Clinical trial NCT05014438
Conditions: Dermatitis, Atopic
Keywords: Atopic Dermatitis BMS-986166 BMS-986195 Branebrutinib
Sponsor: Bristol-Myers Squibb
Start date: 2021-08-17; Completion date: 2022-08-22
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and tolerability of BMS-986166 and of branebrutinib, each versus placebo, for the treatment of participants with moderate to severe atopic dermatitis.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BMS-986166 intervention 2: Branebrutinib intervention 3: 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 documents:
Prot_SAP_000.pdf: 
Protocol for 
 
Official Title of Study 
A Phase 2, Randomized, Double-blinded, Placebo-controlled, 5 Parallel-group Study of 
BMS-986166 or Branebrutinib for the Treatment of Patients with Moderate to Severe 
Atopic Dermatitis 
 
NCT05014438 
June 30, 2021 


Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Protocol Amendment No.: 01
Date: 30-Jun-2021
2
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 
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 
(CRO).
2.0
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930158234
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Approved
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Approved
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Approved
1.0
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Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & Title
Description of Change
Brief Rationale
Section 9.4 Safety
Added that an external, 
independent DMC will be 
empaneled to review safety on 
a prescheduled and ad-hoc 
basis, in addition to 
contemporaneous safety 
monitoring by the Study 
Team.
Added for clarification.
Section 9.4.9 Clinical Safety 
Laboratory Assessments
Added PT/INR test to the 
coagulation panel and SARS-
CoV-2:RT-PCR test or 
Antigen test to “Other 
Analyses.”.
Coagulation tests are to be performed at 
screening to ensure normal clotting 
function upon study entry.
SARS-CoV-2 RT-PCR test or Antigen 
test is added to exclude participants who 
test positive for COVID-19.
Section 9.8 Biomarkers
Clarified that serum collected 
at baseline and end of study 
for SARS-CoV-2 (anti-SARS-
CoV-2 IgM and/or IgG and/or 
IgA) measurements are 
optional.
To clarify and align with other sections of 
the protocol stating the analysis is 
optional.
Section 10.2 Populations for 
Analyses 
Added description to the 
Safety Population for a 
participant that is randomized 
to placebo treatment who then 
receives non-placebo 
treatment. 
To add clarity to the description of the 
safety population used in the safety 
analyses, with regard to exposure to 
active drug(s).
APPENDIX 2 STUDY 
GOVERNENCE 
CONSIDERATIONS
Updated information on the 
Informed Consent Process and 
Source documents. 
Added Information on remote 
monitoring that will be 
included in the monitoring 
plan. 
Updated “Return of Study 
Treatment”’ Section: Added 
information on handling of 
partially used supplies 
Removed information on the 
process when on-site drug 
destruction is not allowed.
Added new section ‘Study and 
Site Start and Closure
To align with the current BMS processes.
To address the details of remote 
monitoring if it is utilized in the study.
To provide guidance on partially used 
supplies.
The process is not applicable for the sites 
participating in this study.
To provide guidance on study and site 
closure.
Informed consent will be restricted to the 
study participant; consent by LAR is not 
allowed.
Protocol Amendment No.: 01
Date: 30-Jun-2021
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930158234
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1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & Title
Description of Change
Brief Rationale
Removed “legally acceptable 
representative” (LAR) 
language.
Added new section 
Dissemination of Clinical 
Study Data
BMS will make information about 
clinical research studies and results 
available to the public as per regulatory 
and BMS requirements.
APPENDIX 3 ADVERSE 
EVENTS AND SERIOUS 
ADVERSE EVENTS: 
DEFINITIONS AND 
PROCEDURES FOR 
RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING
Updated the Assessment of 
Intensity table. 
Updated the Serious Adverse 
Event (SAE) contact 
information for reporting 
SAEs.
To clarify expectations and contact 
information for evaluating and reporting 
AEs and SAEs.
APPENDIX 4 WOMEN OF 
CHILDBEARING POTENTIAL 
DEFINITIONS AND METHODS 
OF CONTRACEPTION
Updated description of 
Appendix 4. Updated the 
listing of highly effective 
contraceptive methods that are 
user dependent. 
These updates are to align with
the BMS standards of contraceptive 
methods.
All as applicable
Minor formatting and 
typographical corrections 
throughout.
Minor, therefore have not been 
summarized.
Protocol Amendment No.: 01
Date: 30-Jun-2021
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Disease Rationale .................................................................................... 
 
3.1.2 Rationale for Study Drug Mechanisms .................................................... 
 
3.1.3 Rationale for Study Population ................................................................ 
 
3.1.4 Rationales for Primary and Secondary Efficacy Endpoints .................... 
 
3.1.5 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 BMS-986166 ............................................................................................ 
 
3.2.1.1 In Vitro Pharmacology ................................................................... 
 
3.2.1.2 In Vivo Pharmacology .................................................................... 
 
3.2.1.3 Nonclinical Toxicology ................................................................... 
 
3.2.1.4 Pharmacokinetic Drug Interaction Summary ................................. 
 
3.2.1.5 Clinical Safety ................................................................................. 
 
3.2.2 Branebrutinib ........................................................................................... 
 
3.2.2.1 In Vitro Pharmacology ................................................................... 
 
3.2.2.2 In Vivo Pharmacology .................................................................... 
 
3.2.2.3 Nonclinical Toxicology ................................................................... 
 
3.2.2.4 Pharmacokinetic Drug Interaction Summary ................................. 
 
3.2.2.5 Clinical Safety ................................................................................. 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
3.3.1 BMS-986166 ............................................................................................ 
 
3.3.2 Branebrutinib ........................................................................................... 
 
3.3.3 COVID-19-associated Risks .................................................................... 
 
3.3.3.1 BMS-986166 ................................................................................... 
 
3.3.3.2 Branebrutinib .................................................................................. 
 
3.3.3.3 COVID-19-related Mitigations ....................................................... 
 
3.3.3.4 Vaccination Against SARS-CoV-2 .................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period Days -35 to -1 .............................................................. 
 
5.1.2 Treatment Period, Days 1-113 ................................................................. 
 
5.1.3 Follow-up Period, Days 114-169 ............................................................ 
 
5.1.4 Data Monitoring Committee .................................................................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
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Clinical Protocol
BMS-986166 and BMS-986195
IM018005
S1P Receptor Modulator and Branebrutinib
Protocol Amendment No.: 01
Date: 30-Jun-2021
9
2.0
Approved
930158234
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5.4 Scientific Rationale for Study Design .............................................................. 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 BMS-986166 ............................................................................................ 
 
5.5.2 Branebrutinib ........................................................................................... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.3.1 Meals and Dietary Restrictions ............................................................... 
 
6.3.2 Caffeine, Alcohol, and Tobacco ............................................................... 
 
6.3.3 Activity ..................................................................................................... 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence / Biocomparability
..................................................................................................................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Rescue Therapy ........................................................................................ 
 
7.7.3 Use of Concomitant Emollient ................................................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-
AD) .............................................................................................................. 
 
9.1.2 Eczema Area and Severity Index (EASI) .................................................. 
 
9.1.3 Body Surface Area (BSA) ......................................................................... 
 
9.1.4 Pruritus and Sleep Quality Numerical Rating Scale (NRS) ..................... 
 
9.1.5 Dermatology Life Quality Index (DLQI) ................................................. 
 
9.1.6 Patient Oriented Eczema Measure (POEM) ............................................ 
 
9.1.7 Patient Global Impression of Change (PGI-C) ....................................... 
 
9.1.8 Patient Global Impression of Severity (PGI-S) ....................................... 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
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Clinical Protocol
BMS-986166 and BMS-986195
IM018005
S1P Receptor Modulator and Branebrutinib
Protocol Amendment No.: 01
Date: 30-Jun-2021
10
2.0
Approved
930158234
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9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Monitoring of Participants with Adverse Events of Interest (AEIs) ........ 
 
9.2.9 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 TB Screening and Chest Imaging ............................................................ 
 
9.4.5 Pulmonary Function Tests ....................................................................... 
 
9.4.6 Neurological Safety .................................................................................. 
 
9.4.7 Ophthalmological Examination ............................................................... 
 
9.4.8 Male Sex Hormones ................................................................................. 
 
9.4.9 Clinical Safety Laboratory Assessments .................................................. 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.5.1 Sampling Schedule ................................................................................... 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.6.1 Blood Collection for Immunocyte Profiling ............................................. 
 
9.6.2 Blood Collection for Plasma Cytokines ................................................... 
 
9.6.3 Blood Collection for Gene Expression .................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.7.1 ADME Sampling ...................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Pathway Engagement Assays ................................................................... 
 
9.8.2 Additional Exploratory Biomarkers ......................................................... 
 
9.8.3 Additional Research Collection ............................................................... 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.1.1 Primary Endpoint.......................................................................... 
 
10.3.1.2 Secondary Endpoint ...................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.4 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
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Clinical Protocol
BMS-986166 and BMS-986195
IM018005
S1P Receptor Modulator and Branebrutinib
Protocol Amendment No.: 01
Date: 30-Jun-2021
11
2.0
Approved
930158234
2.0
v
Approved
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APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 DIAGNOSTIC CRITERIA FOR ATOPIC DERMATITIS ................. 
 
APPENDIX 6 NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION 
OF CARDIOVASCULAR DISABILITY .............................................................. 
 
APPENDIX 7 DSM-5 DIAGNOSTIC CRITERIA FOR SUBSTANCE USE 
DISORDER............................................................................................................. 
 
APPENDIX 8 VALIDATED INVESTIGATOR GLOBAL ASSESSMENT SCALE 
FOR ATOPIC DERMATITIS (VIGA-ADTM) ..................................................... 
 
APPENDIX 9 ECZEMA AREA AND SEVERITY INDEX (EASI) .......................... 
 
APPENDIX 10 BODY SURFACE AREA ESTIMATE WORKSHEET (SCORAD-A 
METHOD) .............................................................................................................. 
 
APPENDIX 11 PRURITUS AND SLEEP QUALITY NUMERICAL RATING 
SCALES (NRS) ...................................................................................................... 
 
APPENDIX 12 DERMATOLOGY LIFE QUALITY INDEX (DLQI) ....................... 
 
APPENDIX 13 PATIENT ORIENTED ECZEMA MEASURE (POEM) ................... 
 
APPENDIX 14 PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) ............ 
 
APPENDIX 15 PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) .......... 
 
APPENDIX 16 ADME GENE LIST ............................................................................ 
 
