, and any SAEs. Additional screening data from screen 
failure subjects, such as clinical data for disease assessment, laboratory tests, and other clinically 
relevant data, may be required. 
RA 5.4.1 Rescreening and Retesting During Screening Period 
This RA sub-protocol permits the rescreening of a subject who has been previously screen failed. 
If rescreened, the subject must be re-consented and will be assigned a new identification number, 
and a full screening visit must be performed again. A subject can only be rescreened 1 time  
(ie, if the subject fails 1 rescreening attempt, no additional rescreening is allowed). 
Laboratory parameters and/or other assessments that are included in Section RA 1.3 (Screening 
Procedural Outline for RA sub-protocol) that initially do not meet eligibility requirements within 
the screening period may be repeated once in an effort to find all possible well-qualified subjects. 
Consultation with the Medical Monitor may be needed to identify whether repeat testing of a 
parameter is clinically relevant. 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the subject’s most current clinical state. 
The MRI conducted at screening is considered the baseline MRI for the study. If a subject requires 
rescreening, the MRI results obtained as part of the first screening instance may be used for the 
rescreening, if the MRI performance date is within 30 days of randomization. 
RA 6 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), PBO, or 
medical device intended to be administered to a study subject according to the study randomization 
or treatment allocation. 
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Study treatment includes both IP/IMP and non-IP/non-IMP and is shown in RA Table 5. 
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or PBO being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
For the RA sub-protocol, it is required that all subjects have background MTX therapy but have 
had inadequate response to the treatment based on investigator’s judgment. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as noninvestigational 
products. 
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RA Table 5 
Study Treatments for IM014029 
Product Description/ 
Class and Dosage Form 
Potency 
IP/ 
Non-IMP 
Blinded or 
Open-Label 
Packaging/ 
Appearance 
Storage Conditions 
(per label) 
Branebrutinib oral capsulea 
3 mg dose × 3 capsules 
(9 mg total dose) 
IP 
Blinded 
HDPE bottles (33 capsules/bottle) with 
child-resistant cap and heat-induction 
seal (tamper-evidence and moisture 
barrier); size #0 hard gelatin capsules 
Store refrigerated at 2° to 
8°C (36° to 46°F) in 
original packaging; 
protected from moisture 
PBO matching branebrutinib 
oral capsule 
NA 
IP 
Blinded 
HDPE bottles (33 capsules/bottle) with 
child-resistant cap and heat-induction 
seal (tamper-evidence and moisture 
barrier); size #0 hard gelatin capsules 
Store refrigerated at 2° to 
8°C (36° to 46°F) in 
original packaging; 
protected from moisture 
Abatacept SC injection 
125 mg in 1 mL solution 
IP 
Open-label 
Pack of 4 single-dose disposable 
prefilled glass syringes with passive 
needle safety guard. Solution is clear to 
slightly opalescent, and colorless to 
pale-yellow. Do not use if solution 
contains particulate matter or 
discoloration. 
Store refrigerated at 2° to 
8°C (36° to 46°F) in 
original package to protect 
from light until use. Do 
not allow to freeze. 
HDPE = high-density polyethylene; IP = investigational product; NA = not applicable; PBO = placebo; SC = subcutaneous. 
a Dosages of 0.5 mg are also available but are not planned for use in the current study. 
 
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RA 6.1 
Treatments Administered 
The investigator must ensure that the IP will be used only in accordance with the protocol. The 
selection and timing of dose for each subject is shown in RA Table 6. Study treatment will be 
supplied in bottles (branebrutinib and PBO) or prefilled syringes (abatacept). If a subject forgets a 
dose, but remembers within 12 hours of the expected dose, the dose should be taken. Any dose 
> 12 hours should be missed, and the next expected dose should be taken at the usual time. No 
dose reductions or modifications are allowed. For the open-label part of the study, all efforts should 
be made to have abatacept administered weekly on the same day of the week. If a dose is missed, 
contact the 
 Medical Monitor. 
RA Table 6 
Selection and Timing of Dose 
Study Treatment 
Unit Dose 
Strength 
Dosage Formulation 
Frequency of Administration 
Route of 
Administration 
Branebrutinib 9 mg 
3 mg 
3 active capsules; QDa 
Oral 
Branebrutinib PBO 
0 mg 
3 PBO capsules; QDa 
Oral 
Abatacept 
125 mg 
Prefilled syringe; QW 
SC 
PBO = placebo; QD = once daily; QW = once weekly; SC = subcutaneous 
a The last day of dosing of branebrutinib or PBO in the RA sub-protocol should be the day prior to the Week 12/Day 85 
visit. 
Note: At all study visits, the study treatment should not be taken at home but should be taken to 
the site by the subject; at the site, the study treatment should be taken only when instructed by the 
site study staff according to the schedule listed below. These requirements also apply to 
concomitant medications at Day 1 and Week 4 only; at these visits, concomitant medications will 
be administered together with the study treatment at the site. 
When multiple assessments are conducted at a single visit, the following is the order in which they 
should be performed: 
1. Patient-reported Outcomes (eg, SGA, EQ-5 D-5 L, etc) 
2. Safety assessments (eg, vitals, AEs) 
3. Investigator-administered Assessments (eg, PGA, joint count, etc) 
4. Laboratory tests (eg, safety laboratory tests, PK assessments, biomarker assessments) 
5. Treatment dosing 
Doses of branebrutinib at 9 mg (3x3 mg capsules) or matching placebo are to be administered 
orally QD (one time/day) with water and may be taken with or without food. The drug should be 
taken every morning at approximately the same time. 
On Day 1 and at Weeks 2, 4 and 8 (Day 57), study treatment will be administered in the morning 
at the study site after blood samples have been collected and questionnaires have been completed. 
In addition, on Day 1 and at Week 4, branebrutinib will be administered together with concomitant 
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medications to allow predose sampling for concomitant medication. Branebrutinib and 
concomitant medications are to be taken together with water. 
RA 6.2 
Method of Treatment Assignment 
All subjects will be centrally randomized according to a computer-generated block randomization 
scheme using IRT to 1 of the 3 sub-protocols depending on disease type determined at screening. 
Subjects in this sub-protocol will be randomized in a 3:1 ratio to receive the same double-blind 
treatment from Week 0 to Week 12. 
Subjects in the RA sub-protocol will receive open-label abatacept from Week 12 to Week 24. 
At the time of the screening visit, the investigative site will access the enrollment option of the 
IRT system for assignment of a subject number after written informed consent is obtained and 
before any study-related procedures are performed. This number is assigned sequentially by the 
system and will be unique across all sites. If a potential subject is rescreened, a new identification 
number will be used. 
Randomized schedules will be generated by the IRT vendor. 
Stratification will not be employed. 
Before the study is initiated, each investigator will receive log-in information and directions on 
how to access the IRT. Study treatment will be dispensed at the study visits as listed in the SoA 
(Section RA 1.3). 
RA 6.3 
Blinding 
Blinded treatment assignments will be managed using IRT. All capsules (branebrutinib 3 mg and 
branebrutinib PBO) are identical in appearance. Capsules will be supplied in tamper-evident 
HDPE bottles with each daily dose made up of either active or PBO capsules (as presented in 
RA Table 5). Prefilled syringes for abatacept will be supplied in 4-packs (all 4 syringes in each 
pack will be active abatacept). Investigative site staff, Sponsor and designee personnel, and 
subjects and their families will remain blinded to treatment assignments. 
In addition to the treatment blind, results from potentially unblinding biomarkers, whole blood 
BTK occupancy and pBTK from the baseline measurements on Day 1 onward will be blinded to 
the investigator and study personnel involved in the study at both the clinical site and the Sponsor, 
as required. 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the IP 
is critical to the subject’s management, the blind for that subject may be broken by the investigator. 
The subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded. 
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the IP, the 
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problem may be properly managed by assuming that the subject is receiving active product. It is 
highly desirable that the decision to unblind treatment assignment be discussed with the Medical 
Monitor, but the investigator always has ultimate authority for the decision to unblind. The PI 
should only call in for emergency unblinding AFTER the decision to discontinue the subject has 
been made. 
In case of an emergency, the investigator has unrestricted access to randomization information via 
IRT and is capable of breaking the blind through the IRT system without prior approval from the 
Sponsor. After the unblinding, the investigator shall notify the Medical Monitor and/or study 
director. For information on how to unblind in an emergency, consult the IRT manual. Subject and 
unblinded treatment information and the reason for the blind being broken must be recorded on 
the appropriate study status page of the eCRF. After unblinding via IRT, the investigator shall 
notify the Medical Monitor. 
Any request to unblind a subject for nonemergency purposes should be discussed with the Medical 
Monitor. 
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. 
Designated staff of BMS Company may be unblinded (obtain the randomization codes) prior to 
database lock to facilitate the bioanalytical analysis of PK samples and immunogenicity. A 
bioanalytical scientist in the Bioanalytical Sciences department of BMS Company (or a designee 
in the external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples. 
RA 6.4 
Dosage Modification 
There is no provision for dose modification of study treatment. If a subject interrupts or temporarily 
discontinues treatment due to an AE, study treatment can be restarted in consultation with the 
Medical Monitor. 
RA 6.5 
Preparation/Handling/Storage/Accountability 
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and BMS or designee should be contacted immediately. 
Branebrutinib and branebrutinib PBO should be stored per labeled conditions in tamper-evident 
HDPE bottles. Abatacept should be stored per labeled conditions in prefilled syringes. 
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
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administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
Further guidance and information for final disposition of unused study treatment are provided in 
APPENDIX 2. 
RA 6.5.1 Retained Samples for Bioavailability/Bioequivalence 
At the time of receipt of the IP by the investigator or designees, BMS will specify the appropriate 
number of containers or units to select for retention, the conditions of sample storage, required 
duration of sample retention, and provisions for returning or disposing of the IP. When samples 
are selected, containers or units should be placed in packaging with a tamper-evident seal provided 
by BMS. Package labeling should clearly identify the contents as BA/BE samples and state that 
the IP should be stored in the restricted area with limited access. 
RA 6.6 
Treatment Compliance 
Study treatment compliance will be periodically monitored using standard drug accountability 
procedures (comparing the number of capsules/prefilled syringes returned to number dispensed, 
considering the expected regimen and any reported missed doses). Drug accountability will be 
reviewed by the site study staff at each visit to confirm treatment compliance. Site staff will discuss 
discrepancies with the subject at each on-treatment study visit and remind the subject of the 
importance of compliance with the assigned regimen. See Section RA 8.3 for information related 
to treatment overdose. 
RA 6.7 
Concomitant Therapy 
RA 6.7.1 Prohibited and Restricted Treatments 
Table 1 in the IM014029 Master Protocol lists exclusions and restrictions for all concomitant 
medications, regardless of indication. RA Table 7 presents prohibited and/or restricted medications 
taken by subjects with RA prior to or during study treatment administration with branebrutinib. 
All prior concomitant medications taken for RA since diagnosis must be recorded on the eCRF. 
All prior and/or concomitant medications taken for any indication within 4 weeks prior to study 
drug administration must be recorded on the eCRF. The prior use of medications after a sufficient 
washout period prior to study randomization is allowed for some medications, as indicated in the 
table and must be recorded in the eCRF. Details of prohibited (excluded) and/or restricted 
medications are provided in Section RA 5.2. 
RA Table 7 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
BTK inhibitors 
Marketed drugs, eg, ibrutinib, 
acalabrutinib 
Experimental drugs, eg, 
tirabrutinib, vecabrutinib, 
Prohibited lifetime use 
Not applicable 
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RA Table 7 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
zanubrutinib, ARQ-531, 
GDC-0853, and any others 
JAK inhibitors 
Tofacitinib, baricitinib, 
filgotinib, and upadacitinib 
Prohibited lifetime use 
Not applicable 
Oral CS 
Prednisone or equivalent 
Oral CS use is permitted, but 
WKHGRVHPXVWEH 10 mg/day 
prednisone or equivalent and 
stable for  28 days before 
randomization and throughout 
study participation 
If not continuing as 
SOC must discontinue 
4 weeks before 
randomization 
Other CS 
IM, IA, intrabursal, IV, and 
oral modified-release CS 
Prohibited during the study 
4 weeks 
 
Topical and Inhaled CS 
Must follow stable regimen 
throughout the study; cannot 
be used on as-needed basis. 
Only allowed for 
nonrheumatologic indications. 
Inhaled CS for non-RA 
conditions will not count 
against the maximum CS dose 
Not applicable 
Antimalarial drugs 
Chloroquine and quinacrine 
Prohibited during the study 
12 weeks 
 
Hydroxychloroquine 
Prohibited during the study 
12 weeks 
Anticoagulant or 
Antiplatelet 
therapies 
Anticoagulant or antiplatelet 
therapies, including aspirin 
for cardioprotection 
Treatment with anticoagulant 
or antiplatelet therapies, 
including aspirin for 
cardioprotection, within 2 
weeks prior to randomization 
or during the study 
2 weeks 
Anti-TNF therapy 
Adalimumab, certolizumab, 
etanercept, golimumab, 
infliximab, and TNF 
biosimilars 
Prohibited during the study 
History of use 
prohibited 
Biologics 
Rituximab, belimumab 
 
 
Denosumab 
Prohibited during the study 
History of use 
prohibited  
 
6 months 
 
Abatacept 
 
Lifetime (naïve) 
 
Other Biologics, including 
tocilizumab, anakinra 
 
History of use 
prohibited 
 
IVIG 
Prohibited during the study 
8 weeks 
DMARD 
MTX 
'RVHPXVWEHVWDEOHIRU
weeks before randomization. 
New initiation or dose 
Not applicable 
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RA Table 7 
Prohibited and Restricted Medications 
Type of Medication 
Examples of Medications 
Restrictions 
Required Washout 
Period Prior to and 
Postrandomization 
changes during treatment are 
not permitted. 
Other DMARDs 
Leflunomide 
Prohibited during the study 
36 weeks prior to 
screening 
 
Cyclosporine and tacrolimus 
Prohibited during the study 
8 weeks 
 
Azathioprine, sulfasalazine, 
and similar 
Prohibited during the study 
8 weeks 
 
Gold salts (sodium 
aurothiomalate, auranofin) 
(seldom used today) 
Prohibited during the study 
12 weeks 
NSAIDs 
Ibuprofen, etc 
Only 1 oral NSAID is allowed 
concurrently. 
Can be combined with 1 or 
more topical NSAID but must 
be on a stable regimen 
Not allowed on day of 
study visit until after 
study assessments. 
Non-narcotic 
analgesics 
Acetaminophen 
Brief course for up to 7 days 
allowed 
Not applicable 
Narcotic analgesics 
Oxycodone and hydrocodone 
Prohibited during the study 
Not applicable 
Immunization 
against agents other 
than influenza or 
SARS-CoV-2 
All live vaccines 
 
Nonlive vaccines 
unassociated with influenza 
or SARS-CoV-2 
Prohibited during the study 
90 days before and 
28 days after EOT 
 
30 days before and 
14 days after EOT 
Immunization for 
influenza or 
SARS-CoV-2 
All live vaccines 
 
Nonlive vaccines for 
influenza or SARS-CoV-2 
Prohibited during the study 
 
Not allowed during the 
screening period within 
30 days prior to 
randomization 
 
During the Treatment and 
Follow-up Periods, vaccine 
doses must be given at least 
5 days before a study visit. 
Doses may be given on a 
study day visit once all 
protocol-specific procedures 
are complete. 
90 days before and 
28 days after EOT 
Other treatments 
Diquafosol, rebamipide 
Prohibited during the study 
4 weeks 
BLQ = below limit of quantitation; BTK = Bruton’s tyrosine kinase; CS = corticosteroid; EOT = end of treatment; 
DMARDs = disease-modifying anti-rheumatic drugs; IA = intra-articular; IM = intramuscular; IV = intravenous; 
IVIG = intravenous immunoglobulin; JAK = Janus kinase; MTX = methotrexate; NSAID = nonsteroidal 
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anti-inflammatory drug; pSS = primary Sjögren’s syndrome; RA = rheumatoid arthritis; SLE = systemic lupus 
erythematosus. 
 