 
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Clinical Protocol
BMS-986166 and BMS-986195
IM018005
S1P Receptor Modulator and Branebrutinib
Protocol Amendment No.: 01
Date: 30-Jun-2021
12
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
1
SYNOPSIS
Protocol Title: A Phase 2, Randomized, Double-blinded, Placebo-controlled, 5 Parallel-group 
Study 
of 
BMS-986166 
or 
Branebrutinib 
for 
the 
Treatment 
of 
Patients 
with 
Moderate to Severe Atopic Dermatitis
Short Title: BMS-986166 or Branebrutinib for Treatment of Atopic Dermatitis
Study Phase: 2
Rationale:
Atopic dermatitis (AD) is a common, chronic inflammatory skin condition, with approximately 
40% of patients meeting the criteria for moderate-to-severe disease. The substantial biological 
heterogeneity of AD warrants new medications acting through different mechanisms to 
comprehensively treat patients, such that they all achieve remission or near-remission. Thus, 
moderate-to-severe AD represents a clear unmet need. Signals transduced by receptors for 
sphingosine-1-phosphate (S1P) and by Bruton Tyrosine Kinase (BTK) are implicated in the 
pathobiology of AD, making these pathways attractive targets for potential AD therapies. 
Study IM018005 will evaluate the efficacy and safety of BMS-986166 (the prodrug of 
BMS-986166-P [BMT-121795]), a sphingosine-1-phosphate (S1P) receptor modulator); and of 
branebrutinib, an oral, potent, and highly selective irreversible inhibitor of BTK. Each will be 
administered as a single agent to a population of AD participants having moderate-to-severe 
disease who are intolerant of treatment or inadequately treated and are candidates for systemic 
therapy. IM018005 is a Phase 2 study to assess the clinical benefit measured primarily by mean 
percentage change from baseline in Eczema Area and Severity Index (EASI) score provided by 
each of 3 dose levels of BMS-986166 and of a single dose level of branebrutinib after 16 weeks 
of treatment. Should this study demonstrate plausible efficacy and safety of either or both of these 
agents, their evaluation will be expanded with confirmatory studies.
Study Population:
Males and females aged 18 (or local age of majority) to 65, inclusive, with confirmed 
moderate-to-severe AD who are candidates for systemic therapy. 
Protocol Amendment No.: 01
Date: 30-Jun-2021
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Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Objectives and Endpoints:
Objectives
Endpoints
Primary
• To evaluate the efficacy of BMS-986166 and of 
branebrutinib, each versus placebo, at Week 16 in 
participants with moderate-to-severe AD.
• Mean percentage change from baseline in EASI 
score at Week 16
Secondary
• To further evaluate the efficacy of BMS-986166 and 
of branebrutinib, each versus placebo, at Week 16 in 
participants with moderate-to-severe AD.
• Proportion of participants exhibiting a vIGA-AD 
score of 0 (cleared) or 1 (almost cleared) AND a ≥ 2 
point reduction from baseline at Week 16
• Proportion of participants exhibiting a ≥ 50% 
(EASI-50) reduction from baseline in EASI score at 
Week 16
• Proportion of participants exhibiting a ≥ 4-point
improvement from baseline in Pruritus NRS at 
Week 16
• Mean percentage change from baseline in Pruritus 
NRS at Week 16
• Mean change from baseline in percentage of affected 
BSA at Week 16
• To assess the safety and tolerability of BMS-986166 
and of branebrutinib in participants with moderate-
to-severe AD.
• Incidence and severity of all AE and SAE 
• Incidence and severity of clinically significant 
changes in vital signs, ECG, OCT, PFT, and safety 
laboratory tests 
Abbreviations: AD = atopic dermatitis; AE = adverse event; BSA = body surface area; EASI = Eczema Area and 
Severity Index; ECG = electrocardiogram; NRS = numerical rating scale; SAE = serious adverse event; OCT = optical 
coherence tomography; PFT = pulmonary function test; vIGA-AD = Validated Investigator Global Assessment Scale 
for Atopic Dermatitis
Overall Design:
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 5 parallel-group 
study of BMS-986166 or branebrutinib for the treatment of moderate-to-severe AD. The overall 
study design is outlined in Figure 1-1.
Participants will have confirmed moderate-to-severe AD. Participants will be assessed for clinical 
responses to placebo, BMS-986166, or branebrutinib for 16 weeks and monitored for 
treatment-emergent safety outcomes for a total of approximately 29 weeks.
White blood cell (WBC) counts and lymphocyte counts will be monitored centrally and will not 
be provided to the site to prevent potential unblinding of the investigator. 
An external independent Data Monitoring Committee (DMC) will be empaneled to monitor for 
safety with periodic and as-needed review. 
Protocol Amendment No.: 01
Date: 30-Jun-2021
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930158234
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Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Figure 1-1:
Study Design Schematic
Abbreviations: n = number of participants; PO = taken orally; QD = once daily; R = randomization; V = visits
Study day visits will be ± 3 days, except for Day 8 visit (± 1 days).
Screening Period Days -35 to -1
Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease 
activity, and safety assessments. Screening and randomization must be completed within 35 days 
of signing the informed consent form. Participants who experience an AD flare, defined as
doubling of the EASI score between Screening and Baseline, or worsening that requires 
administration of prohibited medications within 3 weeks of randomization should be discontinued 
from the study. 
Treatment Period, Days 1 to 113
On Day 1, eligible participants will be randomly allocated to receive: placebo, BMS-986166 
0.25 mg orally (PO) once daily (QD), BMS-986166 0.5 mg PO QD, BMS-986166 0.75 mg PO 
QD, or branebrutinib 9 mg PO QD for 16 weeks. Randomization will be in a 1:1:1:1:1 ratio.
Participants will visit the clinic 7 times (including baseline) during the treatment period. Safety 
and efficacy will be assessed at each of these visits. This visit density is intended to balance, on 
the one hand, monitoring of sufficiently high resolution to detect infections, excessively low 
leukocyte counts, inefficacy and/or flares, and other problems in a timely fashion; with on the other 
hand, subject burdens and potential risk of SARS-CoV-2 (severe acute respiratory syndrome 
coronavirus 2) exposure associated with clinic visits. This frequency reflects customary practice 
in the field, as reflected in other clinical studies of medicines having similar mechanisms.
Protocol Amendment No.: 01
Date: 30-Jun-2021
15
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930158234
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Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Topical rescue treatments may be provided at the discretion of the investigator to alleviate 
intolerable AD symptoms. Participants escalating to systemic rescue medications or not 
responding adequately after at least 7 days of topical rescue treatment will be immediately 
discontinued from study treatment and considered treatment failures for categorical endpoints. 
Follow-up Period, Days 114 to 169
Follow-up after dosing cessation is planned for approximately 60 days (5x mean half-life for 
BMS-986166), with visits on Days 127, 141 and 169; participants will be followed for disease 
activity, safety, and washout of pharmacodynamics (PD) effects. If applicable, participants will be 
followed until absolute neutrophil count (ANC) > 1500/μL and absolute lymphocyte count (ALC) 
> 1000/μL – demonstrating sufficient washout of pharmacodynamics (PD) effects to permit 
discharge from the study.
Number of Participants: 
Approximately 150 participants will be randomized 1:1:1:1:1 into 5 parallel treatment groups.
Treatment Arms and Duration:
Participants will be randomized to one of the following dose levels of BMS-986166 or 
branebrutinib or placebo in blinded fashion: 
•
BMS-986166 0.25 mg PO QD
•
BMS-986166 0.50 mg PO QD
•
BMS-986166 0.75 mg PO QD
•
Branebrutinib 9 mg PO QD
•
Placebo PO QD
•
The first dose of double-blind study medication (BMS-986166 or branebrutinib or placebo) 
will be taken in the morning on Day 1 after fasting for at least 8 hours. 
•
Study medication should be taken at approximately the same time each day.
•
Participants will take 3 capsules each day, one from each of 3 distinct bottles.
Study Treatment
Treatment 
Group
Double-
blind Kit
Bottle A
Bottle B
Bottle C
Placebo
Each kit 
contains
Bottle A,
Bottle B, 
Bottle C
Placebo capsule
Placebo capsule
Placebo capsule
`166 0.25 mg QD
`166 capsule, 0.25 mg
Placebo capsule
Placebo capsule
`166 0.5 mg QD
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg
Placebo capsule
`166 0.75 mg QD
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg 
BRA 9 mg QD
BRA capsule, 3 mg
BRA capsule, 3 mg
BRA capsule, 3 mg
Abbreviations: ‘166 = BMS-986166-04; BRA = branebrutinib; QD = once daily
Note: all capsules are identical in size (size 0).
Protocol Amendment No.: 01
Date: 30-Jun-2021
16
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Data Monitoring Committee: Yes
Statistical Considerations: 
The sample size calculation is driven by the power to compare mean percentage change from 
baseline in EASI score at Week 16 between BMS-986166 or branebrutinib versus placebo. 
Thirty participants per group will provide 84% power to detect a treatment difference (versus 
placebo) of 30% at the type I error of α = 0.05 (1-sided), assuming a common standard deviation 
of 43%. The assumed treatment difference of 30% is similar to the mean difference observed from 
historical data on approved drugs across different mechanism of actions. No adjustment will be 
made for multiplicity.
Assuming a 15% dropout rate (ie, the fraction of participants not completing Week 16 assessment), 
25 participants per group will still provide 78% power to detect a treatment difference of 30%.
An interim analysis (IA) may be performed when approximately 50% of the participants have 
reached Week 16 or discontinued. Safety and efficacy analysis will be performed to accelerate 
internal decision making. The IA will be performed by individuals or vendor independent of the 
study team. The study team will remain blinded during IA.
Protocol Amendment No.: 01
Date: 30-Jun-2021
17
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (IM108005)
Procedure
Screening
Visit
(Day -35 to -1)
Notes
Administrative and Historical 
Assessments
Informed Consent
X
A participant is considered enrolled when a protocol-specific informed consent form (ICF) 
is signed. If re-enrolled, the participant must be reconsented and assigned a new participant 
number from IRT.
Optional ICFs
X
• AD-related Genomics and Pharmacogenetics
• 12-hour Pharmacokinetics sample
• Skin Biopsy
Enrollment in the IRT System
X
Contact IRT for participant number. If participant does not meet eligibility criteria, contact 
IRT to screen-fail participant.
Inclusion/Exclusion Criteria
X
Demographics Collection
X
Atopy History with Targeted Questionnaire; 
AD-related Treatment
X
Medical History
X
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.
Disease Assessment
DLQI
X
Patient reported 10 item questionnaire to evaluate the impact of skin condition on health 
related quality of life over the past week. (Appendix 12)
POEM
X
Patient reported 7-item questionnaire to evaluate atopic dermatitis symptoms in the past 
7 days. (Appendix 13)
EASI
X
EASI score 12 or higher at screening (Appendix 9)
vIGA-AD
X
vIGA-AD ≥ 3 (Appendix 8)
BSA Assessment
X
BSA ≥ 10% affected (Appendix 10)
Protocol Amendment No.: 01
Date: 30-Jun-2021
18
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-1:
Screening Procedural Outline (IM108005)
Procedure
Screening
Visit
(Day -35 to -1)
Notes
Pruritus and Sleep Quality NRS
X
Participants will be trained at Screening, and will be familiarized with its use at that time. 
The diary will be completed every day at waking thenceforth. Data collected starting on 
Day -6 will be used for analysis. (Appendix 11)
Safety Activities
Counseling on Contraception Use
X
Vital Signs
X
Includes body temperature, respiratory rate, blood pressure and heart rate. Blood pressure 
and heart rate should be measured after the participant has been supine quietly for at least 
5 minutes. 
Complete Physical Examination
X
Includes height and weight. See Section 9.4.1.
12-lead ECG
X
ECGs should be recorded after the participant has been supine for 5 to 10 minutes. Lab 
work must be done after the ECG.
SAE Assessment
X
SAEs must be collected from the time of signing the ICF, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of 
dosing or participation in the study if the last scheduled visit occurs at a later time.
Chest Radiography
X
PA & lateral CXR
Pulmonary Function Test
X
FEV1, FVC, and DLCO
Visual Acuity Testing and Optical 
Coherence Tomography
X
Laboratory Tests
Hematology
X
CBC with differential
Chemistry Panel
X
Includes liver function testing 
Lipid Panel
X
Non-fasting
Hemoglobin A1c
X
Coagulation Panel
X
PT and INR
Screening for Drugs of Abuse (urine or 
serum)
X
Performed locally and entered by the site into the eCRF
eGFR Calculation
X
Urinalysis (UA)
X
Abnormal results trigger reflex microscopic exam
Protocol Amendment No.: 01
Date: 30-Jun-2021
19
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-1:
Screening Procedural Outline (IM108005)
Procedure
Screening
Visit
(Day -35 to -1)
Notes
Pregnancy Test
X
WOCBP only; performed locally
Follicle Stimulating Hormone (FSH)
X
For select women only, serum FSH level will be determined to confirm menopausal status
FSH and LH, and Total Testosterone
X
Male participants only. Samples should be taken in the morning
Hepatitis and HIV Screening
X
Includes HCV antibody, HBsAg, HBcAb, and HIV antibodies
QuantiFERON-TB Gold test
X
SARS-CoV-2: RT-PCR test or Antigen test
X
COVID-19 Mitigation
X
Measures (eg, viral testing, temperature readings, interviews, social distancing, PPE, etc.) 
required by the clinical research site will be implemented according to approved 
institutional procedures.
Abbreviations: AD = Atopic Dermatitis; BSA = Body Surface Area; CBC = Complete Blood Count; COVID-19 = coronavirus disease 2019; CXR = Chest X-ray; 
DLCO = Diffusion Capacity; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eCRF = Electronic 
Case Report Form; eGFR = estimated Glomerular Filtration Rate; FEV1 = Forced Expiratory Volume in 1 second; FVC = Forced Vital Capacity; FSH = Follicle 
Stimulating Hormone; HBcAb = Hepatitis B core antibody; HBsAb = Hepatitis B surface antibody; HBsAg = Hepatitis B surface antigen; HCV = Hepatitis C 
virus; HIV = Human Immunodeficiency virus; ICF = Informed Consent Form; INR = international normalized ratio; IRT = Interactive Response Technology; LH 
= Luteinizing hormone; NRS = Numerical Rating Scale; PA = Posteroanterior; POEM = Patient Oriented Eczema Measure; PPE = Personal Protective Equipment; 
PT = prothrombin time; RT-PCR = Reverse transcriptase polymerase chain reaction; SAE = Serious Adverse Event; SARS-CoV-2 = severe acute respiratory 
syndrome coronavirus 2; TB = Tuberculosis; UA = urinalysis; vIGA-AD = validated Investigator Global Assessment scale for Atopic Dermatitis; WOCBP = 
Women of Childbearing Potential. 
Protocol Amendment No.: 01
Date: 30-Jun-2021
20
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-2:
On-treatment Procedural Outline (IM018005)
Procedure
Day 1a
(Rand)
Day 8
W1
(± 1 
days)
Day 15
W2
(± 3 
days)
Day 29
W4
(± 3 
days)
Day 57
W8
(± 3 
days)
Day 85a
W12
(± 3 
days)
Day 113
(EOT)
W16
(± 3 
days)
Notes
Administrative and Historical 
Assessments
Inclusion/Exclusion Criteria
X
Review of inclusion/exclusion criteria that are 
specified on or defined relative to the 
randomization day
Randomization via IRT
X
Disease/Efficacy Assessment
EASI
X
X
X
X
X
X
X
EASI at baseline must be ≥ 16 (prior to 
randomization).
vIGA-AD
X
X
X
X
X
X
X
BSA Assessment
X
X
X
X
X
X
X
Pruritus and Sleep Quality NRS
X
X
X
X
X
X
X
Will be collected daily in an electronic diary –
represents preceding 24 hours. Data will be 
collected at each specified visit.
DLQI
X
X
X
X
X
X
X
Data will be collected at each specified visit.
POEM
X
X
X
X
X
X
X
PGI-S
X
X
X
X
PGI-C
X
X
X
Pulmonary Function Test
X
X
FEV1, FVC & DLCO may be collected within 
a window of ± 5 days of visit.
Visual Acuity Testing and 
Optical Coherence Tomography
X
X
May be collected within a window of ± 7 days 
of visit.
Safety Activities
Body Weight
X
X
Protocol Amendment No.: 01
Date: 30-Jun-2021
21
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-2:
On-treatment Procedural Outline (IM018005)
Procedure
Day 1a
(Rand)
Day 8
W1
(± 1 
days)
Day 15
W2
(± 3 
days)
Day 29
W4
(± 3 
days)
Day 57
W8
(± 3 
days)
Day 85a
W12
(± 3 
days)
Day 113
(EOT)
W16
(± 3 
days)
Notes
Vital Signs
Xb
X
X
X
X
X
X
Includes body temperature, respiratory rate, 
blood pressure and heart rate. Blood pressure 
and heart rate should be measured after the 
participant has been supine for at least 
5 minutes. 
Complete Physical Examination
X
X
Includes height and weight. See section 9.4.1
Targeted Physical Examination
X
X
X
X
X
See section 9.4.1 for assessed organ systems.  
12-lead ECG
Xc
X
X
X
X
X
X
The duration of the Day 1 visit will be 
approximately 7 hours, except at select sites. 
AE and SAE Assessment
X
X
X
X
X
X
X
AEs and SAEs must be collected from the time 
of the first dose of the study drug through the 
date of the follow-up or last visit.
SARS-CoV-2: RT-PCR test or 
Antigen test
X
Participants must have a negative SARS-CoV-
2 PCR test result within 3 days prior to Day 1 
dosing in accordance with site standard 
practices.
COVID-19 Mitigation
X
X
X
X
X
X
X
Measures (eg, temperature readings, 
interviews, social distancing, PPE, etc.) 
required by the clinical research site will be 
implemented according to approved 
institutional procedures.
Concomitant Medication Use
X
X
X
X
X
X
X
Laboratory Tests
Hematology (CBC)
X
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
Protocol Amendment No.: 01
Date: 30-Jun-2021
22
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-2:
On-treatment Procedural Outline (IM018005)
Procedure
Day 1a
(Rand)
Day 8
W1
(± 1 
days)
Day 15
W2
(± 3 
days)
Day 29
W4
(± 3 
days)
Day 57
W8
(± 3 
days)
Day 85a
W12
(± 3 
days)
Day 113
(EOT)
W16
(± 3 
days)
Notes
eGFR calculation
X
X
X
X
X
X
X
Urinalysis (UA)
X
X
Abnormal results trigger reflex microscopic 
exam.
Pregnancy Test
X
X
X
X
X
X
X
WOCBP only; performed locally.
Drugs of abuse (urine or serum)
X
Predose, performed locally and entered into 
the eCRF by the site
FSH, LH, and Total 
Testosterone
X
X
Male participants only. Samples should be 
taken in the morning.
SARS-CoV-2 Serology
X
Serum to be collected for optional
measurements of anti-SARS-CoV-2 IgM 
and/or IgG and/or IgA.
Pharmacokinetics 
Assessments
Collect Blood or Plasma 
Samples for PK
See Table 9.5.1-1
Biomarkers Assessments and 
Pathway Engagement
Biomarker samples collection
See Table 9.8-1
Study Treatment
Access/Login IRT
X
X
X
X
Register visit in the IRT every 4 weeks (± 3 
days).
Study Drug Dispensing
X
X
X
X
Dispense study drug every 4 weeks (± 3 days).
Protocol Amendment No.: 01
Date: 30-Jun-2021
23
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-2:
On-treatment Procedural Outline (IM018005)
Procedure
Day 1a
(Rand)
Day 8
W1
(± 1 
days)
Day 15
W2
(± 3 
days)
Day 29
W4
(± 3 
days)
Day 57
W8
(± 3 
days)
Day 85a
W12
(± 3 
days)
Day 113
(EOT)
W16
(± 3 
days)
Notes
Study Drug Compliance Check
X
X
X
X
X
X
Participants must bring their pill bottles with 
them for pill counts and compliance queries.
a The visit duration on Days 1 and 85 will be approximately 7 hours for either PK and/or 12-lead ECG collection. At selected sites, the visit duration will be 
approximately 12 hours for PK.
b Day 1 visit to include vital signs recorded predose then hourly at 1, 2, 3, 4, 5, and 6 hours (± 10 minutes) post-dose.
c Day 1 predose 12-lead ECG will be performed, and following dosing, participants will have ECGs recorded at 1, 2, 4, and 6 hours (± 10 minutes) post-dose.
Abbreviations: AD = atopic dermatitis; AE = adverse event; BSA = body surface area; CBC = complete blood count; COVID-19 = coronavirus disease 2019; 
DLCO = Diffusion Capacity; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eGFR = estimated 
Glomerular Filtration Rate; EOT = end of treatment; FEV1 = Forced Expiratory Volume in 1 second; FVC = Forced Vital Capacity; FSH = Follicle Stimulating 
Hormone; ICF = informed consent form; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; IRT = Interactive Response Technology; 
LH = Luteinizing hormone; NRS = Numerical Rating Scale; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PK = 
pharmacokinetics; POEM = Patient Oriented Eczema Measure; RT-PCR = Reverse transcriptase polymerase chain reaction; SAE = serious adverse event; SARS-
CoV-2 = severe acute respiratory syndrome coronavirus 2; UA = urinalysis; vIGA-AD = Validated Investigator Global Assessment scale for Atopic Dermatitis; W 
= week; WOCBP = Women of Childbearing Potential.
Protocol Amendment No.: 01
Date: 30-Jun-2021
24
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-3:
Post-treatment Follow-up and Additional Visit Types
Procedure
Day 127
(± 3 days) 
W18
Day 141
(± 3 days) 
W20
Day 169
(± 3 days) 
W24 EOSa
Study 
Withdrawal
Unscheduledb
Notes
Administrative Activities
Contact IRT for EOS
X
X
Disease/Efficacy Assessment
EASI
X
X
X
X
X
vIGA-AD
X
X
X
X
X
BSA assessment
X
X
X
X
X
Pruritus and Sleep Quality 
NRS
X
X
X
X
Will be collected daily in an electronic diary –
represents preceding 24 hours. Data will be 
collected at each specified visit.
DLQI
X
X
X
X
X
Data will be collected at each specified visit.
POEM
X
X
X
X
X
PGI-S
X
PGI-C
X
Pulmonary function test 
X
X
Visual Acuity Testing and 
Optical Coherence 
Tomography
X
X
Safety Activities
Body Weight
X
X
X
Data will be collected at each specified visit.
Vital Signs
X
X
X
X
X
Body temperature, blood pressure, respiratory 
rate, and heart rate. Data will be collected at 
each specified visit.
Protocol Amendment No.: 01
Date: 30-Jun-2021
25
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-3:
Post-treatment Follow-up and Additional Visit Types
Procedure
Day 127
(± 3 days) 
W18
Day 141
(± 3 days) 
W20
Day 169
(± 3 days) 
W24 EOSa
Study 
Withdrawal
Unscheduledb
Notes
Complete Physical 
Examination
X
X
Data will be collected at each specified visit.
Targeted Physical 
Examination
X
X
X
Data will be collected at each specified visit.
12-lead ECG
X
X
X
X
X
Data will be collected at each specified visit.
AE and SAE Assessment
X
X
X
X
X
Data will be collected at each specified visit.
Concomitant Medication Use
X
X
X
X
X
Data will be collected at each specified visit.
Laboratory Tests
Hematology (CBC)
X
X
X
X
X
Data will be collected at each specified visit.
Chemistry Panel
X
X
X
X
X
Data will be collected at each specified visit.
eGFR calculation
X
X
X
X
X
Data will be collected at each specified visit.
Urinalysis (UA)
X
X
X
Abnormal results trigger reflex microscopic 
exam. Data will be collected at each specified 
visit.
Pregnancy Test
X
X
X
X
WOCBP only; performed locally. Data will be 
collected at each specified visit.
FSH and LH, and Total 
Testosterone
X
X
Male participants only. Samples should be 
taken in the morning.
SARS-CoV-2 Serology
X
X
For contingent/optional analysis
Protocol Amendment No.: 01
Date: 30-Jun-2021
26
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 2-3:
Post-treatment Follow-up and Additional Visit Types
Procedure
Day 127
(± 3 days) 
W18
Day 141
(± 3 days) 
W20
Day 169
(± 3 days) 
W24 EOSa
Study 
Withdrawal
Unscheduledb
Notes
Biomarker Assessments and 
Pathway Engagement
Biomarker samples collection
See Table 9.8-1
a Participants follow-up may be extended as needed until absolute lymphocyte count is > 1000/μL and absolute neutrophil count is > 1500/μL.
b Ad hoc safety procedures required to address the circumstances and if applicable EASI, vIGA, BSA and DLQI assessments
Abbreviations: AD = Atopic Dermatitis; AE = Adverse Event; BSA = Body Surface Area; CBC = Complete Blood Count; DLQI = Dermatology Life Quality 
Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; eGFR = estimated Glomerular Filtration Rate; EOS = end of study; FSH = Follicle 
Stimulating Hormone; ICF = Informed Consent Form; IRT = Interactive Response Technology; LH = Luteinizing hormone; NRS = Numerical Rating Scale; PGI-
C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; PK = pharmacokinetics; POEM=Patient Oriented Eczema Measure; SAE = 
serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; UA = urinalysis; vIGA-AD = validated Investigator Global Assessment 
scale for Atopic Dermatitis; WOCBP = women of childbearing potential.
Protocol Amendment No.: 01
Date: 30-Jun-2021
27
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
When multiple assessments are conducted at a single visit, the following is the order in which they 
should be performed:
1) Safety assessments (eg, vitals, electrocardiograms [ECG], adverse events [AEs])
2) Laboratory tests (eg, safety laboratory tests, pharmacokinetic assessments, biomarker 
assessments)
3) Clinical efficacy assessments
4) Treatment dosing
3
INTRODUCTION
IM018005 is a Phase 2 study to assess the clinical benefit provided by each of 3 dose levels of 
BMS-986166, a modulator of sphingosine-1-phosphate receptor 1 (S1PR1), and of a single dose 
level of branebrutinib (an inhibitor of Bruton Tyrosine Kinase [BTK]) in participants with 
moderate-to-severe atopic dermatitis (AD). 
Interventions that are safe and highly effective in a large majority of AD patients with moderate 
or severe disease remains an unmet medical need (Section 3.1.1). Despite the recent approval of 
dupilumab (anti-interleukin-4 receptor alpha monoclonal antibody) for the treatment of AD, after 
16 weeks of treatment, approximately 40% of patients with moderate or severe AD, demonstrated 
a reduction of the Investigators̓ Global Assessment (IGA) to either 1 (almost clear) or 0 (clear). 
The substantial biological heterogeneity of AD warrants development of new medications acting 
through different mechanisms to treat patients, so that all may achieve remission or near-remission.
Signals transduced by receptors for sphingosine-1-phosphate (S1P) and by BTK are implicated in 
the pathobiology of AD (Section 3.1.2), making these pathways attractive targets for potential AD 
therapies. 
BMS-986166 and branebrutinib demonstrated satisfactory safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) in Phase 1 clinical studies following extensive and promising 
nonclinical evaluations (Section 3.2). Thus, they are being evaluated in this Phase 2 study for their 
initial safety and efficacy in participants with moderate or severe AD.
3.1
Study Rationale
3.1.1
Disease Rationale
AD is one of the most common inflammatory skin diseases, affecting 3% to 10% of the US 
population.1 Worldwide, it affects up to 20% of children and 3% of adults, with higher prevalence 
in younger children (ages 6 years to 7 years as compared with ages 13 years to 14 years) and also 
in some countries which have emerged as regions of relatively high prevalence.2 In the majority 
of cases, AD has an onset before age 5 years, and prevalence data in children show a slight female 
to male preponderance (1.3 to 1).3 Persistent AD may be present in approximately 50% of patients 
diagnosed with atopic dermatitis during childhood.4,5 Of those affected, about 40% have 
moderate-to-severe disease.6 Beyond the characteristic skin pathology, AD is associated with 
increased anxiety, depression, sleep disorders, reduced productivity, and impaired activity – all of 
Protocol Amendment No.: 01
Date: 30-Jun-2021
28
2.0
Approved
930158234
2.0
v
Approved
1.0
v