Chronic medications that could be sensitive to modulation of CYP2C8/P-gp (and other potentially 
relevant drug metabolizing enzymes that may lead to drug-drug interaction with branebrutinib) 
and with sufficient representation in the study population (eg, > 10% per sub-protocol), are 
allowed in the study for accompanying conditions, such as but not limited to statins and 
antidepressants. For optional measurement of the concentrations of these medications, PK samples 
will be collected at predose and 2 hours postdose at Week 0 (Day 1) and Week 4 (Day 29) for 
potential post-hoc analysis. The measurements of concentrations of the select concomitant 
medications can be performed after the end of the study and will be based on the totality of 
information about the frequency of use of the drugs, clinical manifestations of possible 
interactions, availability of validated bioanalytical assays and therapeutic index. The results of the 
post-hoc analysis of the concomitants medications, if performed, will be reported separately, 
together with the reasons for the selection. Additionally, concentrations of HCQ will be measured 
and reported. 
The dosing of allowed chronic medications must be maintained at the same level throughout the 
study unless safety concerns arise. Any changes of dose will be recorded, and additional PK 
sampling may be performed as a result. 
Tobacco use will be allowed in the study. Branebrutinib concentrations will be compared between 
smoking and nonsmoking subgroups to evaluate the effect of smoking on glutathione-s-transferase 
mediated metabolism of branebrutinib. 
No new concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the eCRF. 
For subjects on MTX background therapy, the investigator must refer to the label for any potential 
interaction with concomitant medications. 
RA 6.7.2 Rescue Medications 
No rescue treatment will be provided from Week 1 to Week 12. From Week 12 to Week 24, 
open-label abatacept treatment will be provided for all subjects. Any subject needing additional 
treatment for worsening of RA symptoms from Week 12 to Week 24 will receive SOC treatment 
for RA, but will be withdrawn from study treatment, and will be encouraged to complete the study 
safety assessments through Week 24 and the Week 28 FU visit. 
RA 6.7.3 Other Restrictions and Precautions 
No other restrictions and precautions have been identified. 
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RA 6.8 
Treatment After the End of the Study 
At the end of the study, BMS will not continue to provide BMS-supplied study treatment to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate SOC to treat the condition under study. 
RA 7 
DISCONTINUATION CRITERIA 
RA 7.1 
Discontinuation from Study Treatment 
RA 7.1.1 Permanent Discontinuation from Study Treatment 
Subjects MUST discontinue study treatment (and non-IP at the discretion of the investigator) for 
any of the following reasons: 
x A subject request to stop study treatment; subjects who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol-specified follow-up 
procedures. The only exception to this is when a subject specifically withdraws consent for 
any further contact with him/her or persons previously authorized by the subject to provide 
this information. 
x Any clinical AE, laboratory abnormality, or intercurrent illness that, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject. If treatment is discontinued due to an AE, the AE eCRF must be completed to show 
that the AE caused discontinuation. 
x Termination of the study program by BMS. 
x Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. 
x Unblinding of a subject’s treatment assignment for any reason (emergency or nonemergency). 
x Inability or failure to comply with protocol requirements. 
x Pregnancy. 
Discontinuation of the study treatment for abnormal liver tests indicative of DILI (see 
Section RA 8.2.8 for definition) should be considered by the investigator when the DILI meets one 
of the conditions necessary to be defined as an SAE outlined in APPENDIX 3 or if the investigator 
believes that it is in the best interest of the subject. 
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the Medical Monitor/designee of this event. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (eg, dose tapering, if necessary, for 
subject safety). Refer to Section RA 8.2.6. 
All subjects who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in the SoA (Section RA 1.3). The only exception to this requirement is 
when a subject withdraws consent for all study procedures including post-treatment study 
follow-up or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for 
the treatment of either a psychiatric or physical illness). Following the decision to permanently 
discontinue a subject from treatment, an EOT visit should be performed as soon as possible, 
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followed by a Safety FU visit approximately 4 weeks later – each respectively according to Table 2 
and Table 3 of Section RA 1.3. 
x If early permanent treatment discontinuation occurs during blinded treatment, then the EOT 
visit includes each activity specified for the Week 12 visit in RA Table 2. 
x If early permanent treatment discontinuation occurs during open-label abatacept treatment, 
then the EOT visit includes each activity specified for the Week 24 visit in RA Table 3. 
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate eCRF page. 
RA 7.1.2 Temporary Discontinuation from Study Treatment 
Branebrutinib may be discontinued temporarily at the discretion of the investigator/Medical 
Monitor due to AE, laboratory abnormality or overdose (Section RA 8.3). 
Branebrutinib may be discontinued temporarily due to concomitant medication use 
(Master Protocol Table 1), as follows: 
x Digoxin, “For acute use only; exclude at baseline; limit highest dose and monitor trough 
concentrations; stop treatment with branebrutinib during treatment with digoxin and for 3 days 
afterwards.” 
x Posaconazole: “Dose up to 300 mg QD can be used as maintenance dose, for acute infections 
stop using branebrutinib until dosing with posaconazole is discontinued.” 
RA 7.1.3 Post-study Treatment Study Follow-up 
Subjects who discontinue study treatment will not be followed beyond the planned Safety FU Visit. 
RA 7.2 
Discontinuation from the Study 
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the subject to provide this information. 
x Subjects should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
x The withdrawal of consent should be explained in detail in the medical records by the 
investigator and entered on the appropriate eCRF page. 
x In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
x If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
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The following procedures must be performed upon subject withdrawal: 
x Assessments for the EOT visit must be performed, provided that the subject has not withdrawn 
consent for these activities. 
x All required eCRF pages must be completed, including the date of and explanation for the 
withdrawal. 
RA 7.3 
Lost to Follow-up 
x All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject. 
x Lost to follow-up is defined by the inability to reach the subject after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by subject to 1 registered 
mail letter. All attempts should be documented in the subject’s medical records. 
x If it is determined that the subject has died, the site will use permissible local methods to obtain 
date and cause of death. 
x If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. 
x The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
x If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records. 
RA 8 
STUDY ASSESSMENTS AND PROCEDURES 
x Study procedures and timing are summarized in the SoA (Section RA 1.3). 
x Protocol waivers or exemptions are not allowed. 
x All immediate safety concerns must be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue treatment. 
x Adherence to the study design requirements, including those specified in the SoA 
(Section RA 1.3), is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria before randomization. The investigator will maintain a screening 
log to record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
x Procedures conducted as part of the subject’s routine clinical management (eg, BP, physical 
examination, medical history) on the day of the screening visit and obtained before signing of 
the informed consent may be used for screening provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the SoA 
(Section RA 1.3). 
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RA 8.1 
Efficacy Assessments 
The following tests and procedures have been selected to evaluate the efficacy of branebrutinib 
and describe clinical improvements in subjects with RA and will be performed according to the 
SoA (Section RA 1.3). 
The investigator will perform all efficacy- and safety-related assessments, except for the 
66/68 joint count, which will be performed by an independent joint count assessor who is blinded 
to all other assessments (eg, safety evaluation, laboratory test assessments, etc). For both the 
investigator and independent joint count assessor, every effort must be made to ensure that the 
same individual performs the specified required assessments al all visits across the study for each 
subject. Visit scheduling must take into account the availability of necessary assessors. Training 
and instruction will be provided to ensure that joint count assessments are conducted in a standard 
manner across sites. If the evaluator(s) is unable to complete the evaluation, then a qualified 
individual with overlapping experience may perform the evaluation. Documentation of the 
individual performing the evaluation is to be recorded in source documents. 
The PI, or sub-investigator designated by the PI and confirmed by the Sponsor, may be a Doctor 
of Medicine or Doctor of Osteopathy, Physician’s Assistant, or Nurse Practitioner with experience 
in the diagnosis and management of subjects with RA. 
All assessments should be performed or administered prior to study drug administration unless 
otherwise indicated. Assessments are to be conducted at approximately the same time of day 
throughout the duration of the study for a given subject. Assessments conducted on Day 1, Week 0 
must be performed per protocol (assessments performed as part of SOC may not be used in lieu of 
these assessments). Procedures not specified in the protocol that are part of standard care may be 
performed if they do not interfere with study procedures; any data arising from such procedures 
are not to be reported in the eCRF. 
RA 8.1.1 Patient-reported Outcomes 
Patient-reported health outcomes, as studied in RA, include questionnaires and scales that focus 
on general health, rheumatology, and RA disease-specific issues. The results of these health 
outcomes will be recorded electronically on eCOA devices provided by the Sponsor or designee 
to the sites. 
RA 8.1.1.1 Health Assessment Questionnaire Disability Index (HAQ-DI) 
The HAQ-DI is a patient-completed questionnaire specific for RA, which assesses the degree of 
difficulty a patient has experienced in 8 domains: dressing/grooming; arising; eating; walking; 
hygiene; reach; grip; and other activities. A decrease from baseline in HAQ-DI score indicates 
improvement; a change of < 0.22 is considered to be clinically meaningful (APPENDIX 23). The 
results and scoring of the HAQ-DI will be captured on an eCOA device. 
RA 8.1.1.2 
PROMIS-Fatigue Instrument Form 6 a 
The PROMIS™ Form 6 a, provides item banks that offer the potential for PRO measurement that 
is efficient (minimizes number of items without compromising reliability), flexible (enables 
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optional use of interchangeable items), and precise (has minimal error in estimate) measurement 
of commonly studied PROs.78, 79, 80, 81 In the health outcomes measurement perspective, eg, the 
fatigue item bank consists of 95 items assessing the intensity, frequency, and duration of fatigue 
and the impact of fatigue upon physical, mental, and social activities. Most PROMIS items employ 
response scales with 5 options (APPENDIX 12). 
RA 8.1.1.3 Euro Quality of Life Five Dimensions Questionnaire: 5-Level Version 
(EQ-5 D-5 L) 
The EQ-5 D-5 L consists of 2 parts – the EQ-5 D-5 L descriptive system and the EQ VAS. The 
descriptive system comprises the same 5 dimensions as the EQ-5 D-3 L (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems; slight 
problems; moderate problems; severe problems; and extreme problems. The respondent indicates 
his/her health state by ticking in the box against the most appropriate statement in each of the 
5 dimensions. The resulting 1-digit number expresses the level selected for that dimension. The 
digits for all 5 dimensions can then be combined in a number describing the respondent’s health 
state. 
The numbers 1 through 5 have no arithmetic properties and should not be used as a cardinal score. 
During the development of the EQ-5 D-5 L, the opportunity was also taken to improve some of 
the wording in the dimensions to enhance consistency and facilitate understanding. For example, 
the old wording of “confined to bed” to indicate the upper extreme in the EQ-5 D-3 L has been 
replaced with “I am unable to walk about,” which is more consistent with the wording within the 
Mobility dimension and with the extreme levels on other dimensions. 
The EQ VAS records the respondent’s self-rated health on a 20-cm vertical VAS with endpoints 
labeled “the best health you can imagine” and “the worst health you can imagine.” This 
information can be used as a quantitative measure of health as judged by the individual 
respondents. The instructions for the EQ VAS task have also been simplified (APPENDIX 13). 
RA 8.1.1.4 
Subject Global Assessment of Disease Activity (SGA) 
The SGA is a visual analog scale (VAS) a subject uses to rate the ways in which RA has effected 
them (APPENDIX 24). 
RA 8.1.2 
Clinical Assessments 
RA 8.1.2.1 Tender Joint Count 68/Swollen Joint Count 66 
(TJC68/SJC66) – RA Sub-protocol 
The number of tender, painful, and swollen joints will be determined by examination of 68 joints 
(34 joints on each side of the subject’s body) by an independent joint count assessor, and entered 
into the eCOA device. The 68 joints to be assessed and classified as tender or not tender include: 
2 temporomandibular joints (TMJs), 2 sternoclavicular joints, 2 acromioclavicular joints, 
2 shoulder joints, 2 elbow joints, 2 wrist joints, 10 metacarpophalangeal joints, 2 interphalangeal 
joints of the thumb, 8 proximal interphalangeal joints of the hands, 8 distal interphalangeal joints 
of the hands, 2 hip joints, 2 knee joints, 2 ankle joints, 2 tarsi, 10 metatarsophalangeal joints of the 
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feet, 2 great toes (first proximal interphalangeal joint of the feet), and 8 proximal interphalangeal 
joints of the feet. 
Joints will be assessed for tenderness by pressure and joint manipulation on physical examination. 
The subject will be asked for pain sensations on these manipulations and watched for spontaneous 
pain reactions. Any positive response on pressure, movement, or both will then be translated into 
a single tender-versus-nontender dichotomy. 
Sixty-six joints (68-joint count minus both hips) will be classified as either swollen or not swollen. 
Swelling is defined as palpable fluctuating synovitis of the joint. Swelling secondary to 
osteoarthrosis will be assessed as not swollen, unless there is unmistakable fluctuation. 
Joint assessments of 1 particular subject should be performed (if at all possible) by the same 
assessor throughout the study to minimize inter-observer variation. 
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the assessor at the 
screening visit and will be excluded from evaluation during the study. The locations (or a listing) 
of surgical procedures should be documented in the subject’s source documents/eCRF pages. 
RA 8.1.2.2  Physician Global Assessment of Disease Activity (PGA) 
The PGA is a VAS that the physician uses to assess the manner in which RA has affected the RA 
subject (APPENDIX 26). 
RA 8.1.2.3 
RA Magnetic Resonance Imaging (MRI) Scoring System 
The MRI scanners used in the RA sub-protocol study must be deemed qualified by the 
Sponsor-assigned core imaging lab prior to subject scans. The hand/wrist that is clinically most 
swollen at screening will be imaged using a whole-body MRI system. The screening visit MRI is 
considered the baseline MRI assessment for this study. If a subject requires rescreening, the MRI 
results obtained at the initial screening visit may be used for the rescreening, if the MRI was 
obtained within 30 days of randomization. It is recommended that sites should schedule 2 MRI 
appointments with the radiology department 7 days apart in the event that an MRI exam needs to 
be repeated due to technical difficulties. MRI exams with quality issues identified at the 
investigator site or core imaging lab should be repeated within 7 days of notification. 
The same hand/wrist that was imaged at screening will be imaged at Week 12 and Week 24 on the 
same MRI scanner as the one used at screening. The screening visit MRI is to be performed 
approximately 14 days prior to randomization. Week 12 and Week 24 MRI exams are to be 
performed within 7 days of both scheduled Week 12 visit and Week 24 visits. Subjects who 
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GDWHRIUDQGRPL]DWLRQRU 4 weeks from Week 12 and should have the EOT MRI no more than 
7 days from the EOT visit. 
Subjects with moderate renal insufficiency (ie, eGFR or GFR < 50 mL/min/1.73 m2), will be 
excluded from the study, as they are at increased risk of nephrogenic systemic fibrosis, a rare, but 
serious, condition associated with the use of gadolinium-based MRI contrast agents. Subjects in 
the RA sub-protocol who enter the study with eGFR or GFR > 50 mL/min/1.73 m2, but whose 
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levels decline to < 50 mL/min/1.73 m2 during the study will be excluded from further imaging 
during the study. 
Synovitis, osteitis (bone marrow edema), bone erosion, and cartilage loss (joint-space narrowing) 
will be scored according to the Outcomes Measurement in Rheumatology (OMERACT) 
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS).89 Change at 
follow-up from baseline in each RAMRIS score will be calculated. Scoring will be performed 
centrally by 2 independent, experienced readers who will be blinded to clinical details, 
radiographic findings, treatment arm, and the chronology of MRI exams (screening, Week 12, 
Week 24, and/or the EOT visit, if applicable). 
Images will be submitted to a core imaging lab. Sites should be trained prior to scanning the first 
study subject. Image acquisition guidelines and submission process will be outlined in the 
Study IM014029 Imaging Manual to be provided by the core imaging lab (APPENDIX 25). 
RA 8.1.3 Composite-Assessments of Disease Activity in Rheumatoid Arthritis 
(RA) 
Composite indices or pooled indices are useful tools for the evaluation of disease activity in 
patients with RA. They allow the integration of various aspects of the disease into a single 
numerical value that may help to facilitate consistent patient care and improve patient compliance, 
both of which can lead to improved outcomes. 
The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) 
are composite tools for the evaluation of disease activity in RA. They have been developed to 
provide physicians and patients with simple and more comprehensible instruments. Moreover, the 
CDAI is the only composite index that does not incorporate an acute-phase response and can 
therefore be used to conduct a disease activity evaluation essentially anytime and anywhere. These 
tools are not replacements for instruments such as the DAS28 but are options for different 
environments. The ACR Responder Index is a composite of clinical, laboratory, and functional 
measures in RA that assess the signs and symptoms of relief. ACR responses are presented as the 
minimal numerical improvement from baseline in the 68 tender joint count and the 66 swollen 
joint count and at least 3 of the 5 following disease assessment criteria: PGA, SGA, HAQ-DI, and 
ESR or hsCRP. These tools can be used in clinical studies. 
x The SDAI is composed of the sum of the tender joint score (range 0 to 28), the swollen 
joint score (range 0 to 28), the SGA of disease activity (range 0 to 10, in increments of 0.5), 
the PGA of disease activity (range 0 to 10, in increments of 0.5), and C-reactive protein 
(range 0 to 10 mg/dL) (APPENDIX 20). 
x The CDAI is composed of joint responses from the 66/68 Tender and Swollen Joint Count 
as well as the SGA and PGA of Disease Activity. At Week 12, for the RA cohort only, the 
CDAI score will be calculated as the sum of the tender joint score (range 0 to 28), the 
swollen joint score (range 0 to 28), the SGA of disease activity (range 0 to 10, in increments 
of 0.5), and the PGA of disease activity (range 0 to 10, in increments of 0.5). Unlike other 
measures, CDAI does not include the use of an acute-phase reactant (CRP or ESR). A 
CDAI score of > 22 represents high disease activity (APPENDIX 21). 
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x The Disease Activity Score (DAS) can be used to assess subjects’ RA disease activity, 
determine whether it is under control and if any treatment adjustments are required. It can 
also assist in establishing a target score to aim for, help inform treatment decisions, and 
optimize disease management. DAS28-CRP (APPENDIX 16) and DSR28-ESR 
(APPENDIX 22) are composite outcome assessments that measure: 
o How many joints in the hands (including metacarpophalangeal and proximal 
interphalangeal joints but excluding distal interphalangeal joints), wrists, elbows, 
shoulders, and knees are swollen and/or tender over a total of 28. 
o CRP, or ESR, in the blood to measure the degree of inflammation. 
o SGA of disease activity. 
o The results are combined to produce the DAS28-CRP (or DAS28-ESR) score, which 
correlates with the extent of disease activity: 
- < 2.6: Disease remission 
- 2.6 – 3.2: Low disease activity 
- 3.2 – 5.1: Moderate disease activity 
- > 5.1: High disease activity 
x ACR Response Measures 
o The ACR20 is a composite measure defined as both improvement of 20% in the number 
of tender and number of swollen joints, and a 20% improvement in 3 of the following 
5 criteria: SGA, PGA, functional ability measure (eg, the Health Assessment 
Questionnaire [HAQ]), pain VAS, and ESR or CRP. 90 
o The ACR50 and ACR70 are the same instruments with improvement levels defined as 
50% and 70%, respectively, versus 20% for ACR20. 
RA 8.2 
Adverse Events 
The definitions of an AE or SAE can be found in APPENDIX 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver or surrogate,). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the subject to 
discontinue before completing the study. 
Contacts for SAE reporting are specified in APPENDIX 3. 
RA 8.2.1 AEs of Interest 
AEIs are AEs for a particular product or class of products that a Sponsor may wish to monitor 
carefully. AEIs may be serious or nonserious. Such events may require further investigation to 
better characterize and understand them. In the branebrutinib clinical development program, 
infection AEs have been identified as potential AEIs; however, there has been no definitive 
assessment on the causal relationship between these events and treatment with branebrutinib. 
Therefore, additional information about infection AEs may be collected on the eCRF in order to 
better characterize and understand them. 
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The core AEIs for abatacept encompass specific identified and potential risks based on the 
mechanism of action of abatacept and extensive data from clinical studies and postmarketing 
experience. For abatacept, infections and systemic injection reactions are considered by the 
Sponsor to be events for which there is adequate evidence of association with the product 
(identified risks). Malignancies, immune-mediated disorders, and infections associated with 
immunization with live vaccines are considered by the Sponsor to be events for which there is 
some basis for suspicion of an association with the product, but where this association has not been 
confirmed (potential risks). These AEIs will be closely monitored in the study. 
RA 8.2.2 Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 
discharge, at the timepoints specified in the SoA (Section RA 1.3). Nonserious AE information 
should also be collected from the start of a PBO lead-in period or other observational period 
intended to establish a baseline status for the subjects. The Reference Safety Information in 
Sections 5.6.1 and 5.6.2 of the IB12 should be used to determine the expectedness of SAEs for 
expedited reporting. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing or 
subject’s participation in the study if the last scheduled visit occurs at a later time. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
x Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the designated eCRF. 
x All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in APPENDIX 3. 
x The investigator will submit any updated SAE data to the Sponsor or designee within 24 hours 
of updated information being available. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study treatment 
or study participation, the investigator must promptly notify the Sponsor. 
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in APPENDIX 3. 
RA 8.2.3 Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) Nonserious RA-related AE will 
be collected solely on the disease assessment instruments and will not be reported as AEs, unless 
characterized as an SAE. 
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RA 8.2.4 Follow-up of AEs and SAEs 
x Nonserious AEs should be followed to resolution, stabilization, or reported as SAEs if they 
become serious (see APPENDIX 3). 
x Follow-up is also required for nonserious AEs that cause discontinuation of study treatment 
and for those present at the end of study treatment as appropriate. 
x All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the eCRF. Completion of supplemental eCRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study. 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and nonserious AEIs (as defined in Section RA 8.2.1) will 
be followed until resolution, until the condition stabilizes, until the event is otherwise explained, 
or until the subject is lost to follow-up (as defined in Section RA 7.3). 
Further information on follow-up procedures is provided in APPENDIX 3. 
RA 8.2.5 Regulatory Reporting Requirements for SAEs 
x Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities toward the safety of subjects and the safety of a product 
under clinical investigation are met. 
x An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
The Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations (CFR) 21 CFR Parts 312 and 320. A SUSAR is a subset of SAEs and will be 
reported to the appropriate regulatory authorities and investigators following local and global 
guidelines and requirements. 
RA 8.2.6 Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify 
 Drug 
Safety of this event and complete and forward a Pregnancy Surveillance Form to 
 Drug Safety 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in APPENDIX 3. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
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Any pregnancy that occurs in a female partner of a male study subject should be reported to 
 