Clinical Protocol
IM018005
BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
approximately equivalent magnitudes to those observed in psoriasis.7 Patients with AD have 
increased risk of other atopic disorders, including asthma, allergic rhinitis, and chronic sinusitis 
with nasal polyposis.8,9,10 Taken together, the burdens of AD resulted in an estimated > $5B in 
societal costs in 2016.11   
A multiplicity of factors, including epidermal barrier defects, dysregulation of innate immune 
responses, and altered Type 2 immunity, are implicated in the pathogenesis of AD, culminating in 
an inflammatory response involving multiple cell types, cytokines, and chemokines. The epidermis 
of patients with AD is characterized by a genetically impaired skin barrier function with increased 
transepidermal water loss. These abnormalities may be present at birth and predict the 
development of AD in the first year of life.12 Higher levels of transepidermal water loss in patients 
with AD have been associated with greater disease severity.13,14 Enhanced allergen/antigen 
penetration through an impaired skin barrier resulting in a type 2 helper T-lymphocyte (Th2)-type 
milieu has been proposed as a critical link between the primary barrier defect in patients and Th2 
polarization.15 Th2 differentiation of naive CD4+ T-cells predominates in AD causing an increased 
production of interleukins (IL), primarily IL- 4, IL-5, and IL-13 (Figure 3.1.1-1), which then leads 
to an increased level of immunoglobulin E (IgE), and corresponding inhibition of type 1 helper 
T-lymphocyte (Th1) differentiation. In 80% of AD patients, the disease is associated with 
hypersensitivity to environmental or food allergens, increased specific serum IgE levels, and 
eosinophilia.16,17 Thus, AD is often part of (even the first manifestation of) a multi-system, 
Th2-dependent disease constellation that can include allergy, elevated IgE, and asthma.18,19,27 The 
barrier defects, other genetic and environmental factors, and exaggerated Th2 biology also involve 
activation of dermal keratinocytes and Langerhans cells, accompanied by in situ lymphocyte 
proliferation and activation – potentially accompanied by allergic phenomena in many cases20 and 
possibly immune -mediated phenomena in a fraction of cases.21 This pathobiology further worsens 
barrier function and causes the chronic, self-sustaining syndrome of skin rash, pruritus, xerosis, 
and gram-positive skin dysbiosis that imposes the personal and societal burdens summarized above 
(Figure 3.1.1-1). 
Until recently, treatment for moderate or severe AD involved hydration of the skin, and/or 
application of topical treatments such as glucocorticoids, calcineurin inhibitors, phosphodiesterase 
4 (PDE4) inhibitors, tar, vitamin D, or dilute bleach. Severe, complex, or refractory cases invoked 
wet-wrap dressings, phototherapy, or systemic treatment with glucocorticoids, cyclosporine, and 
azathioprine -- for most patients, these approaches were, at best, partially satisfactory.10 More 
recently, biologic and small molecule therapies have proven to be promising investigational 
treatments for AD (Figure 3.1.1-1).22 In particular, the recent European Medicines Agency (EMA) 
and FDA approvals of dupilumab (anti-IL-4Rα monoclonal antibody) represent a significant 
advance for AD patients.29 Nevertheless, AD exhibits biological and clinical heterogeneity,23,24
and new medications employing different mechanisms are needed to provide a complete treatment 
armamentarium; indeed, the placebo-adjusted fraction of patients with moderate or severe AD 
demonstrating a reduction of Investigators’ Global Assessment (IGA) to either 1 (almost clear) or 
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0 (clear) after 16 weeks of dupilumab treatment is only ~36%.25,26 Furthermore, dupilumab 
requires periodic injections which may be associated with inconvenience, discomfort, and 
injection-site reactions. New treatments for moderate and severe AD thus still represent a clear 
unmet need.
Figure 3.1.1-1:
Schematic of Selected Immune Mechanisms in Atopic Dermatitis
Abbreviations: DC = dendritic cell; IgE = immunoglobulin E; IL = interleukin; ILC2 = type 2 innate lymphoid cell; 
LC = Langerhans cell; S. aureus = Staphylococcus aureus; TSLP = thymic stromal lymphopoietin.
Schematic model of interplay between microbiome, skin barrier, and immunity in atopic dermatitis highlighting targets 
of novel biologic agents.22
3.1.2
Rationale for Study Drug Mechanisms
Exaggerated activation, local proliferation, and in-migration of leukocytes in the skin characterize 
AD (Figure 3.1.2-1).27,28 Th2 cells contribute by producing IL-4, -5, and -13, which, amongst 
other effects, recruit and activate eosinophils. Together, the Th2 cells and eosinophils directly and 
indirectly contribute to multiple phenomena associated with AD – including IL-31 production, 
which helps drive the intense itch associated with the disease. Products of these cells are validated 
targets of both approved and experimental treatments for AD, including dupilumab (anti-IL-
4Rα);29 and nemolizumab (anti-IL-31).30,31 Th2 cells and a subset of myeloid dendritic cell (DC) 
also play significant roles; their function and products have likewise been targeted by experimental 
therapies (Figure 3.1.1-1). 
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S1P is a lysophospholipid mediator that evokes a variety of cellular responses by the stimulation 
of 5 members of a G-protein coupled receptor family: S1PR1, 2, 3, 4, 5.32 S1PR1 is ubiquitously 
distributed across multiple tissues, notably endothelial cells and lymphoid cells. Among its 
numerous biological activities, S1PR1 controls the egress of lymphocytes from peripheral 
lymphoid organs and their subsequent peripheral localization. Thus, S1PR1 has been targeted in 
the treatment of immune-mediated diseases.33 In particular, S1P also figures prominently in the 
migratory behavior and activation states of the cells operative in AD;34 and is important to 
keratinocyte homeostasis,35,36 accordingly, S1PR modulation is a promising approach for the 
treatment of AD. The dotted boxes in Figure 3.1.2-1 highlight S1P-associated elements of AD 
pathobiology. Hence, the second-generation S1PR agonist (S1PR1 full agonist, S1PR4/5 partial 
agonist) etrasimod is already being studied in a Phase 2 study for this indication.37
BMS-986166 (henceforth meaning either the parent or its phosphorylated derivative, depending 
on context) differentiates from other S1PR drugs by virtue of its partial agonist activity on S1PR1 
(Section 3.2) – leading to reduced macular, pulmonary, and cardiac liabilities both in vivo 
nonclinical and in vitro pharmacology models.38 Furthermore, the safety data for BMS-986166 
from two Phase 1 studies of healthy participants (IM018001 and IM018003) demonstrated no 
significant effects on ECG (after the first dose or after multiple doses), vital signs, and clinical 
laboratory parameters at the doses to be tested in this study.
Based on the preceding, BMS-986166 is an appropriate investigational drug for AD. For 
justification of doses, refer to Section 5.5.1.
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BTK inhibition is thus expected to block antigen-dependent B-cell signaling and function without 
depleting B-cells43, lead to decreases in IC-mediated production of pro-inflammatory cytokines, 
reduce IC signaling to monocytic cells, and block FcεRI-mediated activation of basophils and 
eosinophils by allergen-specific IgE.47 Many of the processes mediated by BTK are shared across 
immune-mediated diseases, including AD,48 making it a plausible target for the treatment of 
multiple immune-mediated disorders, including AD. 
Branebrutinib is an oral, potent, and highly selective, irreversible inhibitor of BTK that covalently 
modifies a cysteine residue within the active site of the enzyme; it is thus an appropriate 
investigational drug for AD in this study. For justification of dose, refer to Section 5.5.2.
3.1.3
Rationale for Study Population
Mild AD generally responds well to skin hydration and topical agents.10 Treatment of moderate-to-
severe AD, however, still represents a significant unmet need because the majority of patients do 
not achieve durable clear or almost-clear status in investigator assessments, despite topical 
treatment or systemic therapy (Section 3.1.1).
AD, like most inflammatory disorders, exhibits a waxing and waning course; thus, careful patient 
selection is required to avoid unexpected “regression to the mean” and other confounding effects 
in clinical studies. This study will recruit adult participants with moderate or severe chronic AD 
of at least 2-years duration. They must also demonstrate Eczema Area and Severity Index (EASI) 
score ≥ 16, validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD) ≥ 3, 
and ≥ 10% body surface area (BSA) affected by AD at baseline visit. In addition, a stable regimen 
(≥ 4 weeks) of topical corticosteroids, calcineurin inhibitors or biologics must have failed to 
provide adequate response within the 6 months prior to randomization. Consistent use of additive-
free, basic bland emollients twice-daily for ≥ 7 days before the baseline visit and throughout the 
treatment period will be mandatory. These factors will minimize selection of patients with 
inconsistent or exceptionally variable disease. Only adults will be studied due to the early 
developmental phases of both active investigational products. 
3.1.4
Rationales for Primary and Secondary Efficacy Endpoints
The primary efficacy endpoint is mean percentage reduction from baseline in EASI score at 
Week 16. The EASI is a widely used clinical study endpoint in AD. Thus, it allows 
contextualization with the full spectrum of approved and experimental drugs – offering maximum 
opportunity for benchmarking and modeling of the relationships between PK, PD, safety, and 
efficacy. This study will use it on a continuous scale to maximize statistical efficiency – though 
the categorical endpoints of EASI-50/75/90 will be assessed as secondary/exploratory endpoints. 
(Table 4-1)
The secondary endpoints include the mean reduction in affected BSA, the proportion of 
participants achieving EASI-50, and the proportion of participants achieving a score of “cleared” 
or “almost cleared” on the vIGA-AD and pruritus NRS (4-point improvement and mean % 
change). These endpoints are important adjuncts to the continuous-scale EASI and can provide 
insight into the registrational plausibility of the study drugs. The FDA, in particular, has assigned 
significant weight to the vIGA-AD response in registrational packages of other compounds.
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3.1.5
Research Hypothesis
Inhibition of S1PR1, 4, 5 or BTK with BMS-986166 or branebrutinib, respectively, will safely 
reduce disease activity in participants with moderate-to-severe AD.
3.2
Background
3.2.1
BMS-986166
A detailed description of pharmacology, toxicology, and clinical safety can be found in 
BMS-986166 investigator brochure.38 Key highlights are provided below.
3.2.1.1
In Vitro Pharmacology
BMS-986166 is a novel prodrug that is phosphorylated to its pharmacologically active moiety, 
BMS-986166-P (BMT-121795). BMS-986166-P is a sphingosine 1 phosphate (S1P) receptor 
modulator; a biased agonist of S1PR1, with agonist activity for S1PR4 and S1PR5. BMS-986166-P 
relies predominantly on sphingosine kinase 2 (SphK2), similar to fingolimod (FTY-720, 
GILENYA®). Importantly however, BMS-986166-P differentiates from fingolimod phosphate 
(FTY-P) and other S1PR1 agonists in its differential effects on various signaling pathways 
downstream of S1PR1, ie, it is a biased ligand.49
BMS-986166-P fully displaces S1P binding to S1PR1 transfected Chinese hamster ovary (CHO) 
cells with an half maximal inhibitory concentration (IC50) of 0.014 nM, and acts as a full agonist 
in a cyclic adenosine monophosphate (cAMP) assay in these cells with an EC50 of 0.0079 nM, 
comparable to fingolimod phosphate. In an S1PR1 GTPγS binding assay in S1PR1/CHO cells, 
however, BMS-986166-P acts as a partial agonist with maximum efficacy that reaches only 79% 
of the maximum efficacy of endogenous ligand S1P. In an S1PR1 internalization assay (in 
S1PR1/CHO/ green fluorescent protein [GFP] cells), BMS-986166-P also acts as a partial agonist 
with an efficacy that reaches 72% of maximum effect observed with S1P. This partial agonism is 
unique to BMS-986166-P, as fingolimod phosphate and S1PR1 selective agents (eg, BAF-312, 
KRP-203, and CS-0777) are S1PR1 full agonists in both the GTPγS and the internalization assays. 
Lastly, in an S1PR1 extracellular signal-related kinase (ERK)-phosphorylation assay (in 
S1PR1/CHO cells), BMS-986166-P is shown to be a full agonist but with an EC50 more than 
100-fold higher than the EC50 of fingolimod phosphate. Taken together, the above demonstrate 
the biased agonism properties of BMS-986166-P.
Despite the above-mentioned differences in receptor pharmacology in S1PR1/CHO cells, 
BMS-986166-P completely blocks S1P-induced T-cell chemotaxis in a primary T-cell system, 
similar to fingolimod phosphate. Lastly, similar to fingolimod phosphate, BMS-986166-P is a 
potent agonist for S1PR4 and S1PR5 receptors with EC50 values comparable to fingolimod 
phosphate: 3.4 and 2.47 nM vs. 1.6 and 0.67 nM, correspondingly. Similar to second-generation 
S1P-1 modulators, BMS-986166-P is inactive in S1P-3R GTPγS assays with an EC50 greater than 
1 μM. 
In summary, BMS-986166-P appears to be a biased ligand of S1PR1 based on its partial agonist 
activity in the S1PR1 internalization assay (S1PR1/CHO cells) and right-shifted potency in ERK 
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phosphorylation assays (vs. fingolimod phosphate). BMS-986166 thus demonstrates differentiated 
in vitro pharmacology relative to prior-generation S1PR1 modulators, offering promise for 
improved clinical performance.
3.2.1.2
In Vivo Pharmacology
S1PR1 agonists cause lymphocyte sequestration in lymphoid organs, which results in rapid 
lymphopenia. Accordingly, in rats receiving vehicle or escalating doses of BMS-986166, 
BMS-986166 reduces lymphocyte counts in a dose-dependent manner at 24 hours post-dose, 
achieving a decline of ~80% compared with vehicle-treated controls. The EC50 was determined 
to be 6.5 nM in rats.38
Mouse skin contact hypersensitivity models share many of the features of human atopic dermatitis. 
Accordingly, contact hypersensitivity was induced in BALB/c mice by sensitizing the flanks with 
0.5% fluorescein isothiocyanate (FITC) on Days 0 and 5 of the study and challenging the ears with 
the same solution on Days 11, 12, and 13. Treatments included BMS-986166 administered via oral 
gavage at 0.1, 0.5, or 2 mg/kg/day or dexamethasone at 1 mg/kg/day with first dose initiated on 
the day before sensitization. BMS-986166 demonstrated robust efficacy in this 14-day 
FITC-induced AD model based on the dose-dependent reduction in 1) ear swelling, 2) total serum 
IgE levels, 3) ear histology scores, 4) scratching events, 5) skin inflammatory cytokine gene 
expression (Th1, Th2, Th17, Th22), and 6) the numbers of infiltrating immune cells.50 The effect 
for BMS-986166 at 2 mg/kg was comparable to that of the dexamethasone positive control. BMS-
986166 thus modulates the complex inflammatory pathways involved in this model of AD disease 
pathogenesis. 
BMS-986166 has also demonstrated maximal lymphopenia and efficacy in the experimental 
allergic encephalomyelitis rodent model of MS, and the MRL/lpr mouse lupus model -- similar to 
that of fingolimod, and efficacy superior to anti-tumor necrosis factor (TNF)α antibody in 
oxazolone-induced mouse colitis models. Although these models differ phenomenologically from 
those of AD, the latter share key cellular and molecular mechanisms with the former,51 as 
demonstrated by published reports of beneficial pharmacologic S1PR1 modulation in murine AD 
models.52
Taken together, the in vivo pharmacology properties of BMS-986166 support efficacy testing in 
human immune-mediated diseases, including AD.
3.2.1.3
Nonclinical Toxicology
A comprehensive nonclinical toxicology program was executed for BMS-986166 and is 
summarized in BMS-986166 Investigator Brochure (IB).38 Results of 6-month and 9-month good 
laboratory practice (GLP) toxicity studies in rats and dogs, respectively, are highlighted below.
In a 6-month repeat dose, oral GLP toxicity study in rats with an 8-week recovery period, 
BMS-986166 was administered at doses of 0 (vehicle), 1, 3, or 10 mg/kg/day to groups of 
25 rats/sex. Potential effects of BMS-986166 on mating and fertility in male rats and early 
embryonic development of their offspring were also evaluated.53 BMS-986166 was well tolerated 
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at doses of up to 10 mg/kg/day with no BMS-986166-related clinical observations or effects on 
physical and ophthalmologic examinations, NCV measurements, male reproductive performance 
and early embryonic development of their offspring, and coagulation and urinalysis parameters. 
Findings consistent with the intended pharmacology of BMS-986166 were observed at all doses 
(≥ 1 mg/kg/day; mean sex-combined AUC[0-24] ≥ 1.13 μg·h/mL), including decreased 
lymphocytes in blood and lymphoid tissue. All BMS-986166-related changes were partially or 
completely reversible following the 8-week post-dose recovery period. As there were no adverse 
findings at any dose, the NOAEL was considered to be 10 mg/kg/day (mean sex-combined 
AUC[0-24h] 7.29 μg·h/mL for BMS-986166 and AUC[0-24h] 22.3 μg·h/mL for BMS-986166-
P).
In a 9-month repeat dose, oral GLP toxicity study in dogs with a 12-week recovery period, 
BMS-986166 was administered by oral gavage at doses of 0 (control; males/females), 0.1 (males), 
0.3 (males/females), 1 (males/females) and 3 (females) mg/kg/day to groups of 4 to 6 dogs per 
sex.54 BMS-986166 was clinically well tolerated when administered at an oral dose of 
≤1 mg/kg/day in males (mean AUC[0-24h] 4.44 μg·h/mL), and ≤ 3 mg/kg/day in females (mean 
AUC[0-24h] 7.51 μg·h/mL) with no drug-related clinical observations or effects on neurological, 
ECG or ophthalmic examinations; respiratory assessments; coagulation, urinalysis or urine 
chemistry parameters; and organ weights or gross pathology. Findings consistent with the intended 
pharmacology were observed at all doses included decreases in lymphocytes in blood and 
lymphoid tissue. There were no adverse BMS-986166-related findings at 0.1 mg/kg/day in males 
and ≤ 3 mg/kg/day in females; however, adverse changes of seminiferous tubule 
degeneration/atrophy of the testis that were reversible were observed in males at 0.3 mg/kg/day 
and 1 mg/kg/day. Therefore, the NOAEL was considered to be 0.1 mg/kg/day in males and 
3 mg/kg/day in females (AUC[0-24h] 0.528 μg·h/mL and 7.51 μg·h/mL, respectively, for 
BMS-986166, and AUC[0-24h] 2.16 μg·h/mL for males at 0.1 mg/kg/day, and 25.3 μg·h/mL for 
females at 3 mg/kg/day for BMS-986166-P).
3.2.1.4
Pharmacokinetic Drug Interaction Summary
A complete summary of the nonclinical PK of BMS-986166 can be found in the IB. Drug-drug 
interaction (DDI) potential of BMS-986166 is briefly discussed in this section. In vitro data in 
human liver microsomes suggested that BMS-986166 is metabolized via cytochrome P450 
(CYP)3A4/3A5 (~68%) and CYP2C8 (~36%).55 Thus, the PK of BMS-986166 may be altered 
when co-administered with CYP3A4/3A5 inhibitors or inducers.
In vitro studies with recombinant enzymes showed that BMS-986166 did not inhibit uridine 
diphosphate glucuronosyltransferase (UGT)1A1 at clinically relevant concentrations.56 In human 
liver microsomes, BMS-986166 was not a reversible or time-dependent inhibitor of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 (IC50 > 6 μM).56 In 
cryopreserved human hepatocytes, BMS-986166 was not an inducer of CYP1A2, CYP2B6, or 
CYP3A4 (EC50 > 2.5 μM).56
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BMS-986166 did not inhibit digoxin transport in Caco-2 cells (IC50 > 15 μM),56 suggesting that 
it is not a P-glycoprotein (P-gp) inhibitor. In vitro studies with cells expressing single transporters 
showed that BMS-986166 is not an inhibitor of various human transporters including breast cancer 
resistance protein (BCRP), organic anion transporting polypeptide (OATP1)B1, OATP1B3, bile 
salt export pump, organic anion transporter (OAT)1, OAT3, sodium taurocholate co-transporting 
polypeptide, or multidrug resistance-associated protein 2 (IC50 > 16.7 μM).56
Overall, the present results indicate that the potential for BMS-986166 as a perpetrator of DDI is 
minimal. There have been no formal clinical DDI studies with BMS-986166.
3.2.1.5
Clinical Safety
Clinical safety of BMS-986166 has been evaluated in 2 studies performed in healthy participants.
Study IM018001
Study IM018001 was a randomized, double-blind, placebo-controlled study evaluating the safety, 
tolerability, PK, and PD of single ascending doses (SAD) of BMS-986166 and an ascending dose 
titration of BMS-986166 over 16 days, as well as the effect of food and pH on the relative 
bioavailability of BMS-986166. It was performed in healthy women not of childbearing potential 
(WNOCBP) and in males. BMS-986166 was administered as SAD (Panels 1-3), an intrasubject 
ascending dose titration (Panel 4), and as a single fixed dose with or without food and famotidine 
(Panel 5a/b/c). 
•
In Panels 1-3, eligible participants were randomized in a 4:1 ratio to receive an oral solution 
formation of BMS-986166 or placebo. The doses for Panels 1, 2, and 3 were 0.75 mg, 2.0 mg, 
and 5.0 mg, respectively.
•
Panel 4 enrolled 16 participants who were randomized in a 3:1 ratio to receive double-blind 
treatment with an oral solid dosage formulation of BMS-986166 or placebo. Participants
randomized to BMS-986166 received increasing daily doses of 0.25 mg, 0.5 mg, 0.75 mg, 