Drug Safety. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
RA 8.2.7 Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the AE eCRF page. 
x Any laboratory test result that is clinically significant or meets the definition of an AE or SAE 
x Any laboratory test result abnormality that required the subject to have study treatment 
discontinued or interrupted 
x Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy 
If a laboratory test result meets the definition of an AE or SAE, the laboratory test result should be 
reported as an AE or SAE and submitted to 
 Drug Safety, as specified in APPENDIX 3. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value). 
RA 8.2.8 Potential DILI 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs meeting 
the defined criteria must be reported as SAEs (See Section RA 8.2 and APPENDIX 3 for reporting 
details). 
Potential DILI is defined as: 
1) ALT or AST elevation > 3× ULN 
AND 
2) Total bilirubin > 2× ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, preexisting chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
RA 8.2.9 Management of Possible Hypersensitivity Reactions to Abatacept 
Any Hypersensitivity resulting in severe, acute allergic reactions may occur as a result of the 
protein nature of abatacept. Anaphylaxis is highly likely if 2 or more of the following occur 
rapidly after administration of the study drug (minutes to several hours): 
x Involvement of the skin-mucosal tissue (eg generalized hives; itching or flushing; swollen lips, 
tongue, or uvula). 
x Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
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exploratory flow, hypoxemia). 
x Reduced BP or associated symptoms (eg, hypotonia/collapse, syncope, and incontinence). 
x Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting). 
Sites must be appropriately prepared to handle medical emergencies such as severe 
hypersensitivity including anaphylaxis. Subjects must be rapidly assessed and stabilized at the site 
and transferred to an emergency facility as required. If subjects experience symptoms of severe 
allergic reactions at home, they should be advised to seek immediate medical attention, including 
a visit to the local emergency facility, as needed. The site will provide emergency contact 
information to the subject. A blood sample for analysis of anti-abatacept antibodies should be 
obtained in case of a hypersensitivity reaction. 
The decision whether to continue treatment with the study drug will be left to the medical judgment 
of the investigator. Care should be taken to treat any acute toxicity, expeditiously, should they 
occur. Adequate equipment and trained healthcare personnel should be available to handle medical 
emergencies when they occur at the site. 
RA 8.2.10 Other Safety Considerations 
Any significant worsening of a preexisting medical condition noted during interim or final physical 
examination, electrocardiogram (ECG), x-ray filming, or any other potential safety assessment 
required or not required by protocol should also be recorded as a nonserious AE or SAE, as 
appropriate, and reported accordingly. 
RA 8.3 
Overdose 
For this study, any dose of branebrutinib greater than 2 daily doses of study treatment within a 
24-hour time period will be considered an overdose. See APPENDIX 3 for AE assessment and 
reporting procedures regarding suspected overdose and intentional overdose. 
Based on the IB, there has been no clinical experience with overdose of branebrutinib.12 There is 
no known specific antidote for overdose with branebrutinib. 
Based on the abatacept package insert,91 doses of abatacept up to 50 mg/kg have been administered 
IV without apparent toxic effect. In case of overdose, it is recommended that the subject be 
monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment 
instituted. 
In the event of an overdose for either study treatment, the investigator should: 
1) Contact the Medical Monitor immediately. 
2) Closely monitor the subject for AEs/SAEs and laboratory abnormalities. 
3) Obtain a plasma sample for PK analysis within 4 hours of the overdose if requested by the 
Medical Monitor (determined on a case-by-case basis). 
4) Document the quantity of the excess dose as well as the duration of the overdosing in the eCRF. 
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject. 
RA 8.4 
Safety 
Planned time points for all safety assessments are listed in the SoA (Section RA 1.3). 
RA 8.4.1 Physical Examinations 
A complete physical examination will include general appearance, vital signs, eyes, ears, nose, 
mouth, throat, neck, respiratory, cardiovascular, respiratory, gastrointestinal/abdomen, lymphatic, 
musculoskeletal, skin, psychiatric, and neurologic examinations. A targeted physical examination 
will include any organ system associated with an AE, a laboratory abnormality, or an RA-related 
SAE not captured elsewhere. 
RA 8.4.2 Vital Signs 
Refer to RA SoA (Section RA 1.3). 
RA 8.4.3 Electrocardiograms 
A 12-lead ECG will be performed at the visits indicated in the SoA (Section RA 1.3). The subject 
will remain supine for 5 to 10 minutes prior to the ECG and must have lab work done after the 
tracing so that the ECG results remain as accurate as possible. The ECG results will be read by the 
primary study investigator or a designee. 
RA 8.4.4 TB Screening and Chest Imaging 
A subject must not have active signs or symptoms of TB, as judged by the investigator, to be 
eligible for the study. 
In addition to a complete physical examination and medical history to evaluate exposure to TB, all 
subjects will have a screening test, an IGRA (eg, QuantiFERON®-TB Gold) performed centrally. 
A subject with an indeterminate IGRA test result from the central laboratory must be retested for 
confirmation. If the second result is again indeterminate, the subject will be excluded from the 
study, unless there is documentation of a local negative TB Spot test result. If the second result 
from the central laboratory is positive, the subject should be considered as having LTBI provided 
there are no signs or symptoms of active TB. If the second result is negative, the subject may be 
eligible provided no other exclusion criteria for TB are met. A chest x-ray is also required if one 
has not been performed within 6 months of screening; a copy of the radiology report must be on 
file and reviewed by the investigator. If unable to obtain central laboratory results, an IGRA test 
could be obtained locally, after consultation with the 
 Medical Monitor. 
RA 8.4.5 Clinical Safety Laboratory Assessments 
A central laboratory will perform assessments of safety laboratory assessments (except urine 
pregnancy tests and ESR) and provide reference ranges and laboratory reports. Investigators must 
document their reviews of each laboratory safety report. Any laboratory test result that the 
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investigator considers clinically relevant is to be recorded on the appropriate AE page of the eCRF 
(Section RA 8.2.7). 
ESR laboratory samples should be collected and recorded by an unblinded staff member who does 
not perform/have access to other subject procedures, including joint counts. All samples after 
screening should be collected and recorded in a blinded fashion. 
Additional safety assessments may be performed at local laboratories at the investigator’s 
discretion. The laboratory parameters to be assessed are included in RA Table 8. 
In addition, serum or urine pregnancy testing will be performed for WOCBP. 
RA Table 8 
Clinical Safety Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including manual differential 
Platelet count 
Red blood cell count 
Prothrombin time/INR 
PTT 
aPTT 
Serum Chemistry 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyltransferase 
hsCRP 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Lactate dehydrogenase 
Creatinine 
Blood urea nitrogen 
Uric acid 
Fasting glucose (nonfasting at screening only) 
Creatinine clearance – screening only 
Estimated glomerular filtration rate 
Total Protein 
Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphorus 
Magnesium 
Creatine kinasea 
Fasting lipid panel (total cholesterol, high-density 
lipoprotein, low-density lipoprotein, and triglycerides; 
nonfasting at screening only) 
Urinalysis 
Protein 
Glucose 
Blood 
Leukocyte esterase 
Specific gravity 
pH 
Microscopic examination of sediment (if blood, protein, 
or leukocyte esterase are positive on dipstick) 
Urine chemistry – Spot urine for urine protein:creatinine ratio 
Infectious Serologies 
Anti-HCV antibodies with reflex testing of HCV RNA if positive 
HBsAg 
Anti-HbsAb 
Anti-HbcAb 
Anti-HIV-1 and anti-HIV-2 antibody 
Other Analyses 
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RA Table 8 
Clinical Safety Laboratory Assessments 
Serum will be collected at baseline (Week 0) and at the EOT visit (Week 24) for optional measurements of anti-
SARS-CoV-2 immunoglobulins. 
Tuberculosis test (QuantiFERON®-TB Gold) at screening 
Direct Coomb’s test (only if clinically indicated) 
Pregnancy TesWIRU:2&%3VHUXPRUXULQHȕ-HCG test every 4 weeks) 
Follicle-stimulating hormone if needed to confirm menopausal status (see APPENDIX 4), at screening 
HbA1c 
Thyroid-stimulating hormone (if above normal reference range, test free T4; if below normal range, test free T4 
and T3) 
IgM, IgG, IgA, IgE, free Kappa/Lambda light chains 
Erythrocyte sedimentation rate 
Rheumatoid factor 
C3, C4 
 