1.0 mg, and 1.5 mg. 
•
Panel 5 enrolled 24 participants who were randomized in a 1:1:1 ratio to receive a single dose 
of 2.0 mg BMS-986166 solid dosage formulation in the fasted state (Panel 5a), in the fed state 
(Panel 5b), or 2 hours following administration of 40 mg famotidine (Panel 5c). Panel 5 did 
not include a placebo lead-in period. 
Sixty participants received BMS-986166 in this study. Single oral doses of BMS-986166 were 
administered to 48 participants at doses of 0.75 mg (8 participants), 2.0 mg (32 participants), or 
5.0 mg (8 participants). The other 12 participants received multiple oral doses of BMS-986166, 
which were titrated from 0.25 mg to 1.5 mg over a dosing period of 16 days. BMS-986166 was 
administered as an oral solution formulation to 24 participants (8 participants each at doses of 
0.75 mg, 2.0 mg, or 5.0 mg) and as a capsule formulation in the other 36 participants. Ten 
participants received matching placebo.
BMS-986166 was well tolerated by the healthy participants in this study when administered as 
single oral dose from 0.75 mg to 5.0 mg, or as multiple oral doses with titration from 0.25 mg to 
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1.5 mg over 16 days. All AEs reported in the study were assessed as non-serious, mild in intensity 
(Grade 1), and unrelated to study treatment. There were no deaths, SAEs, or treatment 
discontinuations due to AEs. Treatment-emergent AEs were reported with similar frequency for 
BMS-986166-treated participants (any dose) and placebo participants. Among participants 
receiving BMS-986166, there were no dose-related trends in the frequency of AEs, nor were there 
any meaningful differences in the AE profile when BMS-986166 was administered as a solid 
dosage versus solution formulation or following administration of BMS-986166 with a high-fat 
meal or famotidine compared with administration of BMS-986166 alone under fasting conditions.
Transient, dose-dependent reductions in mean absolute lymphocyte count (ALC) deemed not 
clinically relevant were observed following treatment with BMS-986166 compared with placebo, 
an effect that was expected based on the mechanism of action of BMS-986166 and that was 
evaluated as a PD endpoint in this study. Furthermore, no subject experienced an infection that 
was attributed to study treatment and could potentially be related to lymphopenia. 
Cardiac monitoring and frequent ECG analyses were performed throughout the study. Though 
dose-dependent decreases in hourly heart rate (HR) were observed following administration of 
single doses of BMS-986166, no adverse treatment-related reductions in HR or other ECG 
abnormalities were identified. For the interval from 0 to 12 hours post-dose, the time-matched, 
placebo-corrected, 
median 
largest 
decreases 
in 
hourly 
HR 
were 
-0.29 beats 
per 
minute (bpm), -6.38 bpm, and -8.37 bpm for the 0.75, 2.0, and 5.0 mg dose panels, respectively. 
The 2 highest dose panels met the prospective definition for treatment-related bradycardia during 
the 0 to 12-hour and/or 0 to 24-hour time intervals (ie, median time-matched largest decrease from 
baseline in hourly HR showed a ≥ 7 bpm difference for active relative to placebo); however, no 
subject had a reduction in HR below an absolute value of 45 bpm, and no subject experienced an 
AE of syncope, dizziness, atrioventricular (AV) block, or other event that could be attributed to a
reduction in HR. It is important to note that the 2.0 mg and 5.0 mg doses administered in Study 
IM018-001 are well above the dose levels to be administered in this Phase 2 study (IM018-005). 
Section 5.5.1 details the relationship between dose and HR expected for the present study.
A similar effect on hourly HR was not observed following dose titration of BMS-986166 up to 
1.5 mg in Panel 4. In addition, an evaluation of ECG HR during treadmill testing in Panel 4 did 
not indicate any clinically meaningful effect on the target physiologic HR achieved during exercise 
following dose titration of BMS-986166. A concentration-response analysis of ΔQTcF interval 
versus plasma concentration of BMS-986166 or BMS-986166-P did not show any trends toward 
increases in QTcF with increasing concentration of either analyte; the apparent slight decrease in 
QTcF with increasing concentration of BMS-986166 was not deemed clinically relevant. 
In summary, the safety data from Study IM018001 indicated that single doses of BMS-986166 up 
to 5.0 mg were generally safe and well-tolerated, and did not suggest association with unexpected 
infection risk, or an increased risk of clinically significant bradycardia, AV conduction 
delays/blocks, or hypotension.
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Study IM018003
Study IM018003 was a randomized, double-blind, placebo-controlled study designed to assess the 
safety, tolerability, PK, and PD of MAD of BMS-986166 for 28 days in healthy male or female 
(WNOCBP) participants. There were 3 sequential multiple-dose panels designated as Panels 1, 2, 
and 3. A total of 32 participants received QD doses of blinded study treatment for 28 days; 
24 participants received BMS-986166 at doses of 0.25, 0.75, or 1.5 mg (8 participants per dose), 
and 8 participants received placebo.
•
Multiple oral doses of BMS-986166 up to 1.5 mg QD for 28 days were safe and generally well 
tolerated in the healthy participants in this study.
•
No drug-related SAEs or deaths occurred during this study. One subject administered placebo 
had an SAE reported as vasovagal symptoms graded as moderate (Grade 2).
•
Twenty-two of 24 participants (91.7%) experienced AEs following administration of 
BMS-986166, and 6 of 8 participants (75.0%) had AEs following administration of placebo. 
The most frequently occurring AEs during BMS-986166 administration were lymphopenia 
(N=15; 62.5%) versus 0 in placebo arm, which is consistent with the pharmacology of the drug; 
contact dermatitis at the site of the ECG monitoring electrode deemed unrelated (N=8; 33.3%) 
versus 1 (12.5%) in placebo group, increased blood creatine phosphokinase (N=7; 29.2%) 
versus 3 (37.5%) in placebo group, and headache (N=5; 20.8%) versus 1 (12.5%) in placebo 
group.
•
Eighteen of 24 participants (75.0%) administered BMS-986166 experienced AEs assessed as 
drug-related by investigators, all graded as mild (Grade 1). The most frequent were 
lymphopenia (N=15; 46.9%), headache (N=3; 9.4%), and alanine aminotransferase (ALT) 
increased (N=3; 9.4%), which were generally dose dependent.
•
Of the 32 participants treated, 2 participants (6.3%) discontinued treatment due to AEs. One 
subject (12.5%) in the 1.5 mg BMS-986166 QD dose group had a single premature ventricular 
contraction (PVC) with retrograde sinus node activation (listed as sinus node exit block), which 
was followed by a 3-beat run of non-sustained ventricular tachycardia (NSVT) and 4 isolated 
PVCs lasting less than 1 minute on continuous clinical monitoring. This event was 
asymptomatic and graded as mild. One subject in the placebo group had a decrease in serum 
testosterone lasting 38 days.
•
There was a dose-related trend in the AE observance of mild lymphopenia, the intended 
mechanism of action of BMS-986166, occurring after multiple oral doses of BMS-986166 
≥ 0.75 mg QD. There were no other treatment, or dose-related trends in the frequency of 
clinical laboratory abnormalities after multiple oral doses of BMS-986166 up to 1.5 mg QD 
for 28 days.
•
There were no apparent dose-related trends in the 12-lead ECG parameters (ie, HR; and PR, 
QRS, QTcF, and QT intervals).
•
There was a dose-related decrease in mean HR, recorded by continuous cardiac monitoring on 
Day 1, after administration of BMS-986166 compared with placebo in a time-matched 
analysis. No arrhythmias of high-grade AV block were noted. There were no differences in 
AEs of dizziness, syncope, pre-syncope, and fatigue between the drug and the placebo arms. 
Overall, in the study, there was 1 subject who had symptoms of pre-syncope at the 0.25 mg 
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dose and 1 subject with dizziness at the 0.75 mg dose. In the placebo arm, there was 1 subject 
with dizziness and 1 subject with pre-syncope.
•
Statistical analysis of continuous cardiac monitoring data identified no treatment-related 
bradycardia (ie, maximal median HR decrease of ≥ 7 bpm compared with time-matched 
predose levels vs placebo participants) in hourly HR at nadir following multiple oral doses up 
to 1.5 mg BMS-986166.
•
Results from the BMS-986166 treatment panels over the 0 to 672 hour (Day 28) study interval 
yielded largest decreases in nadir hourly HR (time matched) from placebo of 0.83 bpm, 
3.46 bpm, and 5.54 bpm at the 0.25 mg, 0.75 mg, and 1.5 mg dose levels, respectively.
•
There were no clinically meaningful changes in vital signs or physical examination findings 
(see Section 9.2.8).
In summary, the safety data from Study IM018003 indicated that (1) multiple ascending doses of 
BMS-986166 up to 1.5 mg were generally safe and well-tolerated, and with no association with 
unexpected infection risk, or an increased risk of symptomatic bradycardia, AV conduction 
delays/blocks, or hypotension; and (2) no dose initiation titration is required.
Taken together, results of Phase 1 studies with BMS-986166 demonstrate a satisfactory safety 
profile for its investigation in patients with immune-mediated diseases.
3.2.2
Branebrutinib
A detailed description of pharmacology, toxicology, and clinical safety can be found in the 
branebrutinib IB.47 Key highlights appear below.
3.2.2.1
In Vitro Pharmacology
Branebrutinib is a potent inhibitor of BTK (IC50 = 0.1 nM) that covalently modifies a cysteine 
residue (Cys-481) within the active site of the enzyme. Against a panel of 245 kinases, the 
compound was shown to inhibit BTK with greater than 5,000-fold selectivity over all but 4 kinases. 
The highly related kinase Tec was inhibited 9-fold less potently than BTK. Of particular note, 
branebrutinib was > 10,000-fold selective over members of the epidermal growth factor receptor 
(EGFR) family of kinases. In contrast, ibrutinib inhibited these EGFR kinase family members with 
much greater potency, with only 10- to 110-fold selectivity for BTK.57 Ibrutinib shows 3-fold 
selectivity for BTK over Tec. 
Branebrutinib potently inhibited multiple functional endpoints in primary human B-cells 
stimulated through the BCR (IC50 values < 1 nM), including production of inflammatory 
cytokines, cell proliferation, and surface expression of CD86. Branebrutinib also inhibited FcγR 
(FcγRIIa and FcγRIIIa)-dependent IL-6 production stimulated from peripheral blood mononuclear 
cells (PBMCs) stimulated by IgG-containing ICs with a potency (IC50 = 0.3 nM) equivalent to 
those measured against BCR-dependent endpoints in B-cells. In assays using human whole blood, 
branebrutinib was shown to inhibit BCR-stimulated expression of CD69 on B-cells with an IC50 
value of 11 nM. Measurements of BTK inactivation in human whole blood showed a similar IC50 
value of 5 nM. Branebrutinib rapidly inactivated BTK in a time-dependent and concentration-
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dependent manner when added to human whole blood. The second-order rate constant for the 
inactivation of BTK in human whole blood by branebrutinib was determined to be 3.5×10-4 nM-1
• min-1. This represents a rate of inactivation 3 times faster than that measured with ibrutinib 
(1.2×10-4 nM-1 • min-1).57
3.2.2.2
In Vivo Pharmacology
A single oral administration of branebrutinib at 1 mg/kg to mice resulted in BTK inactivation of 
89%, 82%, and 72% in blood, popliteal lymph nodes, and spleens, respectively, at 4 hours 
post-dose. The compound dose-dependently inactivated BTK in whole blood after a single oral 
administration, with the dose producing 50% effect (ED50) values of 0.12 and 0.07 mg/kg PO at 
4 hours and 24 hours post-dose, respectively. Ibrutinib at 1 mg/kg provided only 37% and 42% 
BTK inactivation at 4 and 24 hours, respectively, in the same experiment, and demonstrates the 
considerably greater potency of branebrutinib in vivo. After 24 hours, the recovery of available 
BTK active sites in both blood and spleens due to new protein synthesis was measured at a rate of 
25% to 35% per day.58
Branebrutinib was highly effective in New Zealand black/white lupus-prone mice -- dose-
dependently inhibiting the increase in severe proteinuria, a measure of the underlying nephritis. 
All dose levels also protected from the disease-related death in these mice over the course of 
treatment. Serum anti-double-stranded deoxyribonucleic acid (anti-dsDNA) titers, which 
progressively increased over the course of the study in vehicle control mice, were also inhibited in 
a dose-dependent manner by treatment with branebrutinib. 
Branebrutinib also demonstrated robust efficacy in the mouse collagen-induced arthritis and 
collagen antibody-induced arthritis models, demonstrating its ability to attenuate Fc receptor and 
B-cell receptor signaling associated with disease biology, including clinically evident disease, 
histological joint damage, and bone mineral density loss. In both models, maximal efficacy was 
observed with ≥95% inactivation of BTK in vivo.
In summary, branebrutinib is a potent and highly selective small-molecule, irreversible inhibitor 
of BTK that blocks antigen receptor-dependent signaling and functional endpoints in human 
B-cells, including the production of proinflammatory cytokines, co-stimulation molecule (eg, 
CD86) expression, and proliferation with IC50 values of < 1 nM. The compound also potently 
inhibited BTK-dependent cytokine production from PBMCs stimulated through the low-affinity 
activating FcγRs. In human whole blood, branebrutinib rapidly inactivated BTK. Branebrutinib 
was highly efficacious in all tested murine models of immune-associated diseases. Many of the 
BTK-associated pathobiologic mechanisms common to these mouse autoimmunity models apply 
to AD as well (Section 3.1). 
3.2.2.3
Nonclinical Toxicology
Branebrutinib was studied in a comprehensive nonclinical toxicology program. Results of 6-month 
and 9-month GLP toxicity studies in rats and dogs, respectively, are highlighted below. 
In a 6-month oral toxicity study in rats with a 5-week recovery,59 branebrutinib was administered 
by daily oral gavage at doses of 0 (vehicle), 1, 5, or 20 mg/kg/day to groups of 25 rats/sex. Satellite 
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animals consisting of 25 naïve female rats (untreated) per group were used for mating and fertility 
assessment of the males in each dose group. 
Branebrutinib was clinically well tolerated by rats for 6 months at oral doses ≤20 mg/kg/day with 
no BMS-986195-related effects on survival; body weight or food consumption; physical or 
ophthalmic examinations; male reproductive performance (mating and fertility) or early 
embryonic development of the offspring sired by treated males; coagulation, urinalysis or urine 
chemistry parameters; or organ weights. The suppression of T cell-dependent antibody response 
(TDAR) to keyhole limpet hemocyanin (KLH) and decreases in B lymphocytes at all doses were 
consistent with the pharmacologic activity of branebrutinib. The primary effects were noted in the 
pancreas at all doses and were characterized microscopically by islet fibrosis, peri-islet pigment, 
islet hemorrhage, mononuclear cell infiltration, and acinar atrophy. These pancreatic findings were 
not considered adverse, as they represent exacerbation of an age-related background pancreatic 
finding specific to rats, which has been reported from emerging literature for this class of 
compound.60 Comparing the pancreatic findings across studies, there was no progression of the 
lesions, in terms of severity, after 6 months of dosing, when compared with the lesions seen in 
studies of shorter duration (2 weeks61 and 1 month of dosing62,63). For these reasons, it was 
considered unlikely that the pancreatic lesions observed in rats treated with BTK inhibitors would 
have any relevance to the safety assessment for human participants treated with this drug class, 
and this was acknowledged by the FDA. As a result, conclusions from earlier studies of shorter 
duration that these findings were adverse in the rat should not preclude dosing at equivalent 
exposures in humans. Therefore, the NOAEL was considered to be the high dose of 20 mg/kg/day 
(mean sex-combined AUC[0-24h] 61.9 μg·h/mL).
In a 9-month oral toxicity study in dogs with a 4-week recovery,64 branebrutinib was administered 
by oral gavage at doses of 0 (vehicle), 0.5, 3, or 15 mg/kg/day to groups of 6 dogs per sex. 
Overall, branebrutinib was tolerated by dogs for 9 months at oral doses ≤15 mg/kg/day with no 
branebrutinib-related clinical observations, effects on body weights and body weight gains, food 
consumption, physical and ophthalmic examinations, electrocardiology, urinalysis and urine 
chemistry parameters, organ weights changes and gross pathology findings. Consistent with the 
expected pharmacology of branebrutinib, the primary findings at ≥ 0.5 mg/kg/day were minimal 
to mild or moderate germinal center lymphoid depletion in lymph nodes, spleen, and/or 
gut-associated lymphoid tissue (GALT), and suppression of TDAR to KLH. Based on the absence 
of adverse findings at any dose tested, the NOAEL was considered to be 15 mg/kg/day (mean sex-
combined AUC[0-24h] 113 μg·h/mL at Week 39).
3.2.2.4
Pharmacokinetic Drug Interaction Summary
Data from the in vitro DDI interaction studies of branebrutinib with multiple CYP and UGT 
enzymes and multiple drug transporters predicted DDI potential with substrates of CYP3A4 (both 
as inhibitor and inducer), CYP2C8 enzymes, and BCRP drug transporter. In the clinical DDI 
studies, co-administration of branebrutinib (9 mg QD for 14 days, Study IM014013) did not have 
an effect on the exposures of the corresponding substrates of multiple CYP enzymes, including 
the PK of midazolam (sensitive substrate of CYP3A4) or pravastatin (OATP1B1 and OATP1B3), 
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but led to weak interaction with montelukast (CYP2C8) with mild increase in its exposure (1.556× 
Cmax and 1.270× AUC[INF]). Additionally, a mild increase in digoxin (P-gp substrate) Cmax 
(1.565×), and AUC (1.209× AUC[INF]) were also observed in the clinical DDI study with 
branebrutinib. Overall, the data suggest that CYP3A4 inhibitory and induction properties of
branebrutinib may “balance” each other in vivo and co-administration of branebrutinib with
substrates of P-gp (such as digoxin) or CYP2C8 with narrow therapeutic index should be avoided or 
restricted or their serum concentrations be monitored in the presence of branebrutinib.
Furthermore, in clinical DDI studies (IM014013, IM014023), branebrutinib showed no clinically 
relevant interactions either with oral contraceptives (ethinylestradiol/norethindrone) or with 
methotrexate. In another clinical DDI study (IM014032), the effect of coadministration of multiple 
oral doses (9 mg, QD) of branebrutinib on the single-dose PK of rosuvastatin (10 mg) in healthy 
participants was assessed. Rosuvastatin is a sensitive substrate of the BCRP drug transporter.  
Despite in vitro DDI data that showed branebrutinib to inhibit BCRP with an IC50 of 1.8 μM, 
preliminary results from this clinical DDI study showed that the concomitant administration of 
branebrutinib at steady-state resulted in no clinically meaningful effect on the plasma exposure of 
rosuvastatin following a single dose in healthy volunteers.
On the other hand, a human absorption, distribution, metabolism, and excretion (ADME) study 
(IM014016) showed the major metabolic clearance pathway for branebrutinib to be enzyme-
mediated glutathione conjugation catalyzed by multiple glutathione-S-transferase (GST) enzymes 
(please refer to the IB for details). Therefore, clinically significant effect on branebrutinib exposure 
is not likely to occur when co-administrated with other agents that are inhibitors of major drug-
metabolizing enzymes such as CYPs and UGTs.
In summary, branebrutinib is unlikely to be a clinically significant victim of PK drug interactions. 
It also has low likelihood of being a PK drug-interaction perpetrator through most metabolic 
enzymes and transporters. However, it may act as a weak inhibitor of CYP2C8 and P-gp at 
clinically relevant concentrations. 
3.2.2.5
Clinical Safety
Clinical safety of branebrutinib has been evaluated in 4 studies performed in healthy participants. 
Currently 2 studies are ongoing: IM014029 (a Phase 2a study of branebrutinib in systemic lupus 
erythematosus, primary Sjogren’s syndrome, and rheumatoid arthritis), and IM014032 (a Phase 1 
study of drug interactions between branebrutinib and rosuvastatin); neither of these 2 studies 
currently have sufficient data to report.
Studies IM014001, IM014013, IM014016, and IM014023
The FIH study in healthy participants (Study IM014001)65 included a randomized, placebo-
controlled, double-blind, SAD (Part A) and MAD (Part B; 14 days) - study (non-Japanese descent); 
a randomized, placebo-controlled, double-blind, MAD study (Japanese descent; Part C); and an 
open-label, non-randomized, single-sequence relative bioavailability and food effect study (4 
single doses, 4 days apart; Part D). Evaluations included safety and tolerability, PK, PD, target 
engagement characteristics, effects in Japanese participants, and clinical pharmacology 
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assessments of food effect and bioavailability of a suitable formulation for use in patients with 
rheumatoid arthritis (RA). Doses and dose escalation were planned so that the projected mean 
AUC would not exceed the proposed maximum AUC (5400 ng·hr/mL), providing approximately 
a 10-fold safety margin from the AUC in rats (20 mg/kg/day). 
There were no deaths in the study. 
 