T cells, B cells, natural killer cells 
Beta-2-microglobulin 
 ANA = antinuclear antibody; aPTT = activated partial 
WKURPERSODVWLQWLPHȕ-HCG = beta-human chorionic gonadotropin; C3, C4 = serum complement C3 and C4; DNA = 
deoxyribonucleic acid;
; EOT = end of treatment; HbcAb = hepatitis B core antibody; 
HbsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis 
C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; 
INR = international 
normalized 
ratio; 
PTT = partial 
thromboplastin 
time; 
RNA = ribonucleic 
acid; 
 Sm = Smith;
; 
T3 = tri-iodothyronine; T4 = thyroxine; TB = tuberculosis; ULN = upper limit of normal; WOCBP = women of 
childbearing potential 
a If the creatine kinase is > 2.5× ULN, reflex testing of creatine kinase-MB and troponin I will be required. 
RA 8.4.6 Imaging Safety Assessment 
Any incidental findings of potential clinical relevance on chest x-ray or any additional imaging 
performed that is not directly associated with the objectives of the protocol should be evaluated 
and handled by the study investigator as per standard medical/clinical judgment. Images may be 
requested for submission to the assigned imaging core lab for central analysis. Assessment of hand 
and wrist MRI by the investigator is not expected. 
RA 8.5 
PK of Branebrutinib 
The PK sampling schedule for branebrutinib, its metabolites, and concomitant medications will be 
harmonized among all treatments and sub-protocols where applicable. 
For the predose and postdose PK assessments of branebrutinib and metabolites, samples will be 
collected from 2 groups of subjects—all study subjects who receive branebrutinib comprise one 
group; and subjects at preselected clinical sites only and who will have extended PK sampling 
comprise the second group (RA Table 9). 
Samples collected from all study subjects who receive branebrutinib will be analyzed for 
branebrutinib PK only, including samples drawn on days scheduled solely for predose samples. 
Samples collected from subjects at the preselected clinical sites will be analyzed for both 
branebrutinib and metabolites at all scheduled time points as indicated in RA Table 9 and will be 
divided into 2 collection tubes, one tube for branebrutinib and one tube for metabolites analysis. 
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In general, predose (trough) concentrations will be assessed to evaluate the attainment of 
steady-state and accumulation. it is expected that steady-state will be achieved for all analytes at 
Week 4, after 28 days of continuous dosing. 
Pharmacokinetic samples may also be used in correlation analyses for evaluation of PK/PD and 
the effect of pharmacogenomics (PGx) and used for other correlation analyses as well. The 
sampling schedule is based on available information on branebrutinib and its metabolites. 
(Samples for PK analysis collected from subjects receiving PBO will not be analyzed for 
branebrutinib or metabolites.) 
Branebrutinib and Metabolite Analysis: 
Branebrutinib PK samples will be analyzed by a vendor using a validated assay. Plasma samples 
for metabolites will be analyzed by the BMS bioanalytical laboratory. These analyses will be 
reported separately. The BMS laboratory will be unblinded before the end of the study and will 
not communicate unblinded information to the BMS 
 study teams where the data allow. 
Individual subject PK parameter values for branebrutinib will be derived from plasma 
concentration data versus time by noncompartmental methods with a validated PK analysis 
program. Actual times will be used for the analyses. 
For all study subjects, the branebrutinib PK parameters listed below will be calculated and 
summarized with data up to 4 hours postdose. Accumulation ratios for Cmax and AUC(0-4) will 
also be calculated. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
Ctrough 
Trough observed plasma concentration 
AUC(0-4) 
Area under the plasma concentration-time curve from time zero to the 4-hour 
dosing period 
 
For subjects at preselected sites with extended sampling, separate PK concentrations of 
branebrutinib and select metabolites at all timepoints will be summarized by timepoint. The 
branebrutinib parameters listed below will be calculated and summarized. 
Cmax 
Maximum observed concentration 
Tmax 
Time to maximum concentration 
AUC(0-T) 
Area under the plasma concentration-time curve from time zero to time of last 
quantified concentration 
AUC(TAU) 
Area under the concentration-time curve to the end of the dosing period 
Ctrough 
Trough observed plasma concentration 
 
RA Table 9 lists the complete sampling schedule for assessment of the PK of branebrutinib, 
metabolites, and concomitant medications in subjects with RA. 
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To assess steady-state concentrations of branebrutinib, a total of 2 predose PK samples 
(approximately 4 mL each) will be drawn from all study subjects at Week 0 (Day 1) and Week 4 
(Day 29) (Note that these samples will be drawn within a 1-hour window before the next dose is 
administered.) For subjects at preselected sites with extended sampling, predose PK samples 
collected at Week 8 (Day 57) will be aliquoted to assess metabolite concentrations. 
For postdose sampling, all study subjects will have branebrutinib PK samples drawn at Week 0 
(Day 1) and Week 8 (Day 57) at the 0.5, 1, 2, and 4-hour time points. (Note that these samples will 
be drawn within ±15 min from the given time points.) For subjects at preselected sites with 
extended sampling, postdose PK samples will be aliquoted to assess metabolite concentrations at 
these time points. 
In addition, for subjects at preselected sites with extended sampling, postdose PK samples will be 
drawn and assessed for both branebrutinib and metabolite concentrations at Week 0 (Day 1) and 
Week 8 (Day 57) at approximately 06:00 hours, and from 08:00 to 10:00 hours (flexible window) 
and from 10:00 to 12:00 hours (flexible window). Samples will also be collected at Week 0 (Day 2) 
approximately 24:00 hours postdose (predose of branebrutinib on Day 2). Efforts should be made 
to collect the samples within these windows; however, any sample drawn outside the prespecified 
windows will not be considered a protocol deviation. Both planned and actual time points at which 
the blood samples will be taken will be recorded and used in analysis and modeling. 
Concomitant Medications 
Concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant 
drug metabolizing enzymes that may lead to drug-drug interaction with branebrutinib and P-gp 
transporter may be measured (post-hoc) for the levels of exposure for subjects receiving PBO and 
active treatment. Samples for the PK assessment of the relevant concomitant medications will be 
collected at Week 0 and Week 4 from all study subjects. Samples for PK analysis collected from 
subjects receiving branebrutinib or PBO will be analyzed for HCQ and other relevant concomitant 
comedications provided that these subjects are receiving HCQ and other relevant concomitant 
comedications. 
Detailed instructions for the collection, labeling, processing, storage, shipping, and disposition of 
all PK blood samples are provided in the Laboratory Manual. 
RA Table 9 
PK Sampling Schedule for Branebrutinib, Metabolites, and 
Concomitant Medications 
Study 
Day 
Study 
Week Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Meds 
a,b 
Comments 
1 
0 
Predose 
00:00 
X 
 
Xa,b 
 3UHGRVH 3. VDPSOHV ZLOO EH
collected from all study subjects to 
assess 
concentrations 
of 
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RA Table 9 
PK Sampling Schedule for Branebrutinib, Metabolites, and 
Concomitant Medications 
Study 
Day 
Study 
Week Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Meds 
a,b 
Comments 
branebrutinib 
and 
relevant 
concomitant medications 
1 
0 
Postdose 
00:30 
X 
X 
 
 3RVWGRVH 3. VDPSOHV FROOHFWHG
from all study subjects at these time 
points 
will 
be 
assessed 
for 
branebrutinib; 
3RVWGRVH3.VDPSOHVFROOHFWHGDW
these time points from subjects at 
preselected clinical sites will also 
be assessed for metabolites; 
3RVWGRVH3.VDPSOHVFROOHFWHGDW
2 hours after dosing, will be 
assessed for relevant concomitant 
medications. 
1 
0 
Postdose 
01:00 
X 
X 
 
1 
0 
Postdose 
02:00 
X 
X 
Xa,b 
1 
0 
Postdose 
04:00 
X 
X 
 
1 
0 
Postdose 
06:00 
X 
X 
 
3RVWGRVH3.VDPSOHVFROOHFWHGat 
these time points from subjects at 
preselected clinical sites only will 
be assessed for concentrations of 
branebrutinib and metabolites at 
these time points.  
1 
0 
Postdose 
08:00-10:00 
X 
X 
 
1 
0 
Postdose 
10:00-12:00 
X 
X 
 
2 
0 
Postdosec 
24:00 
X 
X 
 
29 
4 
Predose 
00:00 
X 
 
Xa,b 
3UHGRVHand postdose PK samples 
collected at these time points from 
all study subjects for branebrutinib 
(postdose 
branebrutinib 
PK 
samples are not to be collected at 
Week 4) 
and 
for 
relevant 
concomitant medications. 
3ODVPDVDPSOHVZLOOEHFROOHFWHG
from 
all 
study 
subjects 
for 
assessment of relevant concomitant 
medications. 
29 
4 
Postdose 
02:00 
 
 
Xa,b 
57 
8 
Predose 
00:00 
X 
X 
 
3UHGRVHand postdose PK samples 
collected at these time points from 
all study subjects will be assessed 
for branebrutinib only; 
3UHGRVHand postdose PK samples 
collected at these time points from 
subjects at preselected clinical sites 
will 
also 
be 
assessed 
for 
concentrations of metabolites; 
 
57 
8 
Postdose 
00:30 
X 
X 
 
57 
8 
Postdose 
01:00 
X 
X 
 
57 
8 
Postdose 
02:00 
X 
X 
 
57 
8 
Postdose 
04:00 
X 
X 
 
57 
8 
Postdose 
06:00 
X 
X 
 
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RA Table 9 
PK Sampling Schedule for Branebrutinib, Metabolites, and 
Concomitant Medications 
Study 
Day 
Study 
Week Event 
Time 
(Relative to 
Branebrutinib 
Dose) 
Hours:Minutes 
Branebrutinib 
Metabolites 
(collected 
from 
subjects at 
preselected 
sites) 
Concom 
Meds 
a,b 
Comments 
57 
8 
Postdose 
08:00-10:00 
X 
X 
 
)RUVXEMHFWVDWSUHVHOHFWHGFOLQLFDO
sites with extended sampling, 
samples collected at these time 
points will be assessed for both 
branebrutinib and metabolites PK. 
57 
8 
Postdose 
10:00-12:00 
X 
X 
 
PK = pharmacokinetic; Concom Meds = concomitant medications. 
a Concentrations of concomitant medications that are sensitive substrates of CYP2C8 and other potentially relevant 
drug metabolizing enzymes that may have a drug-drug interaction with branebrutinib and P-gp transporter may be 
evaluated post-hoc for subjects receiving PBO and active treatment at predose of branebrutinib on Day 1 and 
Day 29. 
b Subjects being treated with prescription concomitant medications will be informed to bring them to the clinic on 
Day 1 and Day 29 for simultaneous dosing with branebrutinib, but only when it is safe for subjects and operationally 
feasible. This should be based on the investigator’s discretion with consideration that the medications which should 
not be delayed until the time of dosing in the clinic should be taken at home. The self-reported time for all 
prescription medications taken at home should be recorded as accurately as possible. 
c PK sample must be drawn before the branebrutinib dose is administered on Day 2. 
 
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RA 8.5.1 PK and Immunogenicity of Abatacept (Weeks 12 and Later) 
The PK samples for abatacept and for immunogenicity analysis will be taken at predose at clinic 
visits for all subjects. The sampling schedule for abatacept is provided in RA Table 10. 
Samples from all subjects receiving abatacept treatment will be analyzed for abatacept 
concentration as well as for antidrug antibodies (ADAs) and abatacept-neutralizing potential. 
Trough samples within a 30-minute window before each dose will be collected, as well as samples 
at the FU visit at early discontinuation or the EOT. 
RA Table 10 
PK and Immunogenicity Sampling Schedule for Abatacept 
Study Day 
of Sample 
Collection 
Study 
Week of 
Sample 
Collectio
n 
Event 
Time 
(Relative to 
Branebrutinib Dose and 
Abatacept Dose) 
Hour:Minute 
Blood Sample for 
PK and 
Immunogenicity/ 
Abatacept 
Comment – All Samples 
Mandatory for All Subjects 
85 
12 
Predose 
00:00 
X 
Before the first dose of 
abatacept 
99 
14 
Predose 
00:00 
X 
Before the third dose of 
abatacept 
113 
16 
Predose 
00:00 
X 
 
141 
20 
Predose 
00:00 
X 
 
169 
24 
-- 
00:00 
X 
Since abatacept is not 
administered at this visit, this 
blood sample is not collected 
predose; this sample is intended 
to be equivalent to trough 
concentration sampling 
197 
28-week 
FU 
-- 
-- 
X 
To evaluate elimination of 
abatacept and immunogenicity 
signal after stopping the dosing 
FU = Safety follow-up; PK = pharmacokinetic 
 
Detailed instructions for PK and ADA blood collection for abatacept, labeling, processing, storage, 
shipping, and disposition are provided in the Laboratory Manual. Plasma samples will be analyzed 
for abatacept and ADA/nanoantibodies (Nabs) to abatacept by validated assays. 
The trough concentrations of abatacept will be listed and summarized by time point and can be 
compared between subjects who received treatment of branebrutinib versus PBO before the start 
of abatacept treatment. 
The results of immunogenicity will be listed and summarized by time point as well as overall 
occurrence of ADA, Nabs, and time to onset of immune response and resolution, if available. The 
frequency of immunogenicity can be compared between subjects who received treatment of 
branebrutinib versus PBO before the start of abatacept treatment and correlated to trough 
concentrations. 
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RA 8.5.2 PK of Potential Concomitant Medications 
Concentrations of Concomitant medications that are sensitive substrates of CYP2C8 and other 
potentially relevant drug metabolizing enzymes and P-gp transporter may be evaluated for subjects 
receiving PBO and active treatment with the bioanalytical analysis as part of a retrospective 
analysis. The retrospective analysis will be conducted after review of the enrollment records, 
reported concomitant medication use within the enrolled population and on the incidence threshold 
and relevance to drug interaction with branebrutinib based on preclinical and clinical data. Other 
confounding factors will be evaluated as part of the analysis to avoid inclusion of bias or artifact 
results. 
Subjects who are on prescription concomitant medications will be informed to bring them to the 
clinic on Day 1 and Day 29 for simultaneous dosing with branebrutinib, but only when it is safe 
for subjects and operationally feasible. This should be based on the investigator’s discretion with 
consideration that the medications which should not be delayed until the time of dosing in the 
clinic should be taken at home. The self-reported time for all prescription medications taken at 
home should be recorded as accurately as possible. 
The concentration of the relevant concomitant medications will be measured using samples 
collected predose and 2 hours postdose of branebrutinib or placebo on both Day 1 and Day 29 
(Week 4; at which point accumulation of branebrutinib and its metabolites is expected to achieve 
steady-state). Bioanalytical analysis of all relevant concomitant medications will be conducted 
post-hoc. The doses of the concomitant drugs and the time they are taken, will be carefully 
recorded at all times (including Day 1 in Week 0 and on Day 29 in Week 4). The doses of 
concomitant medications will be carefully recorded at all times. Actual and dose-normalized 
trough concentrations will be listed, summarized, and compared between posttreatment and 
pretreatment of branebrutinib and PBO separately; other covariates such as MTX use, gender, etc. 
can be added to the comparison as needed. 
Detailed instructions for PK sample collection for the relevant concomitant medications, labeling, 
processing, storage, shipping, and disposition are provided in the Laboratory Manual. Plasma 
samples will be analyzed for all relevant concomitant medications by available validated assays. 
The results of post hoc analyses will not be recorded in the CSR. 
 
 
 
 
 
 
 
 
 
 
 
 
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RA 8.7 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
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RA 9 
STATISTICAL CONSIDERATIONS 
RA 9.1 
Sample Size Determination 
Sample size is calculated based on the estimated effect size for the primary endpoint comparison 
between branebrutinib and PBO treatment groups. The primary endpoint for the RA sub-protocol 
is the ACR50 response at Week 12. 
Estimates for PBO response rates, treatment differences, and common standard deviations were 
obtained from the published literature. 92,93 Sample size justification is provided below for the 
RA sub-protocol: 
Assuming a total sample size of 80 subjects randomized in a blinded fashion at a 3:1 ratio to 
branebrutinib (60 subjects) or PBO (20 subjects), there will be 82% power to detect a treatment 
difference of 30% assuming the PBO response rate is 15% in ACR50 at Week 12, given a 1 sided, 
two-group test of a difference in binomial proportions with a 5% level of significance. 
RA 9.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled Set 
All subjects who sign informed consent. 
FAS 
All subjects who are randomized. Following the intent-to-treat 
principle, subjects will be analyzed according to the treatment 
assigned at randomization. The FAS will be the primary efficacy 
analysis population. This is the same as the intent-to-treat population. 
Full Abatacept 
Analysis Set (FAAS) 
All FAS subjects who are dispensed Abatacept treatment. 
PPS 
A subset of the FAS wo are compliant with study treatment and who 
do not have any statistically relevant protocol deviations that may 
impact the primary efficacy endpoint assessments. The PPS will be 
analyzed according to the treatment assigned at randomization. The 
PPS will be a supportive efficacy analysis population. 
Safety Analysis Set 
All randomized subjects who receive at least 1 dose of double-blind 
study treatment. Subjects will be analyzed according to treatment 
received. In cases where the subjects take the incorrect treatment, the 
following scenario will be considered. 
)RUVXEMHFWVZKRVKRXOGEHUHFHLYLQJEUDQHEUXWLQLEWUHDWPHQWGXULQJ
the blinded treatment period, if the subject took any placebo dose, the 
subject will still be counted in the branebrutinib treatment group for 
safety analysis set unless the subject took placebo throughout the 
entire course. 
)RUVXEMHFWVZKRVKRXOGEHUHFHLYLQJSODFHERWUHDWPHQWGXULQJ
double the blinded treatment period, if the subject took any 
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Population 
Description 
branebrutinib dose, the subject will be counted in the branebrutinib 
treatment group for safety analysis set.  
PK population for 
branebrutinib 
All randomized subjects who receive at least 1 dose of branebrutinib 
and have any available branebrutinib concentration data. 
Biomarker 
All randomized subjects who receive at least 1 dose of double-blind 
study treatment and have at least 1 posttreatment biomarker 
measurement. Subjects will be analyzed according to treatment 
received. 
 
RA 9.3 
Endpoints 
The following sections outline the efficacy endpoints for the RA sub-protocol: 
RA 9.3.1 Primary Endpoint 
x ACR50 response at Week 12 compared to baseline 
RA 9.3.2 Secondary Endpoints 
The following are the secondary efficacy endpoints as defined at Week 12: 
x Change from baseline in: 
o DAS28-CRP 
o DAS28-ESR 
o SDAI 
o CDAI 
x ACR20 response compared to baseline 
x ACR70 response compared to baseline 
RA 9.3.3 Additional Endpoints 
The following are the additional efficacy endpoints as defined at Week 12: 
x Change from baseline in: 
o Autoantibody titers 
o BTK occupancy 
o ACR component assessments: 
– Tender/painful joint count (68) and SJC (66) 
– PGA of Arthritis 
– SGA of disease activity 
– hsCRP 
– HAQ-DI 
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o RAMRIS scores of synovitis, osteitis (bone marrow edema), bone erosion, and 
cartilage loss (joint-space narrowing) 
o EQ-5 D-5 L score 
o PROMIS Fatigue 6 a 
 
The following are the additional efficacy endpoints as defined at Week 24: 
x Change from baseline in: 
o DAS28-CRP 
o DAS28-ESR 
o SDAI 
o CDAI 
x ACR20 response compared to baseline 
x ACR50 response compared to baseline 
x ACR70 response compared to baseline 
x Change from baseline in EQ-5 D-5 L score 
x Change from baseline in PROMIS Fatigue 6 a 
x Change from Week 12 to Week 24 in efficacy measures: 
o DAS28-CRP 
o DAS28-ESR 
o SDAI 
o CDAI 
x ACR20 response at Week 24 based on activity at Week 12 after pretreatment with 
branebrutinib or PBO (treatment effect of abatacept following treatment with branebrutinib 
versus PBO) 
x ACR50 response at Week 24 based on activity at Week 12 after pretreatment with 
branebrutinib or PBO (treatment effect of abatacept following treatment with branebrutinib 
versus PBO) 
x ACR70 response at Week 24 based on activity at Week 12 after pretreatment with 
branebrutinib or PBO (treatment effect of abatacept following treatment with branebrutinib 
versus PBO) 
x Change from Week 12 to Week 24 in: 
o Autoantibody titers 
o BTK occupancy 
o ACR component assessments: 
– 
Tender/painful joint count (68) and SJC (66) 
– 
PGA of Arthritis 
– 
SGA of disease activity 
– 
hsCRP 
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– 
HAQ-DI 
o RAMRIS scores of synovitis, osteitis (bone marrow edema), bone erosion, and 
cartilage loss (joint-space narrowing) 
o EQ-5 D-5 L 
o PROMIS Fatigue 6 a 
RA 9.3.4 PK Endpoints 
x Concentration values and PK parameters of branebrutinib and metabolites of clinical interest 
RA 9.3.5 Exploratory Endpoints 
x Evaluate the PK of branebrutinib and metabolites of clinical interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RA 9.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock. Section RA 9.4.1 provides a 
summary of planned statistical analyses of the primary and secondary efficacy endpoints. 
Additional and exploratory endpoints will be summarized in a descriptive manner. 
RA 9.4.1 Efficacy Analyses 
Efficacy data will be summarized using the FAS. Data will be summarized using descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum), unless otherwise 
specified, for continuous variables and frequency distributions (counts and percentages) for 
categorical variables. Efficacy data will be summarized separately for each sub-protocol and with 
each sub-protocol combined for variables that are similar among the sub-protocols. 
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For the RA sub-protocol, data through Week 12 will be presented for: 
x Branebrutinib 
x Branebrutinib PBO 
 
After Week 12, data may be presented for the following treatments for the RA sub-protocol: 
x Branebrutinib followed by Abatacept 
x PBO followed by Abatacept 
x Branebrutinib and PBO followed by Abatacept 
 
Endpoint 
Statistical Analysis Methods 
Primary 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for the primary endpoint will 
be analyzed using a Chi-square test. The 95% CI for each treatment group 
response rate and the difference in response rate for branebrutinib compared to 
PBO will be provided. If expected cell counts are not sufficient, then Fisher’s 
exact test will be used. P-values will be provided. 
Supportive Analyses 
A Bayesian approach combines current study PBO data and PBO data from 
historical RA studies will be employed. The probability of response rate 
difference between branebrutinib and PBO greater than 30% will be calculated 
with derived posterior distribution. Fixed borrowing or dynamic borrowing 
method will be implemented. 
Imputation Method 
Nonresponder imputation will be used for binary endpoints for subjects who 
discontinue study treatment early, start a protocol-prohibited medication/therapy 
prior to the specified timepoint, or otherwise have missing endpoint data for the 
specified timepoint. 
Other imputation methods may be considered for sensitivity analyses and will be 
described in the SAP if used. 
Secondary/ 
Additional 
General Analysis Methodology 
Response rates of branebrutinib compared to PBO for binary endpoints 
(responder/nonresponder) will be analyzed using a Chi-square test. The 95% CI 
for each treatment group response rate and the difference in response rate for 
branebrutinib compared to PBO will be provided. If expected cell counts are not 
sufficient, then Fisher’s exact test will be used. 
The same criteria used for primary endpoints for the nonresponder imputation 
will be applied for all secondary/additional binary endpoints. 
Continuous endpoints (change from baseline values) will be analyzed using 
analysis of covariance. The baseline value of the endpoint being tested will be 
added into the model as a covariate. Treatment differences based on 
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Endpoint 
Statistical Analysis Methods 
least-squares means and corresponding 2-sided 95% CIs will be provided for the 
difference between branebrutinib and PBO. 
Supportive analyses for continuous endpoints may be performed using MMRM 
to investigate response over time. Missing data are addressed in these models 
and assumed to be MAR. 
Testing Strategy for Secondary Endpoints 
There will be no alpha level adjustment for multiple endpoint testing. 
 
RA 9.4.1.1 Subgroup Analyses 
Subgroup analyses will be conducted for the primary and secondary efficacy endpoints on the FAS 
population. Subgroups that may be evaluated include the following: 
x Gender 
x Race 
x Tobacco use 
Additional subgroups defined for descriptive summaries may be specified in the SAP. 
RA 9.4.2 Safety Analyses 
Safety data will be descriptive in nature and will be summarized using the Safety Analysis Set. 
Data will be summarized using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum), unless otherwise specified, for continuous variables and frequency 
distributions (counts and percentages) for categorical variables. Safety data will be summarized 
separately for each sub-protocol and with all sub-protocols combined. 
For the RA sub-protocol, data through Week 12 will be presented for: 
x Branebrutinib 
x Branebrutinib PBO 
After Week 12, data may be presented for the following treatments for the RA sub-protocol: 
x Branebrutinib followed by Abatacept 
x PBO followed by Abatacept 
x Branebrutinib and PBO followed by Abatacept 
 
RA 9.4.2.1 
Adverse Events 
TEAEs are defined as AEs that occur after the subject received first dose of study treatment or if 
a preexisting condition worsens in severity or becomes serious after receiving the first dose of 
study treatment up to 30 days after the last dose of study treatment. All reported TEAEs, SAEs, 
deaths, AEs leading to study treatment discontinuation, and target AEIs will be summarized by 
MedDRA system organ class and preferred term. 
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RA 9.4.2.2 
Clinical Laboratory Tests 
Laboratory parameters will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities summarized by visit and shift tables will also be provided. For clinical 
laboratory test results, marked abnormalities will be defined in the SAP. 
RA 9.4.2.3 
Vital Signs and ECGs 
Vital signs and ECGs will be summarized as absolute and change from baseline values by visit. 
Baseline values are defined as the last nonmissing value prior to the first dose of study treatment. 
Marked abnormalities will be summarized by visit as well. For vital signs and ECGs, marked 
abnormalities will be defined in the SAP. 
RA 9.4.3 Other Analyses 
The PK, PD, and exploratory biomarker analyses will be described in the SAP finalized before 
database lock. Any population PK analysis and PD analyses will be presented separately from the 
main CSR. 
RA 9.4.4 Analysis and Reporting 
After all subjects in the RA sub-protocol have completed Week 12 efficacy assessments or 
discontinued treatment/study prior to Week 12, a database lock, inclusive of efficacy, safety, PK 
and PD, will occur for the RA sub-protocol. Analysis using data up to 12 weeks will be performed. 
Results of this 12-week analysis (100% of participants in RA sub-protocol) will be reviewed by 
an unblinded team that is independent of the study team responsible for study conduct. This activity 
will support early planning decisions on clinical development of the compound and will not change 
the conduct of this study (unless there is a safety concern). After all subjects in a sub-protocol have 
finished the respective sub-protocol and the data have been locked for that sub-protocol, final 
analyses for that sub-protocol will be performed. Details of these analyses will be described in the 
SAP. 
The study team responsible for managing the study, including Medical Monitors, will remain 
blinded to treatment assignment and the results of safety analysis until full database lock and 
treatment unblinding has occurred. The data will be reported only after completion of all 3 
sub-protocols. 
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2 
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Randomized, placebo-controlled, single and multiple ascending dose study to evaluate the 
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inadequate response to methotrexate (Study IM101174). Bristol Myers Squibb Company; 
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BMS-986195: One-month oral toxicity study in rats (Study DM16005). Bristol Myers 
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BMS-188667 abatacept (Orencia) Investigator's Brochure, Version 22. Bristol Myers 
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for the management of rheumatic disease in adult patients during the COVID-19 pandemic: 
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Society for Rheumatology for the care of patients with inflammatory rheumatic diseases in 
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infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, 
multi-national, Latin American lupus cohort. Lupus 2019;28(9):1101-10. 
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outcomes. Nat Rev Rheumatol 2021;17(2):71-2. 
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in autoimmune rheumatic diseases treated with disease-modifying anti-rheumatic drugs. 
Rheumatology (Oxford) 2020;59(12):3666-75. 
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Sun C, Gao J, Couzens L, et al. Seasonal influenza vaccination in patients with chronic 
lymphocytic leukemia treated with ibrutinib. JAMA Oncol 2016;2(12):1656-7. 
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against SARS-CoV-2 in immunosuppressed patients with rheumatic diseases: Position 
statement of the Greek Rheumatology Society. Mediterr J Rheumatol 2020;31(4):430-2. 
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Bijlsma JWJ. EULAR December 2020 view points on SARS-CoV-2 vaccination in 
patients with RMDs. Ann Rheum Dis 2021:annrheumdis-2020-219773. 
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Gelfand JM, Armstrong AW, Bell S, et al. National Psoriasis Foundation COVID-19 Task 
Force guidance for management of psoriatic disease during the pandemic: Version 2 - 
advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 
treatments. J Am Acad Dermatol 2021. 
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Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an anti-interferon-alpha receptor 
monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis 
Rheumatol 2017;69(2):376-86. 
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Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus 
International Collaborating Clinics classification criteria for systemic lupus erythematosus. 
Arthritis Rheum 2012;64(8):2677-86. 
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Merrill JT, Furie R, Werth VP, et al. Anifrolumab effects on rash and arthritis: impact of 
the type I interferon gene signature in the phase IIb MUSE study in patients with systemic 
lupus erythematosus. Lupus Sci Med 2018;5(1):e000284. 
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Bartlett SJ, Orbai AM, Duncan T, et al. Reliability and validity of selected PROMIS 
measures in people with rheumatoid arthritis. PLoS One 2015;10(9):e0138543. 
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Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement 
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Lai JS, Cella D, Yanez B, et al. Linking fatigue measures on a common reporting metric. 
J Pain Symptom Manage 2014;48(4):639-48. 
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Katz P, Margaretten M, Gregorich S, et al. Physical activity to reduce fatigue in rheumatoid 
arthritis: a randomized controlled trial. Arthritis Care Res (Hoboken) 2018;70(1):1-10. 
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safety of subcutaneous abatacept in adults with active primary Sjögrens syndrome 
(IM101603). Bristol Myers Squibb Company; 2019. Document Control No. 930138760. 
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IM128035 (Study IM128035). Bristol Myers Squibb Company; 2018. Document Control 
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equivalent of the Schirmer test. Arthritis Rheum 1985;28(10):1128-32. 
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Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for 
assessing keratoconjunctivitis sicca from the Sjogren's Syndrome International Registry. 
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ultrasound scoring system in Sjögren's syndrome using consensual definitions: an 
OMERACT ultrasound working group reliability exercise. Ann Rheum Dis 
2019;78(7):967-73. 
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Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center 
for Devices and Radiological Health. Draft May 2013. Publication UCM354468 Rev. 1. 
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Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT rheumatoid arthritis magnetic 
resonance imaging studies. Core set of MRI acquisitions, joint pathology definitions, and 
the OMERACT RA-MRI scoring system. J Rheumatol 2003;30(6):1385-6. 
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Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology 
preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The 
Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum 
1993;36(6):729-40. 
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Orencia (abatacept) [package insert]. Princeton, NJ: Bristol Myers Squibb Company; 2017. 
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study of abatacept or infliximab in combination with methotrexate in controlling disease 
activity in subjects with rheumatoid arthritis having an inadequate clinical response to 
methotrexate (Study IM101043); Double-blind (12-month) clinical study report synopsis. 
Bristol Myers Squibb Company; 2006. Document Control No. Pending. 
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controlled, adaptive design study to evaluate the efficacy and safety/pharmacokinetics of 
BMS-986142 in subjects with moderate to severe rheumatoid arthritis with an inadequate 
response to methotrexate with or without TNF inhibitors. (Study IM006016). Bristol Myers 
Squibb Company; 2019. Document Control No. Pending. 
 