 
 
 
 
 
Other than this event, there were no AEs leading to discontinuation, 
and all AEs were mild or moderate in intensity. In the SAD panels (Part A), 30 participants 
received branebrutinib (0.3, 1, 3, 10, or 30 mg as oral solution) and 10 received placebo. Eighteen 
participants (60%) who received branebrutinib experienced at least 1 AE. AEs that occurred for 
> 1 subject were: headache (4), upper respiratory tract infection (3), dizziness (3), nausea (2), rash 
(2), throat irritation (2), myalgia (2), and dysmenorrhea (2). Nine participants who received 
branebrutinib had AEs classified as related to study drug by the investigator as follows: headache 
(2); rash (2); and dizziness, dysgeusia, oral herpes, influenza-like illness, malaise, hot flush, 
nausea, tongue ulceration, and dry lips (1 each). Among the 10 participants who received placebo 
in Part A, 5 (50.0%) experienced at least 1 AE; headache was reported for 3 participants, and 
epistaxis was reported for 2 participants (other events were reported for 1 subject each).
In the MAD panels (Part B), 24 participants received branebrutinib (0.3, 1, 3, or 10 mg as oral 
solution) and 8 received placebo QD for 14 days. Seventeen participants (70.8%) of 24 who 
received branebrutinib experienced at least 1 AE. The most frequently reported AEs were 
headache (8); upper respiratory tract infection (4); oral herpes (3); abdominal pain (2); nausea (2); 
and tension headache (2). The abdominal pain events were not associated with abnormalities in 
amylase or lipase values. They were considered unrelated to branebrutinib and they resolved 
without treatment. Ten participants who received branebrutinib experienced at least 1 AE that was 
classified as related to study drug by the investigator as follows: headache (5), oral herpes (3, all 
had history of oral ulcers), abdominal pain, chills, conjunctivitis allergic, cough, dry skin, 
dyspepsia, eye irritation, mouth ulceration, nasal congestion, nausea, oropharyngeal pain, tension 
headache, and upper respiratory tract infection (1 each). Among the 8 participants who received 
placebo in Part B, 7 (87.5%) experienced at least 1 AE (only musculoskeletal pain [2] was reported 
for more than 1 subject).
In Part C, 9 participants (Japanese MAD) had AEs: 7 participants (38.9%) following treatment 
with branebrutinib; and 2 participants (33.3%) after having received placebo. In Part D, 
14 participants received 4 doses of branebrutinib 10 mg as follows: solution formulation under 
fasted condition on Day 1, solution/fed on Day 5, suspension/fasted on Day 9, and suspension/fed 
on Day 13. Six participants (42.9%) experienced at least 1 AE during any period. The most 
frequently reported AE was chest discomfort (2). The AEs of chest discomfort (2) and influenza-
like illness were assessed as related to branebrutinib by the investigator.
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Overall, in Study IM014001, no clinically meaningful safety signals were identified based on 
assessments of AEs, ECGs, vital signs, and clinical laboratory tests. There was no relationship of 
frequency and severity of AE with dose levels. Safety and tolerability of branebrutinib are 
favorable, based on the observed data from the FIH study.
In Study IM014013, a DDI study in 26 healthy male participants to assess the effects of 
co-administration of branebrutinib on the PK of methotrexate (MTX) and on a cocktail of probe 
substrates, there were no deaths and no other SAEs, other significant AEs, or AEs leading to 
discontinuation. Caffeine, montelukast, flurbiprofen, omeprazole, midazolam, pravastatin, and 
digoxin (probe substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4, OATP1B1, 
OATP1B3, and P-gp, respectively) alone, and in combination with branebrutinib were generally 
safe and well tolerated in healthy male participants. 
In Study IM014016, an ADME study in 9 healthy male participants who received 
[14C]branebrutinib, there were no deaths and no other SAEs, other significant AEs, or AEs leading 
to discontinuation. A total of 3 AEs was reported by 3/9 (33.3%) participants. No 
treatment-emergent adverse events (TEAEs) were considered related to branebrutinib, and all 
TEAEs were considered mild in severity and were resolved by end of study. There were no 
clinically relevant changes in laboratory results, ECG intervals, or vital signs reported.
In Study IM014023, a study in 24 healthy female participants designed to investigate the effects 
on PK, as well as the safety and tolerability of branebrutinib co-administered with the high-dose 
OC Loestrin®, there were no deaths and no other SAEs, other significant AEs, or AEs leading to 
discontinuation. Overall, 34 TEAEs were reported in 16 participants. All TEAEs were considered 
to be mild in severity. The most common TEAEs were headache (5 participants); hepatic enzyme 
increased (3 participants); and ALT increased, back pain, dry eye, nausea, and rash papular (all 
reported in 2 participants each). Hepatic marker measurements showed no elevations in total 
bilirubin and alkaline phosphatase but did include elevations of aspartate aminotransferase (AST). 
All changes in ALT and AST were < 3× the upper limit of normal (ULN) and most were < 2× 
ULN. They did not require discontinuation of treatment of the study drug and resolved without 
treatment.
Taken together, results of Phase 1 studies with branebrutinib demonstrate a satisfactory safety 
profile for its investigation in patients with immune-mediated diseases.
3.3
Benefit/Risk Assessment
AD is a common, chronic, or recurrent inflammatory skin condition with significant associated 
social and financial burden. AD affects adults and children with worldwide prevalence rates of 1% 
to 20%. Using US census estimates, based on recent epidemiologic data, 16.5 million adults would 
have a diagnosis of AD, with 6.6 million meeting criteria for moderate-to-severe disease.6
Characterized by often disabling pruritus, scaling, xerosis, and eczematous lesions whose features 
include erythema, induration/papulation, excoriations, and lichenification, severe disease can be 
debilitating due to several factors: psychiatric disorders, sleep loss, and impaired quality of life 
(QOL). The majority of AD patients exhibit hypersensitivity to environmental or food allergens 
characterized by increased serum IgE levels and eosinophilia.16,17,66 Compromised skin barrier 
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function and a dysregulated immune system also render AD patients more susceptible to contact 
irritants and sensitizers, and to skin infections.
Topical corticosteroids have been the mainstay of treatments for AD. However, for patients with 
moderate-to-severe AD, topical therapies have limited efficacy, and long-term application of 
topical corticosteroids carries the risk of side-effects of acneiform eruptions, dyspigmentation, skin 
atrophy, and risks associated with systemic absorption.67 Systemic immunosuppressant drugs are 
generally more effective than topical treatments, but they are associated with more substantial 
toxic effects, including diabetes, hypertension, and osteoporosis.67 Moreover, systemic 
cyclosporin and corticosteroids may result in prominent rebound effects after treatment 
discontinuation. Subsequently, cyclosporine is dosed for a limited duration, with a requirement of 
monitoring of renal function and hypertension.68 Other immunosuppressants such as azathioprine 
(AZA), mycophenolate mofetil (MMF), and methotrexate MTX, are also used with caution in 
severe refractory patients, due to less evident efficacy and potential serious adverse effects. 
An unmet need therefore remains for effective and safe, long-term oral medications for patients 
with moderate-to-severe AD. Given the supportive mechanistic biology of the 2 agents being 
evaluated in this study (Section 3.1.2), it is hypothesized that participants will benefit from
participation by experiencing reductions in disease activity and associated discomfort.
Furthermore, nonclinical and Phase 1 results with both molecules (Sections 3.2.1 and 3.2.2) 
suggest that this reduction in disease activity can be undertaken safely. Appropriate safety 
monitoring, frequent visits, and other risk-minimization measures such as ongoing safety review 
and Data Monitoring Committee (DMC) oversight will be implemented to ensure that the safety 
of the participants is adequately monitored (Section 9.4). In summary, the Sponsor believes that 
the -benefit-risk relationship of participation is favorable for patients with moderate or severe AD.
3.3.1
BMS-986166
Assessments of benefit and risk rely on nonclinical data and on data from completed Phase 1 
studies in healthy volunteer participants. The proposed dosing regimens of 0.25 mg, 0.5 mg, and 
0.75 mg QD reflect implementation of adequate safety margins compared to the projected steady 
state AUC at the clinical dose of 0.75 mg (approximately 23× in rats and female dogs, or 2× in 
male dogs for BMS-986166; or approximately 112× in rats, 127× in female dogs, or 11× in male 
dogs for BMS-986166-P) based on the AUC at the NOAEL in the 6- and 9-month rat and dog 
studies (10 mg/kg/day in rats and 0.1 mg/kg/day or 3 mg/kg/day in male and female dogs, 
respectively) and is within the range of doses tested in MAD study IM018003.
The potential beneficial effects of S1PR1 have been documented in pharmacology studies, 
demonstrating its potential benefit for disorders of immune activation (Section 3.2.1). Moreover 
fingolimod (Gilenya) is an S1P receptor-analogue, acting as a nonselective potent agonist of 
S1PR1, 3, 4, and 5. Gilenya was the first S1PR agonist approved for clinical use for relapsing 
multiple sclerosis (MS).69 S1P content appears to be of great significance for the homeostasis of 
the skin. Diminished S1P concentration is linked to increased endocytosis capacity of DC and 
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proliferation of keratinocytes, and, although not measured in the skin of patients with AD, reduced 
S1P level is found in skin lesions of atopic dogs.70
In terms of risk, findings in nonclinical toxicology studies were consistent with expectations based 
on the pharmacology of BMS-986166 and included on-target PD effects such as dose-dependent 
lymphocyte reduction in peripheral blood, increases/decreases in lymphoid cellularity in lymphoid 
organs, and suppression of the T-cell-dependent antibody response. Increases in trabecular bone 
were noted in the rat 6-month study, and testicular toxicity was noted in dogs in the 10-week and 
9-month toxicity studies. All findings showed evidence of reversibility. For the purposes of 
monitoring the testicular finding, participants with history of significant testicular or epididymal 
disease will be excluded, and male sex hormones (follicle-stimulating hormone (FSH), luteinizing 
hormone (LH) and total testosterone) will be assessed at baseline and different time points 
throughout the treatment period and until study discharge.
Nonclinical studies have shown that BMS-986166 has a reduced risk for cardiovascular effects, 
macular edema, and pulmonary toxicity, compared with other members of the class.
Clinical safety of BMS-986166 was summarized in Section 3.2.1.5.
Based upon nonclinical toxicology findings and the mechanism of action of the compound 
(immunosuppression), this study incorporates appropriate assessments and risk-mitigation 
approaches (including careful consideration of appropriate exclusion criteria and monitoring of 
participants during and after dosing) in combination with conventional safety monitoring. These 
include assessment for latent tuberculosis (TB) infection (LTBI) and chronic viral infections, and 
ongoing clinical and laboratory monitoring to reduce the risk from infection, Pulmonary function 
tests (PFTs), optical coherence tomography (OCT) and close monitoring of vitals and ECGs. 
Frequent study visits are employed to enhance safety monitoring and reduce risk.
Possible CYP3A4-mediated DDI is anticipated with BMS-986166 as a victim drug when co-
administered with CYP3A4 inhibitors or inducers. BMS-986166 did not inhibit any of the human 
UGTs and CYPs tested and did not induce human CYP1A2, CYP2B6, and CYP3A4. In addition, 
no inhibition of a panel of human drug transporters was observed for BMS-986166. The inhibition 
profile, together with the anticipated low efficacious concentration in vivo, suggests low DDI risk 
as a perpetrator drug.
In vivo studies to evaluate the developmental and reproductive effects of BMS-986166 have 
demonstrated that, like other SP1R1 modulators, BMS-986166 is a selective developmental 
toxicant in rats and rabbits, causing cardiac malformations at the lowest doses tested and embryo 
lethality at higher doses. Therefore, to ensure safety, the investigator will counsel WOCBP to use 
highly effective contraception, and pregnant women will not be enrolled in this study. It is not 
known whether BMS-986166 passes into human milk. Therefore, breastfeeding women will not 
be enrolled in this study.
The accumulated toxicology data and preclinical profile, as well as the Phase 1 clinical data for 
BMS-986166 suggest that the risks of S1PR1 class-related AEs such as pulmonary and macular 
edema have been largely mitigated, and the cardiovascular liabilities have been reduced, while 
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retaining marked peripheral lymphopenia. More detailed information about the known and 
expected benefits and risks and reasonably anticipated AEs (see Section 9.2.8) of BMS-986166 
may be found in the IB.38
3.3.2
Branebrutinib
Assessments of benefit and risk rely on nonclinical data and on data from completed Phase 1 
studies in healthy participants. 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 IM014001).
The potential salutary effects of BTK inhibition by branebrutinib have been documented in
pharmacology studies, demonstrating its potential benefit for disorders of immune activation 
(Section 3.2.2); and clinical data support the use of BTK inhibitors for the treatment of RA.71
Because of the functional roles of BTK-expressing immunocytes (eg, mast cells, B-cells, and DC) 
in AD (Figure 3.1.2-1), inhibition of BTK may reduce AD disease activity.
In terms of risk, findings in nonclinical toxicology studies were consistent with expectations based 
on the pharmacology of branebrutinib and included on-target PD effects such as reductions in 
B-cell activity, suppression of KLH-specific IgM and IgG responses, and/or dose-related germinal 
center lymphoid depletion of minimal to moderate severity in the GALT.
Branebrutinib-related pancreatic toxicity was identified in oral Sprague-Dawley rat toxicity studies 
with up to 6 months of exposure. Findings related to branebrutinib were noted at all doses, and 
were generally islet-centric.47 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.57
As such, these findings were considered non-adverse. 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 participants treated with this drug class. Nonetheless, specific monitoring 
of pancreatic function, including assessments of, fasting glucose levels, were implemented in the 
Phase 1 studies to minimize unwanted risks to the healthy participants, and no 
branebrutinib‑related elevations in these parameters were identified.
With the exception of an unrelated SAE that was consistent with the subject’s medical history, AE 
in the FIH study (Study IM014001) 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), this study incorporates appropriate assessments and risk-mitigation 
approaches (including careful consideration of appropriate exclusion criteria and monitoring of 
participants during and after dosing) in combination with conventional safety monitoring. These 
include assessment for LTBI and chronic viral infections, and ongoing clinical and laboratory 
monitoring to reduce the risk from infection. Frequent study visits are employed to enhance safety 
monitoring and reduce risk.
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While blood BTK occupancy persisted longer (~50% at ~7 days and 30% at 10 days) after the 
cessation of multiple doses of branebrutinib as observed in the FIH study (14-day MAD), 
pharmacological inhibition of ex vivo lymphocyte stimulation started to wane within ~2 to 3 days 
after drug cessation. This is because signaling through BTK is very robust, and >95% inhibition 
in the whole blood is required to clearly inhibit lymphocyte function. Thus, 7 days after the last 
dose, the PD effect is considered to be significantly lower. Based on the biomarker data, and based 
on the fact that X-linked agammaglobulinemia (XLA) is essentially never noted in heterozygous 
females (BTK is a gene that escapes X-inactivation), it is anticipated the PD effects will wash out 
within 1 to 2 weeks after end of treatment.
The risk for DDIs with branebrutinib has been assessed in Study IM014013.72 The potential for 
clinically relevant DDIs of branebrutinib with substrates of a number of enzymes and transporters 
(CYP1A2, 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. Branebrutinib may affect the PK of drugs that 
are sensitive substrates of CYP2C8 and P-gp as a weak inhibitor, based on the results of Study 
IM014013 and in vitro studies. Therefore, until more knowledge is gained, drugs that are sensitive 
substrates of CYP2C8 and P-gp (like digoxin) are restricted or excluded based on their therapeutic 
window and metabolism in this study. If such sensitive substrates must be used, therapeutic drug 
levels monitoring is recommended. 
In vivo studies to evaluate the developmental and reproductive effects of branebrutinib have shown 
developmental toxicity in rabbits (at an exposure multiple of 53× relative to the dose of 9 mg 
proposed for this study) that were associated with maternal and developmental toxicity.47 At the 
NOAEL of 40 mg/kg/day, the safety margin was 16× compared with the human AUC at 10 mg 
MAD. Branebrutinib was not associated with maternal or developmental toxicity in pregnant rats 
at exposure multiples up to 437× (versus human AUC at 10 mg MAD). 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,73 which ensures efficacy 
of hormonal contraception co-administered with branebrutinib. 
Ibrutinib, an irreversible inhibitor of BTK used for the first line treatment of chronic lymphocytic 
leukemia (CLL) or mantle cell lymphoma (MCL), has been shown in randomized trials to increase 
the risk for incident atrial fibrillation as compared to alternate treatments.74 Atrial fibrillation (AF) 
and atrial flutter (range, 6 to 9%) have occurred in patients treated with ibrutinib, particularly in 
patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.75
Although the mechanism is not fully elucidated, recent in vitro and in vivo nonclinical 
experiments strongly suggest that ibrutinib-mediated AF results from off-target kinase inhibition 
-- particularly that of C-terminal SRC-kinase,76 though on-target mechanisms cannot yet be ruled 
out.77 Because newer BTK inhibitors are more specific to the Tec kinase family than ibrutinib, 
they may not carry this mechanistic liability78 though clinical confirmation is currently lacking.
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In clinical trials with branebrutinb, no adverse events of atrial fibrillation have been reported. 
Patients with any prior history of atrial fibrillation or atrial flutter will be excluded from 
participation in this clinical trial. Cardiac monitoring with ECG assessments predose and at 1, 2, 
4, and 6 hours post dose will be obtained in addition to hourly monitoring of the HR and blood 
pressure on Day 1. Standard 12-lead ECG will be collected and reviewed with every subsequent 
visit.
In sum, the potential benefits and risks of branebrutinib for patients with moderate or severe AD 
support its investigation in this protocol. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated adverse events (AEs) of branebrutinib may be found in the IB.
3.3.3
COVID-19-associated Risks
3.3.3.1
BMS-986166
 