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3 
APPENDICES 
APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
ACPA 
anti-citrullinated protein/peptide antibodies (also referred to as anti-CCP 
antibodies) 
ACR 
America College of Rheumatology 
ADA 
antidrug antibody 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AEI 
adverse events of interest 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANMAT 
National Administration of Foods, Drugs and Medical Devices (Argentina) 
 
 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC (0-T) 
area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve to the end of the dosing period 
 
 
BA/BE 
bioavailability/bioequivalence 
 
 
BCR 
B cell receptor 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (Germany) 
ȕ-HCG 
Beta-human chorionic gonadotropin 
BID 
twice daily 
BILAG 
British Isles Lupus Assessment Group 
BlyS 
B-lymphocyte stimulator (AKA BAFF) 
BTK 
Bruton’s tyrosine kinase 
C 
complement 
CD 
cluster of differentiation 
CDAI 
Clinical Disease Activity Index  
CEC 
Central Ethics Committee 
CH 
constant region heavy chain 
CI 
confidence interval 
CIA 
collagen-induced arthritis 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
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Cmax 
maximum observed concentration 
Cminss 
steady-state trough concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
Case Report Form 
CS 
corticosteroid 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
Clinical trial agreement 
CTLA 
cytotoxic T-lymphocyte-associated antigen 
Ctrough 
trough observed plasma concentration 
CXCL13 
C-X-C motif chemokine ligand 13 
CYP 
cytochrome P450 
DAS28 
Disease Activity Score 28 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DMARD 
disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
dsDNA 
double-stranded deoxyribonucleic acid 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
eCRF 
electronic case report form 
EDC 
RAVE electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
EQ 
Euro Quality 
EQ-5 D-5 L 
Euro Quality of Life Five Dimensions Questionnaire: 5 Level version 
ESR 
erythrocyte sedimentation rate 
ESSDAI 
EULAR Sjögren’s Syndrome Disease Activity Index 
ESSPRI 
EULAR Sjögren’s Syndrome Patients Reported Index 
EULAR 
European League Against Rheumatism 
FAS 
full analysis set 
)Fİ5 
Fc epsilon receptor 
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)FȖ5 
Fc gamma receptor 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FU 
follow-up 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire – Disease Activity 
HbA1c 
Hemoglobin A1c 
HBV 
hepatitis B virus 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HCQ 
hydroxychloroquine 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
hsCRP 
high-sensitivity C-reactive protein 
IA 
intra-articular 
IB 
Investigator’s Brochure 
IC 
immune complex 
 
 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IFN 
interferon 
Ig 
immunoglobulin 
IGRA 
interferon gamma-release assay 
IL 
interleukin 
IM 
intramuscular 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
intravenous(ly) 
IVIG 
intravenous immunoglobulin 
JAK 
Janus kinase 
LOCF 
last observation carried forward 
LTBI 
latent tuberculosis infection 
MAD 
multiple ascending dose 
MCII 
minimum clinically important improvement 
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mCLASI 
Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MMF 
Mycophenolate mofetil/mycophenolic acid  
MMP 
matrix metalloproteinase 
MMRM 
mixed model repeated measures 
6-MP 
6-mercaptopurine 
MRI 
magnetic resonance imaging 
MTX 
Methotrexate 
MTX-IR 
methotrexate-inadequate response 
Nab 
Nanoantibodies 
NOAEL 
no-observed-adverse-effect-level 
NRS 
Numeric rating score 
NSAID 
nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OATP 
organic anion transporting polypeptide 
PASS 
patient acceptable symptom rate 
PBO 
Placebo 
pBTK 
phosphorylated Bruton’s tyrosine kinase 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PGA 
Physician Global Assessment  
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PNS 
peripheral nervous system 
PRO 
patient-reported outcome 
PROFAD 
Profile of Fatigue and Discomfort 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
pSS 
primary Sjögren’s syndrome 
QD 
once daily 
QRG 
Quick Reference Guide 
QTcF 
QT interval with Fridericia’s correction 
QW 
once weekly 
RA 
rheumatoid arthritis 
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System 
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RANK 
receptor activator of nuclear factor kappa beta 
RANKL 
receptor activator of nuclear factor kappa beta-ligand 
RF 
rheumatoid factor 
RNA 
ribonucleic acid 
 
 
 
 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous(ly) 
 
 
SD 
Sprague-Dawley 
SDAI 
Simplified Disease Activity Index 
SDI 
(SLICC/ACR) Disease Index 
SGA 
Subject Global Assessment 
SG-US 
salivary gland ultrasonography 
SJC 
swollen joint count 
SJC68 
Swollen joint count (68 joints) 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SoA 
schedule of activities 
SOC 
standard of care 
ss 
steady-state 
 
 
 
 
SUSAR 
suspected, unexpected serious adverse reaction 
TB 
tuberculosis 
TBUT 
tear break-up time 
TBNK 
T cells, B cells, and natural killer cells 
TEAE 
treatment-emergent adverse event 
T-HALF 
apparent elimination half-life 
TJC 
tender joint count 
TJC66 
Tender joint count (66 joints) 
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Tmax 
time to maximum concentration 
TMJ 
temporomandibular joint 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
UPCR 
urine protein:creatinine ratio 
VAS 
visual analog scale 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
XLA 
X-linked agammaglobulinemia 
 
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APPENDIX 2 
STUDY GOVERNANCE CONSIDERATIONS 
The term ‘subject’ is used in the protocol to refer to a person who has consented to participate in 
the clinical research study. The term ‘subject’ used in the eCRF is intended to refer to a person 
(subject) who has consented to participate in the clinical research study. 
REGULATORY AND ETHICAL CONSIDERATIONS 
GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with: 
x Good Clinical Practice (GCP), as defined by the International Council for Harmonisation 
(ICH) in accordance with the ethical principles underlying European Union Directive 
2001/20/EC United States (US) CFR Title 21, Part 50 (21CFR50) applicable local 
requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive approval/favorable opinion by Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study. 
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, written consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the IB or product labeling information to be 
provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to: 
x IRB/IEC for Regulatory Authority(ies), if applicable by local regulations (per national 
requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
FINANCIAL DISCLOSURE 
Investigators and sub-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. 
INFORMED CONSENT PROCESS 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
The Sponsor or designee will provide the investigator with an appropriate (ie, global or local) 
sample ICF, which will include all elements required by ICH, GCP, and applicable regulatory 
requirements. The sample ICF will adhere to the ethical principles that have their origin in the 
Declaration of Helsinki. 
Investigators must: 
x Provide a copy of the ICF and written information about the study in the language in which 
the subject is most proficient prior to clinical study participation. The language must be 
nontechnical and easily understood. 
x Allow time necessary for subject to inquire about the details of the study. 
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x Obtain an ICF signed and personally dated by the subject and by the person who conducted 
the informed consent discussion. 
x Obtain the IRB/IEC’s written approval/favorable opinion of the written ICF and any other 
information to be provided to the subjects, prior to the beginning of the study, and after 
any revisions are completed for new information. 
 
Revise the ICF whenever important new information becomes available that is relevant to the 
subject’s consent. The investigator, or a person designated by the investigator, should fully inform 
the subject of all pertinent aspects of the study and of any new information relevant to the subject’s 
willingness to continue participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF and, in 
the US, the subjects’ signed Health Insurance Portability and Accountability Act Authorization. 
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
SOURCE DOCUMENTS 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical study activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
AE tracking/reporting, protocol-required assessments, and/or drug accountability records). 
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS 
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a health authority. 
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If 
Then 
Supplied by BMS (or 
its vendors): 
Records or logs must comply with applicable regulations and guidelines and should 
include: 
x 
amount received and placed in storage area 
x 
amount currently in storage area 
x 
label identification number or batch number 
x 
amount dispensed to and returned by each subject, including unique subject 
identifiers 
x 
amount transferred to another area/site for dispensing or storage 
x 
nonstudy disposition (eg, lost, wasted) 
x 
amount destroyed at study site, if applicable 
x 
amount returned to BMS 
x 
retain samples for bioavailability/bioequivalence, if applicable 
x 
dates and initials of person responsible for investigational product 
dispensing/accountability, as per the Delegation of Authority Form. 
Sourced by site, and 
not supplied by BMS 
or its vendors 
(examples include 
investigational product 
sourced from the sites 
stock or commercial 
supply, or a specialty 
pharmacy) 
The investigator or designee accepts responsibility for documenting traceability and 
study drug integrity in accordance with requirements applicable under law and the 
standard operating procedures of the sourcing pharmacy. 
These records should include: 
x 
label identification number or batch number 
x 
amount dispensed to and returned by each subject, including unique subject 
identifiers 
x 
dates and initials of person responsible for investigational product 
dispensing/accountability, as per the Delegation of Authority Form. 
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the case report form (CRF) must be consistent with the source documents or the 
discrepancies must be explained. Additional clinical information may be collected and analyzed 
in an effort to enhance understanding of product safety. CRFs may be requested for AEs and/or 
laboratory abnormalities that are reported or identified during the course of the study. 
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If an 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
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The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF and SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For electronic CRFs, review and approval/signature is completed electronically 
through the BMS electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals 
MONITORING 
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents. 
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential. 
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study. 
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed. 
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
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RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by BMS, a vendor, or sourced by the investigator) 
such as partially used study treatment containers, vials, and syringes may be destroyed on site. 
If … 
Then 
Study treatments supplied by 
BMS (including its vendors) 
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study treatments 
containers must be immediately destroyed as required for 
safety, or to meet local regulations (eg, cytotoxics or 
biologics). 
If study treatments will be returned, the return will be 
arranged by the responsible Study Monitor. 
Study treatments sourced by site, 
not supplied by BMS (or its 
vendors) (eg, study treatments 
sourced from the site’s stock or 
commercial supply, or a 
specialty pharmacy) 
It is the investigator’s or designee’s responsibility to 
dispose of all containers according to the institutional 
guidelines and procedures. 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
x On-site disposal practices must not expose humans to risks from the drug. 
x On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
x Written procedures for on-site disposal are available and followed. The procedures must 
be filed with the site’s Standard Operating Procedures and a copy provided to BMS upon 
request. 
x Records are maintained that allow for traceability of each container, including the date 
disposed, quantity disposed, and identification of the person disposing the containers. The 
method of disposal (eg, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor) must be documented. 
x Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical study period. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers. 
If conditions for destruction cannot be met, the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of nonstudy 
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treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee. 
For sites that will not destroy study treatment on site, it is the investigator’s or designee’s 
responsibility to arrange for disposal of all empty study treatment containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of full or partially used study treatments supplied by BMS or its vendors will be 
arranged by the responsible Study Monitor. 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory investigator must be selected to sign the CSR. 
For this protocol, the Signatory investigator will be selected as appropriate based on the following 
criteria: 
x External Principal investigator designated at protocol development 
x National Coordinating investigator 
x Study Steering Committee chair or their designee 
x Subject recruitment (eg, among the top quartile of enrollers) 
x Involvement in study design 
x Regional representation (eg, among top quartile of enrollers from a specified region or 
country) 
x Other criteria (as determined by the study team) 
 
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing study site or investigator participation in the 
study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA 
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APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
ADVERSE EVENTS 
Adverse Event Definition: 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and 
that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug. 
Events Meeting the AE Definition 
x Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Note that 
abnormal lab tests or other safety assessments should only be reported as AEs if the 
final diagnosis is not available. Once the final diagnosis is known, the reported term 
should be updated to be the diagnosis. 
x Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected DDI. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, as a verbatim term (as reported by 
the investigator), should not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae and should specify "intentional overdose" as the 
verbatim term.  
Events NOT Meeting the AE Definition 
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
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DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
SERIOUS ADVERSE EVENTS 
Serious Adverse Event Definition: Any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening (defined as an event in which the subject 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 causes prolongation of existing hospitalization (see note 
below) 
Note: The following hospitalizations are not considered SAEs in BMS clinical studies: 
x a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event). 
x elective surgery planned prior to signing consent. 
x admissions as per protocol for a planned medical/surgical procedure. 
x routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy). 
x medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
x admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
x admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols). 
Results in persistent or significant disability or permanent damage 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
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home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important 
medical event (see Section SLE 8.2.8 for the definition of potential DILI; same definition for 
all sub-protocols). 
 
Pregnancy and potential DILI must follow the same transmission timing and processes to BMS as 
used for SAEs (see Section SLE 8.2.6 for reporting pregnancies; same for all sub-protocols). 
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
EVALUATING AES AND SAES 
Assessment of Intensity 
The intensity of AEs is determined by a physician and will use the following levels: 
x Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and 
not interfering with everyday activities. 
x Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
x Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
Assessment of Causality 
x The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. A “reasonable possibility of a relationship” conveys 
that there are facts, evidences, and/or arguments to suggest a causal relationship rather 
than a relationship cannot be ruled out. 
x The investigator will use clinical judgment to determine the relationship. 
x Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
x The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
x For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
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x There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to Sponsor. 
x The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
x The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required. Note: Follow-
up SAE reports must include the same investigator term(s) initially reported. 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 
All SAEs must be followed to resolution or stabilization. 
 
REPORTING OF SAES TO SPONSOR OR DESIGNEE 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
 
Drug Safety within 24 hours of awareness of the event. 
SAEs must be recorded on the SAE Report Form. For studies capturing SAEs through 
electronic data capture (EDC), electronic submission is the required method for reporting. In 
the event the electronic system is unavailable for transmission, paper forms must be used and 
submitted immediately. When paper forms are used, the original paper forms are to remain on 
site. 
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission to: 
SAE Email Address: 
 
SAE Fax Number: 
 
Americas: 
 
 
Europe/East Asia Pacific: 
 
SAE Telephone Contact - For questions on SAE/pregnancy reporting, please call: 
 
Americas: 
 
 
Europe/East Asia Pacific: 
 
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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
Note: Appendix 4 provides general information and definitions related to WOCBP and methods 
of contraception that can be applied to most clinical studies. For information specific to 
Study IM014029 regarding acceptable contraception requirements for female and male subjects, 
refer to Section 5.1 of each sub-protocol. Only the contraception methods as described in 
Section 5.1 are acceptable for this study. 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
x Premenarchal 
x Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
x Postmenopausal female 
 A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause. 
 
Note:  Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines, and the investigators should use their judgment 
in checking serum FSH levels. 
x 1 week minimum for vaginal hormonal products (rings, creams, gels) 
x 4 week minimum for transdermal products 
x 8 week minimum for oral products 
 
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal. 
End of Relevant Systemic Exposure 
x End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant 
for human teratogenicity or fetotoxicity. This should be evaluated in context of safety 
margins from the no-observed-adverse-effect level (NOAEL) or the time required for 5 
half-lives of the IMP to pass. 
 
METHODS OF CONTRACEPTION 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a  
x Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (This method of contraception can only be used 
by WOCBP subjects in studies where hormonal contraception is permitted by the study 
protocol)b 
 oral (birth control pills) 
 intravaginal (vaginal birth control suppositories, rings, creams, gels) 
 transdermal 
x Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy 
x Progestogen-only hormonal contraception associated with inhibition of ovulation (This 
method of contraception can only be used by WOCBP subjects in studies where hormonal 
contraception is permitted by the study protocol)b 
 oral 
 injectable 
x Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy 
Highly Effective Methods That Are User Independent  
x Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
subjects in studies where hormonal contraception is permitted by the study protocol)b 
x Intrauterine device (IUD) 
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x Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP subjects in studies where hormonal contraception is permitted by the study 
protocol)b,c 
x Bilateral tubal occlusion 
x Vasectomized partner 
Having a vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
Male subjects will be required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP; even if the subjects have undergone a successful vasectomy or if 
their partner is already pregnant or breastfeeding. 
x Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
x Continuous abstinence must begin at least 30 days prior to initiation of study therapy. 
x It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
x WOCBP subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 2. 
x Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP subjects chooses to forego complete abstinence. 
x Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine hormone-releasing systems are acceptable methods of contraception in the absence of definitive drug 
interaction studies when hormone exposures from intrauterine devices do not alter contraception effectiveness 
 
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Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly. 
x Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously 
x Diaphragm with spermicide 
x Cervical cap with spermicide 
x Vaginal Sponge with spermicide 
x Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
subjects in studies where hormonal contraception is prohibited) 
Unacceptable Methods of Contraception 
x Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
x Withdrawal (coitus interruptus) 
x Spermicide only 
x LAM 
 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 8.2.6 of each sub-protocol and the Appendix for Adverse 
Events and Serious Adverse Events Definitions and procedures for Evaluating, Follow-up, and 
Reporting. 
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APPENDIX 5 
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING 
CLINICS CLASSIFICATION (SLICC) CRITERIA FOR SYSTEMIC 
LUPUS ERYTHEMATOSUS 
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APPENDIX 6 
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING 
CLINICS/AMERICAN COLLEGE OF RHEUMATOLOGY 
DAMAGE INDEX (SDI) 
 
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APPENDIX 7 
BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG)-2004 
INDEX 
 
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Sources: 
Isenberg, DA, Rahman A, Allen E, et al. BILAG 2004. Development and initial validation of an updated 
version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic 
lupus erythematosus. Rheumatology (Oxford) 2005;44(7):902-6. 
Yee CS, Farewell V, Isenberg DA, et al. Revised British Isles Lupus Assessment Group 2004 Index - A 
Reliable Tool for Assessment of Systemic Lupus Erythematosus Activity. Arthritis Rheum 2006;54:3300–
05. 
Yee CS, Farewell V, Isenberg DA, et al. British Isles Lupus Assessment Group 2004 index is valid for 
assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 2007;56(12):4113-19. 
Yee CS, Cresswell L, Farewell V, et al: Numerical scoring for the BILAG-2004 index. Rheumatology 
(Oxford) 2010 Sep;49(9):1665-9. 
 
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APPENDIX 8 
SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE ACTIVITY 
INDEX 2000 (SLEDAI-2K) 
For Assessment over a 30-Day Window (J. Rheumatol. Copyright©2002) 
For Reference Use Only 
 
Gladman DD, Ibanez D, Urowitz MB. Systematic lupus erythematosus disease activity index 
2000. J Rheumatol. 2002:29:288-91. 
Touma Z, Urowitz MB, Glasman DD. Sledai-2K 10 days versus 30 days in a longitudinal 
evaluation. Lupus. 2011. Jan:20(1): 67-70.) 
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APPENDIX 9 
CUTANEOUS LUPUS ERYTHEMATOSUS DISEASE AREA AND 
SEVERITY INDEX (CLASI) 
The CLASI is a sensitive, validated instrument developed by Victoria Werth, M.D. and her 
colleagues at the University of Pennsylvania in 2005 (copyright 2009 University of Pennsylvania, 
All Rights Reserved) for use in clinical studies to measure Cutaneous Lupus Erythematosus (CLE) 
disease activity and damage. 
The modified (mCLASI) used in this study is defined as the activity portions of CLASI that
describe skin erythema, scale/hypertrophy and inflammation of the scalp. Damage, oral ulcers, and 
alopecia without scalp inflammation are excluded from the mCLASI activity score. 
 
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Sources: 
Albrecht J, Taylor L, Berlin JA, et al. The CLASI (Cutaneous Lupus Erythematosus Disease Area 
and Severity Index): An outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol 
2005;125:889 -94. Highlighted area indicates assessment by modified CLASI (mCLASI) criteria. 
Bonilla-Martinez ZL, Albrecht J, Troxel, AB, et al. The Cutaneous Lupus Erythematosus Disease 
Area and Severity Index - A responsive instrument to measure activity and damage in patients with 
cutaneous lupus erythematosus. Arch Dermatol 2008;144(2):173-80. 
Use of the modified CLASI assessment: 
Merrill JT, Furie R, Werth VP, et al. Anifrolumab effects on rash and arthritis: impact of the type I 
interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus. 
Lupus Science & Medicine 2018;5:e000284, doi:10.1136/lupus-2018-000284 
 
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APPENDIX 10 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(PGA) (SLE; VAS) 
The investigator will rate the overall status of the subject in response to the following statement: 
“How do you assess your patient’s (the subject’s) current lupus disease activity as compared to the 
activity and Physician Global Assessment (PGA) at the last visit? Please indicate by placing a 
mark on the line below.” 
  
 I _________________________________________________________________I 
  
0 mm  
 
 
 
 
 
 
 
100 mm 
No disease activity 
 
 
 
 
Worst possible disease activity 
 
x 
0 is ‘no disease activity’ indicating very good, asymptomatic, with no limitation of normal 
activities. 
x 
100 indicates ‘the worst possible disease activity’ and is at the very end of the scale. This 
refers to the most severe possible disease in SLE, and does not reflect the most severe 
disease ever seen in a particular subject, but the most severe disease ever seen in all SLE 
patients. This extreme level of disease activity would be expected to be seen only in 
hospitalized patients. 
x 
When scoring the PGA, the assessor should always consider current activity as 
compared to the activity and PGA captured at the prior visit. 
After marking the line on the yellow paper PGA Source Document, use the study-specific ruler 
provided to measure the length from 0 to your mark, to the nearest mm. Record this value on the 
paper PGA Source Document form printed on yellow paper and include signature of assessor and 
date assessed. Enter PGA (mm) on the PGA eCRF for the appropriate visit. 
 
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APPENDIX 11 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(SGA) (SLE; VAS) 
The Subject Global Assessment of Disease Activity will be captured on an eCOA device. The 
value will be stored as 0-100. 
 
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APPENDIX 12 
PATIENT-REPORTED OUTCOMES MEASUREMENT 
INFORMATION SYSTEM-FATIGUE INSTRUMENT 
(PROMIS FATIGUE 6 A) (SLE; PSS; RA) 
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APPENDIX 13 
EQ-5 D-5 L, EQ VAS (SLE; PSS, RA) 
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APPENDIX 14 
SYSTEMIC LUPUS ERYTHMASTOSUS PAIN NUMERIC RATING 
SCORE (SLE, NRS) 
 
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APPENDIX 15 
EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) 
SJÖGREN’S SYNDROME DISEASE ACTIVITY INDEX (ESSDAI, 
PSS) 
 
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Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjogren's syndrome disease 
activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2015;74(5):859-66. 
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APPENDIX 16 
DISEASE ACTIVITY SCORE 28 C-REACTIVE PROTEIN 
(DAS28-CRP) (PSS; RA) 
The DAS28-CRP score will be calculated programmatically using the 28 Tender Joint Count, the 
28 Swollen Joint Count, the hsCRP, and the subject global assessment of disease activity VAS 
using the following formula. 
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APPENDIX 17 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(PGA) (PSS) 
The investigator will rate the overall status of the subject in response to the following statement: 
“How do you assess your patient’s (the subject’s) current primary Sjögren’s disease activity as 
compared to the activity and PGA at the last visit? Please indicate by placing a mark on the line 
below.” 
  
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 100 
No disease Worst possible 
activity disease activity 
x 
0 is ‘no disease activity’ indicating very good, asymptomatic, with no limitation of normal 
activities. 
x 
100 indicates ‘the worst possible disease activity’ and is at the very end of the scale. This 
refers to the most severe possible disease in Sjögren’s, and does not reflect the most severe 
disease ever seen in a particular subject, but the most severe disease ever seen in all SLE 
patients. This extreme level of disease activity would be expected to be seen only in 
hospitalized patients. 
x 
When scoring the PGA, the assessor should always consider current activity as 
compared to the activity and PGA captured at the prior visit. 
After marking the line on the paper PGA Source Document, use the study-specific ruler provided 
to measure the length from 0 to your mark, to the nearest mm. Record this value on the paper PGA 
Source Document form printed on green paper and include signature of assessor and date assessed. 
Enter PGA (mm) on the PGA eCRF for the appropriate visit. 
 
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APPENDIX 18 
EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) 
SJÖGREN’S SYNDROME PATIENT-REPORTED INDEX 
(ESSPRI) (PSS) 
 
 
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APPENDIX 19 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(SGA) (PSS;VAS) 
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APPENDIX 20 
SIMPLIFIED DISEASE ACTIVITY INDEX (SDAI) (RA) 
The SDAI is the sum of the tender joint score (range 0 to 28), the swollen joint score (range 0 
to 28), the subject global assessment (SGA) of disease activity (range 0 to 10 in increments of 0.5), 
the PGA of disease activity (range 0 to 10 in increments of 0.5), and C-reactive protein (CRP) test 
result. 
The SDAI score will be calculated programmatically by the Sponsor or designee. 
 
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APPENDIX 21 
CLINICAL DISEASE ACTIVITY INDEX (CDAI) (RA) 
The CDAI is the sum of the tender joint score (range 0 to 28), the swollen joint score (range 0 
to 28), the SGA of disease activity (range 0 to 10 in increments of 0.5), and the PGA of disease 
activity (range 0 to 10 in increments of 0.5) 
The CDAI composite score will be calculated programmatically by eCOA vendor. 
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APPENDIX 22 
AMERICAN COLLEGE OF RHEUMATOLOGY DISEASE 
ACTIVITY SCORE-28 ERYTHROCYTE SEDIMENTATION RATE 
(DAS28-ESR) (RA) 
The DAS28-ESR score will be calculated programmatically using the 28 Tender Joint Count, the 
28 Swollen Joint Count, the ESR, and the subject global assessment of disease activity VAS 
using the following formula. 
 
DAS28-ESR = 0.56*(t28) + 0.28*(sw28) + 0.70*Ln(ESR) + 0.014*VAS 
 
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APPENDIX 23 
AMERICAN COLLEGE OF RHEUMATOLOGY HEALTH 
ASSESSMENT QUESTIONNAIRE DISABILITY INDEX (HAQ-DI) 
(RA) 
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Sources: 
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment questionnaire, 
disability and pain scales. J Rheumatol 1982;9:789-93. 
Fries JF, Spitz PW, Kraines G, Holman H. Measurement of patient outcome in arthritis. Arthritis 
Rheumatol 1980;23:137-45. 
Ramey D, Raynauld JP, Fries JF. The health assessment questionnaire 1992: status and review. 
Arthritis Care Res 1992;5:199-29. 
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APPENDIX 24 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY (RA) 
(VAS) 
 
 
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APPENDIX 25 
RHEUMATOID ARTHITIS MAGNETIC RESONANCE IMAGING 
SCORING SYSTEM (RAMRIS) 
 
 
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APPENDIX 26 
PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
(RA) (VAS) 
The investigator will rate the overall status of the subject in response to the following statement in 
eCOA device:
 