 
 
 
 
 
 
 
3.3.3.2
Branebrutinib
Risk from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to the 
immune response following exposure. The immune system must control viral replication and 
cytopathology,79 while avoiding the exaggerated inflammation associated with severe COVID-
19.80 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 3.2 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).43,81,82
Insights into the effect of deficiency in both BTK activities can be gained by observing COVID-19 
outcomes in patients with 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.83  Published cases 
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Abbreviations: AD = atopic dermatitis; AE = adverse event; ALC = absolute lymphocyte count; AUC(0-T) = area 
under concentration-time curve from time zero to the time of the last quantifiable concentration; AUC(TAU) = area 
under concentration-time curve within a dosing interval; BSA = body surface area; BTK = Bruton Tyrosine Kinase; 
Cmax = maximum concentration; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; 
ECG = electrocardiogram; FEV1 = forced expiratory volume in 1 second; IgE = immunoglobulin E; NRS = numerical 
rating scale; OCT = optical coherence tomography; PD = pharmacodynamic; PFT = pulmonary function test; PK = 
Pharmacokinetics; POEM = Patient Oriented Eczema Measure; SAE = serious adverse event; SARS-CoV-2 =  severe 
acute respiratory syndrome coronavirus 2; vIGA-AD = Validated Investigator Global Assessment Scale for Atopic 
Dermatitis
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2, multicenter randomized, double-blind, placebo-controlled, 5 parallel-group, 
study of BMS-986166 or branebrutinib to evaluate the efficacy and safety of 3 dose levels of 
BMS-986166 and a single dose level of branebrutinib in participants with moderate-to-severe AD 
who are intolerant of treatment, or inadequately treated and are candidates for systemic therapy. 
The overall study design is outlined in Figure 5.1-1.
The study consists of:  
•
A Screening Phase of up to 35 days, during which participants will be confirmed to have 
moderate-to-severe AD, and meet the other entry criteria for the study (Section 6); 
•
A Treatment Phase of approximately 16 weeks during which participants will be assessed for 
clinical responses to either placebo, BMS-986166, or branebrutinib; 
•
A Follow-up Phase of approximately 8 weeks. 
Total duration of participation in the study will be approximately 29 weeks, although follow-up 
maybe extended until ALC recovers to the pre-specified threshold (Section 5.1.3).  
White blood cell (WBC) counts and lymphocyte counts will be monitored centrally (and will not 
be provided to the site) to prevent potential unblinding of the investigator.
An external independent DMC will be empaneled to review safety on a periodic and as-needed 
basis. 
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S1P Receptor Modulator and Branebrutinib
Figure 5.1-1:
Study Design Schematic
Abbreviations: n = number; PO = taken orally; QD = once daily; R = randomization; V = visits
Study day visits will be ± 3 days, except for the Day 7 visit (± 1 days).
Physical examinations, vital sign measurements, 12-lead ECG, OCT, PFT, and clinical laboratory 
evaluations will be performed at selected times throughout the dosing interval. Participants will be 
monitored for adverse events throughout the study. 
Blood samples will be collected for PK and PD analysis as described in Sections 9.5 and 9.8, 
respectively.
5.1.1
Screening Period Days -35 to -1
Eligibility will be based on specified inclusion and exclusion criteria (Sections 6.1 and 6.2), 
medical history, disease activity, and safety assessments. Screening and randomization must be 
completed within 35 days of signing the ICF. Participants who experience an AD flare defined as
doubling of the EASI score between Screening and Baseline or worsening that requires 
administration of prohibited medications within 3 weeks of randomization should be discontinued 
from the study. 
Participants that experience an AD flare prior to randomization should be discontinued from the 
study. 
5.1.2
Treatment Period, Days 1-113
On Day 1, eligible participants will be randomly allocated to receive one of: placebo, BMS-986166 
0.25 mg PO QD, BMS-986166 0.5 mg PO QD, BMS-986166 0.75 mg PO QD, or branebrutinib 
9 mg PO QD for 16 weeks. Randomization will be in a 1:1:1:1:1 ratio. Blinded treatment 
assignment will be managed by Interactive Response Technology (IRT).
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S1P Receptor Modulator and Branebrutinib
Participants will visit the clinic 7 times (including baseline) during the treatment period. Safety 
and efficacy will be assessed at each of these visits. This visit density is intended to allow 
monitoring of sufficiently high resolution to detect infections, excessively low leukocyte counts, 
inefficacy and/or flares, and other problems in a timely fashion; with on the other hand, participant 
burdens and risk of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) exposure 
associated with clinic visits. This frequency reflects customary practice in the field as reflected in 
other published studies.31
Participants may receive topical rescue therapy for intolerable symptoms up to Week 4 as 
described in Section 7.7.2. After Week 4, participants receiving rescue treatments will be 
considered treatment failures for categorical endpoints, those who require systemic rescue therapy 
will be immediately discontinued from study treatment. 
5.1.3
Follow-up Period, Days 114-169
Follow-up after dosing cessation is planned for approximately 60 days (5x T-HALF for 
BMS-986166), with visits on Days 127, 141 and 169; participants will be followed for disease 
activity, safety, and washout of PD effects. If applicable, participants will be followed until 
absolute neutrophil count (ANC) > 1500/μL and ALC > 1000/μL, demonstrating sufficient 
washout of PD effects to permit discharge from the study.
5.1.4
Data Monitoring Committee
To ensure the safety of study participants, an external independent DMC consisting of 2 
experienced dermatologists, 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, pre-specified 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. 
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,
including select efficacy data as needed for the medical assessment for a specific case.
The DMC may also consider external data from other BMS-986166 or branebrutinib studies that 
may be initiated in future, or from novel scientific information that may be generated on related 
compounds.
The DMC will act in an advisory capacity to BMS and will monitor participant safety data for the 
study. The BMS study team has primary responsibility for design and conduct of the study.
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Based on the DMC’s assessment, recommendations of protocol modifications or other actions may 
occur. In addition, hold of enrollment, pending more detailed assessment may be requested by the 
DMC.
Details of the DMC responsibilities and procedures will be specified in the DMC Charter.
5.2
Number of Participants
Approximately 150 participants will be randomized 1:1:1:1:1 into 5 parallel treatment groups. 
5.3
End of Study Definition
The start of the study is defined as the date that the first participant is screened. End of study is 
defined as the last contact with the last participant (either last visit at which the last endpoint data 
is collected or last contact which could be a phone call). Study completion is defined as the final 
date on which data for the study was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
This is a randomized, double-blind, placebo-controlled, 5 parallel-group study to evaluate the 
efficacy and safety of 3 dose levels of BMS-986166 and a single dose level of branebrutinib in 
participants with moderate-to-severe AD who are intolerant of treatment, or inadequately treated 
and are candidates for systemic therapy (ie, not adequately controlled by a stable regimen [≥ 4 
weeks] of topical corticosteroids, calcineurin inhibitors or biologics, or not eligible for topical 
therapy due to side effects or safety risks). 
Two mechanistically distinct compounds will be simultaneously tested for the first time in this AD 
population. This is being done for the following reasons:
•
It is more efficient than 2 separate studies since a single control group is used for both 
compounds – reducing the number of participants with burdensome AD symptoms who must 
be treated with placebo.
•
While not a formal head-to-head comparison, this design best supports the main purpose of 
this study to evaluate provisional efficacy of two different mechanisms in AD – enabling 
Sponsor decision to advance one or both to Phase 2b/3 evaluation.
o
The effects of both compounds on clinical endpoints can be evaluated at the same sites 
simultaneously, and against the same placebo population. The latter point is of special 
interest given the small size of this study, and the well-known variability in placebo 
responses in AD – ranging from ~10% to >30% EASI reduction in Phase 2 
studies.30,103,104,105
o
The effects of the 2 compounds on complex exploratory biomarkers (eg, messenger 
ribonucleic acid [mRNA] profiling of skin biopsies) can be measured at the same sites, 
over the same time interval, and in the same experimental batch runs – maximizing 
comparability.
•
Each compound has extensive PK-PD characterization, both in nonclinical experiments and in 
Phase 1 studies, and both mechanisms are extensively described in the literature. Together, this 
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allows appropriate safety monitoring, general study conduct, and data interpretation to occur 
despite the added complexity of investigating 2 compounds simultaneously.
A parallel group design is being employed because (1) the time course of treatment is relatively 
long (~16 weeks), (2) BMS-986166 has a T-HALF (~12 days), and (3) IP-related changes in 
disease activity of a complex immunologic phenomenon like AD do not occur or “wash out” over 
usefully predictable times. These factors obviate crossover designs.
Five treatment groups will be evaluated: 1 for placebo, 1 for the favored dose of branebrutinib 
(Section 5.5.2), and 3 dose levels for the most promising doses of BMS-986166 (Section 5.5.1).
Sixteen weeks’ treatment duration will be employed because it provides sufficient time for each 
mechanism to act, allows time for BMS-986166 to reach steady state, and provides a reasonable 
observation time to observe AEs. Study treatment durations of 12 to 16 weeks are customary in 
this field (eg, in the dupilumab and upadacitinib Phase 2 programs).41,106 The Follow-up phase 
lasts approximately 60 days to allow 5 mean half-lives of BMS-986166 to pass after the final dose 
before participants are discharged from the study, for safety monitoring. This also allows sufficient 
time for branebrutinib receptor occupancy to decay to baseline.47 Acceptable washout of 
BMS-986166 PD effects (ALC counts) will also be explicitly assessed before participants are 
discharged from the study.
5.5
Justification for Dose
5.5.1
BMS-986166
The BMS-986166 doses to be evaluated in this study (0.25 mg, 0.5 mg, and 0.75 mg) are based on 
their safety, tolerability, PK, and PD findings from FIH studies, as well as on nonclinical 
evaluations as detailed in Section 3.2.1. 
The model predictions for participants receiving the 0.5 mg dose of BMS-986166, with average 
exposures, will typically exhibit reduction in nadir ALC greater than 75% of baseline ALC values 
and a 2-beat/minute net decrease in HR versus placebo. Translation of exposure-response analyses 
using ALC, and its relationship to efficacy in preclinical models lends confidence to the efficacy 
hypothesis at similar exposures yielding similar PD effects in humans. 
Safety – In study IM018003, multiple oral doses of BMS-986166 up to 1.5 mg QD for 28 days 
were safe and generally well tolerated in healthy participants. The most frequently occurring AEs 
during BMS-986166 administration were lymphopenia (N=15; 62.5%) which is consistent with 
the pharmacology of the drug; contact dermatitis (N=8; 33.3%), associated with ECG electrode 
contact sites and increased blood creatine phosphokinase (N=7; 29.2%), assessed by the 
investigator as unrelated to study drug, were of equal frequency in the placebo and BMS-986166 
cohorts; and headache (N=5; 20.8%). Safety results were similarly low and reversible between the 
0.25 and 0.75 mg PO QD groups. The no-observed-adverse-effect level (NOAEL) in pivotal 
nonclinical toxicity studies yield adequate safety margins relative to the projected steady-state 
exposures at 0.75 mg PO QD.
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PK – In the multiple ascending dose (MAD) study IM018003, healthy participants received 
BMS-986166 solution formulation at dose levels of 0.25, 0.75, and 1.5 mg PO QD for 28 days. 
Increases in whole blood maximum observed concentration (Cmax) and area under the 
concentration-time curve (AUC) over the dosing interval (AUC[TAU]) were approximately dose 
proportional within the dose levels tested. The mean half-life (T-HALF) at Day 28 ranged from 
276 to 321 hours across the dose range tested, indicating that BMS-986166 was slowly eliminated 
from the body. Consequently, as expected, accumulation after 28 days of dosing (near steady-state) 
was approximately 14-fold.
PD – Key PD biomarkers in Study IM018003 were peripheral blood absolute lymphocyte counts 
(ALC) and heart rate. Lymphocyte count, is a PD endpoint that roughly reflects efficacy 
endpoints – based on clinical results with preceding S1P receptor modulators such that exposure 
associated with a lymphocyte reduction below approximately 1,000 lymphocytes/μL are also 
associated with satisfactory efficacy in MS.107 In a real-world examination of ALC responses to 
fingolimod in MS patients, typical percent reductions from baseline ALC of approximately 65% -
90% were noted.108
In Study IM018003, predictable, dose-dependent lymphocyte reductions reaching median nadirs 
(ie, largest percent reduction) of 53.7% (range: 31.7% to 55.9%), 75.9% (range: 63.3% to 85.8%), 
and 81.9% (range: 37.9% to 92.2%) occurred at the 0.25 mg, 0.75 mg, and 1.5 mg dose levels, 
respectively, by Day 28 of dosing.38 In the 0.75 mg group 37.5% and 12.5% of patients 
experienced Grade 2 and 3 reduction of lymphocytes respectively without clinically meaningful 
infection implications.
In the same study, continuous Holter monitoring revealed roughly dose-dependent reductions in 
median time-matched nadir heart rates. These were of the order of 8 to 9 absolute beats/minute at 
the highest dose (1.5 mg) and reached maximum effect by 48 hours. At the 0.25 mg and 0.75 mg 
dose levels, placebo-controlled reductions in median time-matched nadir heart rates were always 
below 4 beats/minute. By 12-lead ECG, there were no discernible differences in heart rate from 
placebo at the end of the study (Clinical Study Report IM018003). 
Based on the results from the FIH studies, a comprehensive population exposure-response and 
safety model was developed for both BMS-986166 and BMS-986166-P to guide the dose selection 
for Phase 2 clinical studies using model predictions and to optimize the benefit-risk balance. 
Simulations were conducted using various dosing scenarios to predict the effects of BMS-986166 
and BMS-986166-P on PD (ALC) and safety (HR) parameters. This modeling of the relationships 
between dose, exposure, PD, and measures of lymphocyte and heart rate reduction, predicted that 
a 0.5 mg PO QD dose would lead to median nadir ALC greater than 75% of baseline and a 
2-beat/minute net decrease in HR versus placebo (Figure 5.5.1-1). Hence, 0.5 mg dose is selected 
for evaluation in this study. To address the possibility of suboptimal tissue penetration or drug 
concentration disequilibrium between plasma and tissue, the 0.75 mg dose level is also selected to 
evaluate safety and efficacy at PD intensity levels best-suited for monotherapy. 
 