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APPENDIX 27 
ADME GENES 
ADME Gene List (pharmaadme.org. accessed 09-Aug-2019) 
Gene Symbol 
Full Gene Name 
Core ADME Gene List 
ABCB1 
ATP-binding cassette, subfamily B (MDR/TAP), member 1 
ABCC2 
ATP-binding cassette, subfamily C (CFTR/MRP), member 2 
ABCG2 
ATP-binding cassette, subfamily G (WHITE), member 2 
CYP1A1 
cytochrome P450, family 1, subfamily A, polypeptide 1 
CYP1A2 
cytochrome P450, family 1, subfamily A, polypeptide 2 
CYP2A6 
cytochrome P450, family 2, subfamily A, polypeptide 6 
CYP2B6 
cytochrome P450, family 2, subfamily B, polypeptide 6 
CYP2C19 
cytochrome P450, family 2, subfamily C, polypeptide 19 
CYP2C8 
cytochrome P450, family 2, subfamily C, polypeptide 8 
CYP2C9 
cytochrome P450, family 2, subfamily C, polypeptide 9 
CYP2D6 
cytochrome P450, family 2, subfamily D, polypeptide 6 
CYP2E1 
cytochrome P450, family 2, subfamily E, polypeptide 1 
CYP3A4 
cytochrome P450, family 3, subfamily A, polypeptide 4 
CYP3A5 
cytochrome P450, family 3, subfamily A, polypeptide 5 
DPYD 
dihydropyrimidine dehydrogenase 
GSTM1 
glutathione S-transferase M1 
GSTP1 
glutathione S-transferase pi 
GSTT1 
glutathione S-transferase theta 1 
NAT1 
N-acetyltransferase 1 (arylamine N-acetyltransferase) 
NAT2 
N-acetyltransferase 2 (arylamine N-acetyltransferase) 
SLC15A2 
solute carrier family 15 (H+/peptide transporter), member 2 
SLC22A1 
solute carrier family 22 (organic cation transporter), member 1 
SLC22A2 
solute carrier family 22 (organic cation transporter), member 2 
SLC22A6 
solute carrier family 22 (organic anion transporter), member 6 
SLCO1B1 
solute carrier organic anion transporter family, member 1B1 
SLCO1B3 
solute carrier organic anion transporter family, member 1B3 
SULT1A1 
sulfotransferase family, cytosolic, 1 A, phenol-preferring, member 1 
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Gene Symbol 
Full Gene Name 
TPMT 
thiopurine S-methyltransferase 
UGT1A1 
UDP glucuronosyltransferase 1 family, polypeptide A1 
UGT2B15 
UDP glucuronosyltransferase 2 family, polypeptide B15 
UGT2B17 
UDP glucuronosyltransferase 2 family, polypeptide B17 
UGT2B7 
UDP glucuronosyltransferase 2 family, polypeptide B7 
Extended ADME Gene List 
ABCB8 
ATP-binding cassette, subfamily B (MDR/TAP), member 8 
ABCC12 
ATP-binding cassette, subfamily C (CFTR/MRP), member 12 
ABCC3 
ATP-binding cassette, subfamily C (CFTR/MRP), member 3 
ABCC4 
ATP-binding cassette, subfamily C (CFTR/MRP), member 4 
AHR 
aryl hydrocarbon receptor 
ALDH4A1 
aldehyde dehydrogenase 4 family, member A1 
ALDH5A1 
aldehyde dehydrogenase 5 family, member A1 
ALDH6A1 
aldehyde dehydrogenase 6 family, member A1 
CES1 
carboxylesterase 1 (monocyte/macrophage serine esterase 1) 
CES2 
carboxylesterase 2 (intestine, liver) 
CYP7A1 
cytochrome P450, family 7, subfamily A, polypeptide 1 
EPHX1 
epoxide hydrolase 1, microsomal (xenobiotic) 
FMO3 
flavin containing monooxygenase 3 
GSTA1 
glutathione S-transferase A1 
GSTA2 
glutathione S-transferase A2 
GSTA3 
glutathione S-transferase A3 
GSTA4 
glutathione S-transferase A4 
GSTA5 
glutathione S-transferase A5 
GSTM2 
glutathione S-transferase M2 (muscle),glutathione S-transferase M4 
GSTM3 
glutathione S-transferase M3 (brain) 
GSTM4 
glutathione S-transferase M4 
GSTO1 
glutathione S-transferase omega 1,glutathione S-transferase omega 2 
GSTO2 
glutathione S-transferase omega 2 
GSTT2 
glutathione S-transferase theta 2 
SLC10A1 
solute carrier family 10 (sodium/bile acid cotransporter family), member 1 
SLC15A1 
solute carrier family 15 (oligopeptide transporter), member 1 
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Gene Symbol 
Full Gene Name 
SLC22A11 
solute carrier family 22 (organic anion/cation transporter), member 11 
SLC22A8 
solute carrier family 22 (organic anion transporter), member 8 
SLC7A5 
solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 
SLCO1A2 
solute carrier organic anion transporter family, member 1A2 
SLCO2B1 
solute carrier organic anion transporter family, member 2B1 
SULT1A2 
sulfotransferase family, cytosolic, 1 A, phenol-preferring, member 2 
SULT1A3 
sulfotransferase family, cytosolic, 1 A, phenol-preferring, member 3 
SULT1B1 
sulfotransferase family, cytosolic, 1B, member 1 
UGT1A3 
UDP glucuronosyltransferase 1 family, polypeptide A3 
UGT1A6 
UDP glucuronosyltransferase 1 family, polypeptide A6 
UGT1A7 
UDP glucuronosyltransferase 1 family, polypeptide A7 
UGT1A8 
UDP glucuronosyltransferase 1 family, polypeptide A8 
UGT1A9 
UDP glucuronosyltransferase 1 family, polypeptide A9 
UGT2A1 
UDP glucuronosyltransferase 2 family, polypeptide A1 
UGT2B11 
UDP glucuronosyltransferase 2 family, polypeptide B11 
UGT2B28 
UDP glucuronosyltransferase 2 family, polypeptide B28 
UGT2B4 
UDP glucuronosyltransferase 2 family, polypeptide B4 
ABCA1 
ATP-binding cassette, subfamily A (ABC1), member 1 
ABCA4 
ATP-binding cassette, subfamily A (ABC1), member 4 
ABCB11 
ATP-binding cassette, subfamily B (MDR/TAP), member 11 
ABCB4 
ATP-binding cassette, subfamily B (MDR/TAP), member 4 
ABCB5 
ATP-binding cassette, subfamily B (MDR/TAP), member 5 
ABCB6 
ATP-binding cassette, subfamily B (MDR/TAP), member 6 
ABCB7 
ATP-binding cassette, subfamily B (MDR/TAP), member 7 
ABCC1 
ATP-binding cassette, subfamily C (CFTR/MRP), member 1 
ABCC10 
ATP-binding cassette, subfamily C (CFTR/MRP), member 10 
ABCC11 
ATP-binding cassette, subfamily C (CFTR/MRP), member 11 
ABCC5 
ATP-binding cassette, subfamily C (CFTR/MRP), member 5 
ABCC6 
ATP-binding cassette, subfamily C (CFTR/MRP), member 6 
ABCC8 
ATP-binding cassette, subfamily C (CFTR/MRP), member 8 
ABCC9 
ATP-binding cassette, subfamily C (CFTR/MRP), member 9 
ABCG1 
ATP-binding cassette, subfamily G (WHITE), member 1 
ADH1A 
alcohol dehydrogenase 1 A (class I), alpha polypeptide 
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Gene Symbol 
Full Gene Name 
ADH1B 
alcohol dehydrogenase IB (class I), beta polypeptide 
ADH1C 
alcohol dehydrogenase 1C (class I), gamma polypeptide 
ADH4 
alcohol dehydrogenase 4 (class II), pi polypeptide 
ADH5 
alcohol dehydrogenase 5 (class III), chi polypeptide,methionyl aminopeptidase 1 
ADH6 
alcohol dehydrogenase 6 (class V) 
ADH7 
alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide 
ALDH1A1 
aldehyde dehydrogenase 1 family, member A1 
ALDH1A2 
aldehyde dehydrogenase 1 family, member A2 
ALDH1A3 
aldehyde dehydrogenase 1 family, member A3 
ALDH1B1 
aldehyde dehydrogenase 1 family, member B1 
ALDH2 
aldehyde dehydrogenase 2 family (mitochondrial) 
ALDH3A1 
aldehyde dehydrogenase 3 family, memberA1 
ALDH3A2 
aldehyde dehydrogenase 3 family, member A2 
ALDH3B1 
aldehyde dehydrogenase 3 family, member B1 
ALDH3B2 
aldehyde dehydrogenase 3 family, member B2 
ALDH7A1 
aldehyde dehydrogenase 7 family, member A1 
ALDH8A1 
aldehyde dehydrogenase 8 family, member A1 
ALDH9A1 
aldehyde dehydrogenase 9 family, member A1 
AOX1 
aldehyde oxidase 1 
ARNT 
aryl hydrocarbon receptor nuclear translocator 
CBR1 
carbonyl reductase 1 
CBR3 
carbonyl reductase 3 
CDA 
cytidine deaminase 
CYB5R3 
cytochrome b5 reductase 3 
CYP11A1 
cytochrome P450, family 11, subfamily A, polypeptide 1 
CYP11B1 
cytochrome P450, family 11, subfamily B, polypeptide 1 
CYP11B2 
cytochrome P450, family 11, subfamily B, polypeptide 2 
CYP17A1 
cytochrome P450, family 17, subfamily A, polypeptide 1 
CYP1B1 
cytochrome P450, family 1, subfamily B, polypeptide 1 
CYP20A1 
cytochrome P450, family 20, subfamily A, polypeptide 1 
CYP20A1 
cytochrome P450, family 20, subfamily A, polypeptide 1 
CYP21A2 
cytochrome P450, family 21, subfamily A, polypeptide 2 
CYP24A1 
cytochrome P450, family 24, subfamily A, polypeptide 1 
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2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
350 
Gene Symbol 
Full Gene Name 
CYP26A1 
cytochrome P450, family 26, subfamily A, polypeptide 1 
CYP27A1 
cytochrome P450, family 27, subfamily A, polypeptide 1 
CYP2A13 
cytochrome P450, family 2, subfamily A, polypeptide 13 
CYP2A7 
cytochrome P450, family 2, subfamily A, polypeptide 7 
CYP2C18 
cytochrome P450, family 2, subfamily C, polypeptide 18 
CYP2F1 
cytochrome P450, family 2, subfamily F, polypeptide 1 
CYP2J2 
cytochrome P450, family 2, subfamily J, polypeptide 2 
CYP39A1 
cytochrome P450, family 39, subfamily A, polypeptide 1 
CYP3A43 
cytochrome P450, family 3, subfamily A, polypeptide 43 
CYP3A7 
cytochrome P450, family 3, subfamily A, polypeptide 7 
CYP4B1 
cytochrome P450, family 4, subfamily B, polypeptide 1 
CYP4F11 
cytochrome P450, family 4, subfamily F, polypeptide 11 
CYP51A1 
cytochrome P450, family 51, subfamily A, polypeptide 1 
EPHX2 
epoxide hydrolase 2, cytoplasmic 
FMO1 
flavin containing monooxygenase 1 
FMO2 
flavin containing monooxygenase 2 
FMO4 
flavin containing monooxygenase 4 
FMO5 
flavin containing monooxygenase 5 
GPX2 
glutathione peroxidase 2 (gastrointestinal) 
GPX3 
glutathione peroxidase 3 (plasma) 
GPX7 
glutathione peroxidase 7 
GSR 
glutathione reductase 
GSTK1 
glutathione S-transferase kappa 1 
GSTM5 
glutathione S-transferase M5 
GSTZ1 
glutathione transferase zeta 1 (maleylacetoacetate isomerase) 
NNMT 
nicotinamide N-methyltransferase 
NR1I2 
nuclear receptor subfamily 1, group I, member 2 
NR1I3 
nuclear receptor subfamily 1, group I, member 3 
PNMT 
phenylethanolamine N-methyltransferase 
PON1 
paraoxonase 1 
PON2 
paraoxonase 2 
PON3 
paraoxonase 3 
POR 
P450 (cytochrome) oxidoreductase 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
351 
Gene Symbol 
Full Gene Name 
PPARD 
peroxisome proliferative activated receptor, delta 
PPARG 
peroxisome proliferative activated receptor, gamma 
RXRA 
retinoid X receptor, alpha 
SLC10A2 
solute carrier family 10 (sodium/bile acid cotransporter family), member 2 
SLC13A1 
solute carrier family 13 (sodium/sulfate symporters), member 1 
SLC13A2 
solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 2 
SLC13A3 
solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 3 
SLC16A1 
solute carrier family 16 (monocarboxylic acid Transporter), member 1 
SLC19A1 
solute carrier family 19 (folate transporter), member 1 
SLC22A10 
solute carrier family 22 (organic anion/cation transporter), member 10 
SLC22A12 
solute carrier family 22 (organic anion/cation transporter), member 12 
SLC22A13 
solute carrier family 22 (organic cation transporter), member 13 
SLC22A14 
solute carrier family 22 (organic cation transporter), member 14 
SLC22A15 
solute carrier family 22 (organic cation transporter), member 15 
SLC22A16 
solute carrier family 22 (organic cation transporter), member 16 
SLC22A17 
solute carrier family 22 (organic cation transporter), member 17 
SLC22A18 
solute carrier family 22 (organic cation transporter), member 18 
SLC22A18AS solute carrier family 22 (organic cation transporter), member 18 antisense 
SLC22A3 
solute carrier family 22 (extraneuronal monoamine transporter), member 3 
SLC22A4 
solute carrier family 22 (organic cation transporter), member 4 
SLC22A5 
solute carrier family 22 (organic cation transporter), member 5 
SLC22A7 
solute carrier family 22 (organic anion transporter), member 7 
SLC22A9 
solute carrier family 22 (organic anion/cation transporter), member 9 
SLC27A1 
solute carrier family 27 (fatty acid transporter), member 1 
SLC28A1 
solute carrier family 28 (sodium-coupled nucleoside transporter), member 1 
SLC28A2 
solute carrier family 28 (sodium-coupled nucleoside transporter), member 2 
SLC28A3 
solute carrier family 28 (sodium-coupled nucleoside transporter), member 3 
SLC29A1 
solute carrier family 29 (nucleoside Transporter), member 1 
SLC29A2 
solute carrier family 29 (nucleoside Transporter), member 2 
SLC2A4 
solute carrier family 2 (facilitated glucose transporter), member 4 
SLC2A5 
solute carrier family 2 (facilitated glucose/fructose transporter), member 5 
SLC5A6 
solute carrier family 5 (sodium-dependent vitamin transporter) 
SLC6A6 
solute carrier family 6 (neurotransmitter transporter, taurine), member 6 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
352 
Gene Symbol 
Full Gene Name 
SLC7A8 
solute carrier family 7 (cationic amino acid transporter, y+ system), member 8 
SLCO1C1 
solute carrier organic anion transporter family, member 1C1 
SLCO2A1 
solute carrier organic anion transporter family, member 2A1 
SLCO3A1 
solute carrier organic anion transporter family, member 3A1 
SLCO4A1 
solute carrier organic anion transporter family, member 4A1 
SLCO4C1 
solute carrier organic anion transporter family, member 4C1 
SLCO5A1 
solute carrier organic anion transporter family, member 5A1 
SLCO6A1 
solute carrier organic anion transporter family, member 6A1 
SULT1C1 
sulfotransferase family, cytosolic, 1C, member 1 
SULT1C2 
sulfotransferase family, cytosolic, 1C, member 2 
SULT1E1 
sulfotransferase family 1E, estrogen-preferring, member 1 
SULT2A1 
sulfotransferase family, cytosolic, 2 A, DHEA preferring, member 1 
SULT2B1 
sulfotransferase family, cytosolic, 2B, member 1 
TAP1 
transporter 1, ATP-binding cassette, subfamily B (MDR/TAP) 
UGT1A10 
UDP glucuronosyltransferase 1 family, polypeptide A10 
UGT1A4 
UDP glucuronosyltransferase 1 family, polypeptide A4 
UGT1A5 
UDP glucuronosyltransferase 1 family, polypeptide A5 
UGT2B10 
UDP glucuronosyltransferase 2 family, polypeptide B10 
ABCC13 
ATP-binding cassette, subfamily C (CFTR/MRP), member 13 
ARSA 
arylsulfatase A 
CAT 
catalase 
CHST8 
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 8 
CYP19A1 
cytochrome P450, family 19, subfamily A, polypeptide 1 
CYP26C1 
cytochrome P450, family 26, subfamily C, polypeptide 1 
CYP27B1 
cytochrome P450, family 27, subfamily B, polypeptide 1 
CYP2R1 
cytochrome P450, family 2, subfamily R, polypeptide 1 
CYP2S1 
cytochrome P450, family 2, subfamily S, polypeptide 1 
CYP46A1 
cytochrome P450, family 46, subfamily A, polypeptide 1 
CYP4A11 
cytochrome P450, family 4, subfamily A, polypeptide 11 
CYP4F12 
cytochrome P450, family 4, subfamily F, polypeptide 12 
CYP4F2 
cytochrome P450, family 4, subfamily F, polypeptide 2 
CYP4F3 
cytochrome P450, family 4, subfamily F, polypeptide 3 
CYP4F8 
cytochrome P450, family 4, subfamily F, polypeptide 8 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
353 
Gene Symbol 
Full Gene Name 
CYP4Z1 
cytochrome P450, family 4, subfamily Z, polypeptide 1 
CYP7B1 
cytochrome P450, family 7, subfamily B, polypeptide 1 
CYP8B1 
cytochrome P450, family 8, subfamily B, polypeptide 1 
DHRS13 
similar to dehydrogenase/reductase (SDR) family) member 13 
DHRS2 
dehydrogenase/reductase (SDR family) member 2 
GPX1 
glutathione peroxidase 1 
GPX4 
glutathione peroxidase 4 (phospholipid hydroperoxidase) 
GPX5 
glutathione peroxidase 5 (epididymal androgen-related protein) 
GPX6 
glutathione peroxidase 6 (olfactory) 
GSS 
glutathione synthetase 
GSTCD 
glutathione S-transferase, C-terminal domain containing 
HNF4A 
hepatocyte nuclear factor 4, alpha 
HNMT 
histamine N-methyltransferase 
HSD11B1 
hydroxysteroid (17-beta) dehydrogenase 11 
HSD17B11 
hydroxysteroid (17-beta) dehydrogenase 11 
HSD17B14 
hydroxysteroid (17-beta) dehydrogenase 14 
LOC731356 
SDR family) member 4 like 2 
MGST1 
microsomal glutathione S-transferase 1 
MGST2 
microsomal glutathione S-transferase 2 
MGST3 
microsomal glutathione S-transferase 3 
MPO 
myeloperoxidase 
NOS1 
nitric oxide synthase 1 (neuronal) 
NOS2A 
nitric oxide synthase 2 A (inducible, hepatocytes) 
NOS3 
nitric oxide synthase 3 (endothelial cell) 
PPARA 
peroxisome proliferator-activated receptor alpha 
SERPINA7 
serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 7 
SLC7A7 
solute carrier family 7 (cationic amino acid transporter, y+ system), member 7 
SOD1 
superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) 
SOD2 
superoxide dismutase 2, mitochondrial 
SOD3 
superoxide dismutase 3, extracellular precursor 
SULF1 
sulfatase 1 
SULT4A1 
sulfotransferase family 4 A, member 1 
TAP2 
transporter 2, ATP-binding cassette, subfamily B (MDR/TAP) 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
354 
Gene Symbol 
Full Gene Name 
UGT8 
UDP glycosyltransferase 8 (UDP-galactose ceramide galactosyltransferase) 
XDH 
xanthine dehydrogenase 
ADHFE1 
alcohol dehydrogenase, iron containing, 1 
CHST1 
carbohydrate (keratan sulfate Gal-6) sulfotransferase 1 
CHST10 
carbohydrate sulfotransferase 10 
CHST11 
carbohydrate (chondroitin 4) sulfotransferase 11 
CHST12 
carbohydrate (chondroitin 4) sulfotransferase 12 
CHST13 
carbohydrate (chondroitin 4) sulfotransferase 13 
CHST2 
carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 
CHST3 
carbohydrate (chondroitin 6) sulfotransferase 3 
CHST4 
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4 
CHST5 
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 5 
CHST6 
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6 
CHST7 
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7 
CHST9 
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9 
CYP2D7P1 
cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 1 
DDO 
D-aspartate oxidase 
DHRS1 
dehydrogenase/reductase (SDR family) member 1 
DHRS12 
dehydrogenase/reductase (SDR family) member 12 
DHRS3 
dehydrogenase/reductase (SDR family) member 3 
DHRS4 
dehydrogenase/reductase (SDR family) member 4 
DHRS4L1 
dehydrogenase/reductase (SDR family) member 4 like 1 
DHRS4L2 
dehydrogenase/reductase (SDR family) member 4 like 2 
DHRS7 
dehydrogenase/reductase (SDR family) member 7 
DHRS7B 
dehydrogenase/reductase (SDR family) member 7B 
DHRS7C 
dehydrogenase/reductase (SDR family) member 7C 
DHRS9 
dehydrogenase/reductase (SDR family) member 9 
DHRSX 
dehydrogenase/reductase (SDR family) X-linked 
DPEP1 
dipeptidase 1 (renal) 
FMO6P 
flavin containing monooxygenase 6 
HAGH 
hydroxyacylglutathione hydrolase 
IAPP 
islet amyloid polypeptide 
KCNJ11 
potassium inwardly-rectifying channel, subfamily J, member 11 
2.0
Approved
930168072
2.0
v
Approved
1.0
v


Clinical Protocol 
IM014029 
BMS-986195 
Branebrutinib 
Protocol Amendment No.: 04 
Date: 01-Dec-2021 
355 
Gene Symbol 
Full Gene Name 
LOC728667 
SDR family) member 2 isoform 1 
LOC731931 
SDR family) member 2 isoform 1 
MAT1A 
methionine adenosyltransferase I, alpha 
METAP1 
methionyl aminopeptidase 1 
PDE3A 
phosphodiesterase 3A, cGMP-inhibited 
PDE3B 
phosphodiesterase 3B, cGMP-inhibited 
PLGLB1 
plasminogen-like B1 
ATP7A 
ATPase, Cu++ transporting, alpha polypeptide (Menkes syndrome) 
ATP7B 
ATPase, Cu++ transporting, beta polypeptide 
CFTR 
cystic fibrosis transmembrane conductance regulator 
 
 
2.0
Approved
930168072
2.0
v
Approved
1.0
v