 
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Figure 5.5.1-1:
Model-predicted Reductions in Heart Rate and Lymphocyte Count by 
Dose
The shaded areas represent the 90% confidence intervals around the median lines. The dashed horizontal line at -8 bpm 
represents a drop of 8 bpm relative to placebo. The dashed horizontal line at -70 % represents a drop of 70% in ALC. 
The three vertical dotted lines represent the 0.25 mg, 0.5 mg, and 0.75 mg doses being investigated in this study.
Abbreviations: ALC = absolute lymphocyte; bpm = beats per minute; HR = heart rate
Source: BMS data on file.
Thus, the selected doses of 0.25 mg, 0.5 mg, and 0.75 mg of BMS-986166 are predicted to provide 
optimal evaluation of efficacy and safety for this proof-of-concept study. 
5.5.2
Branebrutinib
The selection of the branebrutinib dose and regimen (9 mg, QD) to be assessed in the current study 
was based on findings in the FIH and nonclinical studies as detailed in Section 3.2.2.
Safety: The drug was well-tolerated at all dose levels, and most AEs observed were similar in 
participants receiving placebo and active treatment. The most common AEs included headache 
and upper respiratory tract infection. Based on the AUC in rats and dogs at the 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  
PK: In the MAD panels of the FIH study (Study IM014001), healthy participants received 
branebrutinib solution QD for 14 days at 4 dose levels (0.3, 1, 3, and 10 mg). Increases in Cmax 
and AUC[TAU] were approximately dose proportional within the dose levels tested. T-HALF was 
shorter than 2 hours across the dose range tested, indicating that branebrutinib was rapidly 
eliminated from the body. Consequently, no accumulation was observed at steady state after 
multiple daily dosing. 
PD: Biomarkers evaluated in Study IM014001 were BTK occupancy by branebrutinib (enzyme 
occupancy [EO]), inhibition of ex-vivo stimulated cluster of differentiation CD69 expression, and 
plasma CXC motif chemokine ligand 13 (CXCL13) levels. 
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Doses yielding high (≥ 95%) BTK occupancy are thought necessary for optimal clinical efficacy 
because only at such doses did (1) in vivo pharmacologic studies of experimental autoimmunity 
(eg, murine collagen-induced arthritis) show maximum efficacy, and (2) deep tissue (eg, spleen)
EO rapidly match peripheral blood EO. 
The maximum occupancy reached ≥ 99% at branebrutinib doses of 1 mg and above (100%; 
maximum occupancy at doses ≥ 3 mg); however, maximum occupancy was achieved faster and 
maintained longer at 3 mg and 10 mg doses (solution formulation). Furthermore, a high and 
sustained (~100%) BTK occupancy was achieved with the 10 mg dose over the dosing interval.
The variability of the effect was also lower for the higher dose of 10 mg. A similar result was 
obtained for CD69 inhibition, for which the largest median inhibition 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 disorders4, the 10 mg dose with the solution formulation is expected to more 
stably and completely inhibit BTK47 -- for optimal chronic treatment of a larger proportion of 
patients. Moreover, based on the nonclinical branebrutinib exposure in rats and dogs at the 
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  
Relationship of 9 mg capsule dose to the 10 mg solution dose in Study IM014001:
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, a Phase 1 study of the effect of branebrutinib on the PK of combined oral 
contraceptives, 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 PD effects.
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.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Understanding of, and willingness to participate in the study after completing all informed 
consent procedures – demonstrated by a signed ICF
b) Willingness and ability to complete all study-specific procedures and visits
2) Type of Participant and Target Disease Characteristics
a) Chronic AD diagnosed according to the Eichenfield modification of Hanifin’s and Rajka’s 
(E-HR) criteria109 at Screening (Appendix 5)
b) Disease duration of at least 24 months since diagnosis by any criteria
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c) EASI score ≥ 12 at Screening visit and ≥ 16 at Baseline visit
d) vIGA-AD ≥ 3 at Screening and Baseline visits
e) ≥ 10% BSA affected by AD at Screening and Baseline visits
f)
Documented history of inadequate control of AD by a stable regimen (≥ 4 weeks) of topical 
corticosteroids, calcineurin inhibitors or biologics, within 6 months of randomization, or 
inappropriateness of therapy due to side effects or safety risks leading to prior 
discontinuation.
♦Inadequate response is defined as either or both of: 
♦Failure to achieve and maintain a disease activity state comparable to vIGA-AD
0 = clear to 2 = mild, despite treatment with a daily regimen of topical corticosteroids
(TCS) of medium to higher potency (± topical calcineurin inhibitors [TCI] as 
appropriate), applied for at least 28 days or for the maximum duration recommended 
by the product prescribing information, whichever was shorter, or
♦Necessity of systemic therapy to control disease.
g) Application of fixed doses of an additive-free, basic bland emollient twice-daily for 
≥7 days before baseline visit and for the duration of the study participant to the guidance 
in Section 7.7.3.
h) Participants must have documentation of positive Varicella Zoster virus (VZV) IgG 
antibody status or complete VZV vaccination at least 90 days prior to randomization.
3) Age and Reproductive Status
Investigators shall counsel women of child bearing potential (WOCBP), and male participants 
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.
•
The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.
•
Local laws and regulations may require the use of alternative and/or additional contraception 
methods.
a) Female Participants 
i)
Females aged 18 (or local age of majority) to 65, inclusive.
ii) Women of non-childbearing potential (WONCBP) are exempt from contraceptive 
requirements. WONCBP must have documented proof that they are not of childbearing 
potential.
iii) Women of childbearing potential (WOCBP) must have a negative, highly sensitive 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG, or as required 
by local regulations) within 24 hours prior to the start of study treatment.
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(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 2, Schedule of Activities.
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 not permitted to use hormonal contraception methods alone as a highly 
effective method (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), with low user dependency, as described in 
Appendix 4 during the intervention period and for at least 3 months after the last 
dose of study intervention, and agrees not to donate eggs (ova, oocytes) for the 
purpose of reproduction for the same time period.
b) Male Participants
i)
Males, ages 18 (or local age of majority) to 65, 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 participants 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 
participants 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 3 months after the last dose of study intervention.
v) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the study intervention period and for at least 
3 months after the last dose of the male participant’s study intervention.
vi) Male participants must refrain from donating sperm during the intervention period and 
for at least 3 months after the last dose of study intervention.
vii)Breastfeeding partners should be advised to consult their health care providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms.
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6.2
Exclusion Criteria
1) Medical Conditions
a) Any major illness/condition or evidence of an unstable clinical condition (eg, cardiac, 
renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, neurologic, 
immunologic, psychiatric) or local active infection/infectious illness that, in the 
investigator’s judgment, will substantially increase the risk to the participant if he or she 
participates in the study or interfere with the interpretation of study results.
b) Pregnancy, lactation, or plans for either during the study or the post-study prohibition 
period (see Inclusion Criteria for prohibition period duration).
c) Clinically relevant cardiovascular conditions, including history or presence of:
i)
Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, 
stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, 
sick sinus syndrome, Class III/IV heart failure (Appendix 6)
ii) Prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females), or at additional 
risk for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT 
syndrome) 
iii) Any prior history of atrial fibrillation or flutter 
iv)Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with 2 or more 
agents in combination known to prolong PR interval
v) Patients with other pre-existing stable cardiac conditions who have not been cleared for 
the study by an appropriate cardiac evaluation by a cardiologist
d) Clinically relevant pulmonary conditions, including:
i)
Unstable asthma or chronic obstructive pulmonary disease (COPD) (eg, acute episodes 
of exacerbation [nocturnal episodes, sudden episodes triggered by unidentifiable 
factors] despite a stable regimen of relevant medications); prior episode(s) of life-
threatening asthma or COPD; or asthma or COPD that requires systemic glucocorticoid 
or biologic treatment, or inhaled budesonide or equivalent at > 1200 μg/day or 
fluticasone propionate at > 880 μg/day along with another anti-asthma/COPD drug 
such as a long-acting beta-agonist.
ii) Severe untreated sleep apnea
iii) Forced expiratory volume (FEV1) or forced vital capacity (FVC) < 70% of predicted 
values at screening
e) 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)
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f)
History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with 
hemoglobin A1c > 8%, or diabetic patients with significant co-morbid conditions such as 
retinopathy or nephropathy
g) Participants with a history of retinopathy, uveitis or other clinically significant ocular 
disease
h) Participants with any history of testicular or epididymal disease/disorder except 
uncomplicated epididymitis successfully treated with antibiotics.
i)
Current or recent (within 3 months before randomization clinically significant) 
gastrointestinal disease, including gastrointestinal surgery, that could impact the absorption 
of study treatment
j)
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.
k) History of any serious condition induced by drug allergy or other hypersensitivity (such as 
anaphylaxis or hepatotoxicity).
l)
Participants with non-AD concomitant illness (eg, asthma) that, in the opinion of the 
investigator, is likely to require systemic corticosteroid or biologic therapy during the study
2) Infection Risk-related Criteria
a) Any of the following TB criteria:
i)
History of active TB prior to screening visit, regardless of completion of adequate 
treatment
ii) Signs or symptoms of active TB (eg, fever, cough, night sweats, and weight loss) 
during screening as judged by the investigator
iii) 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
iv) LTBI defined by QuantiFERON-TB Gold testing at screening, in the absence of 
clinical manifestations 
Note 1: Participant may be eligible if (i) there are no current signs or symptoms of 
active TB and (ii) participant has received adequate documented treatment for LTBI 
within 1 year of screening.
Note 2: An indeterminate QuantiFERON-TB Gold test may be repeated once during 
screening. If the repeat test is positive or indeterminate, the participant is excluded.
b) Hepatitis C, Hepatitis B, or HIV infection as demonstrated, by a positive blood screen for 
HCV antibody and confirmed by positive reflex HCV RNA test, hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (HBcAb), or HIV-1 and -2 antibody. 
i)
Participants who have been vaccinated for hepatitis B (hepatitis B surface antibody 
[HbsAb]-positive) are not excluded.
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ii) Indeterminate tests require negative reflex testing results, or they are exclusionary.
iii) HCV history and documented 24-week sustained virologic response are permitted.
c) History of congenital or acquired immunodeficiency
d) Participants with any acute or chronic bacterial, fungal (except history of tinea pedis or 
ongoing onychomycosis will not be exclusionary) or viral infection, as well as any febrile 
illness within 14 days of screening
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 2 weeks of the screening visit, and/or completion 
of oral antimicrobial agents within 2 weeks of randomization, and/or recurrence prior to 
randomization.
f)
Previous history of recurrent herpes zoster (more than 1 episode), disseminated herpes 
simplex before randomization or a history of disseminated/complicated herpes zoster 
infection (multidermatomal involvement, ophthalmic zoster, eczema herpeticum, central 
nervous system involvement, or postherpetic neuralgia)
g) History of atypical/opportunistic infection (eg, pneumocystis, cytomegalovirus, invasive 
fungal infections, atypical mycobacteria, etc.).
h) Presence of the following COVID-19-related exclusion criteria
i)
Symptoms of COVID-19 at screening or randomization
ii)
COVID-19 (either suspected or confirmed) within 12 weeks of screening, at 
screening, and/or Day 1. 
iii) Known or suspected current sequelae of any sort following any prior episode of 
COVID-19.
iv) COVID-19 vaccination within 14 days of screening or participant has plans to receive 
a vaccination during his/her participation in the study.
3) AD-related Criteria
a) High likelihood - based on participant history, and investigator judgement – of requiring 
rescue therapy in < 4 weeks prior to randomization (see Section 7.7.2)
b) Evidence of acute flare between the Screening and Baseline/ Randomization (eg, doubling 
of the EASI score between Screening and Baseline, or worsening that requires 
administration of prohibited medications).
c) Skin lesion(s) and/or pruritus due to conditions other than AD that would interfere with the 
study specified assessments.
4) Prior/Concomitant Therapy
a) Treatment with anticoagulant or antiplatelet therapies, including aspirin for 
cardioprotection, within 2 weeks prior to randomization or during the study.
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b) AD-related prescription or over-the-counter skin barrier treatments (eg, Cerave, Epicerum, 
etc.) therapy within 2 weeks prior to randomization
c) Any bleach baths within 2 weeks prior to randomization
d) Monoamine oxidase inhibitors (eg, selegiline, phenelzine) within 2 weeks prior to 
randomization
e) Use of strong or moderate inhibitors or inducers of CYP2C8 or CYP3A4 within the longer 
of 5 PK half-lives or 14 days prior to randomization (inhibitors), or within 3 weeks prior 
to randomization (inducers).
i)
Please refer to Table 7.7.1-1 for examples.
ii) Sponsor’s Medical Monitor should be consulted for any uncertainties regarding 
CYP2C8 or CYP3A4 modulators.
f)
Phosphodiestersase-4 (PDE4) inhibitors within 3 weeks prior to randomization.
g)
Use of phototherapy (ie, UVB, UVA) within 4 weeks prior to randomization.
h) Leukotriene inhibitor treatment within 4 weeks prior to randomization.
i)
Diquafosol or rebamipide therapy within 4 weeks prior to randomization.
j)
Systemic corticosteroid treatment within 4 weeks prior to randomization.
k) Systemic immunosuppressive drugs (CsA, MMF, AZA, MTX) or oral preparations of 
herbal immunomodulatory medications within 8 weeks prior to randomization.
l)
Exposure to JAK inhibitors such as tofacitinib, baricitinib, filgotinib, or upadacitinib 
within 8 weeks prior to randomization.
m) Intravenous (IV) immunoglobulin within 8 weeks prior to randomization or during the 
study.
n) Allergen immunotherapy within 4 months of randomization.
o) Biologics depending on the type: 
i)
Cell-depleting agents, including rituximab: within 6 months, or until the targeted 
population (eg, CD19+ lymphocyte counts for rituximab) returns to normal, 
whichever is longer
ii) Biologics such as tocilizumab and anakinra within 8 weeks prior to randomization
iii) Other biologics: within the longer of 5 half-lives (if known) or 6 months of 
randomization (eg. dupilumab) 
p) Prior exposure to BTK inhibitors such as ibrutinib, acalabrutinib, or experimental drugs 
(eg, BMS-986166 or branebrutinib, tirabrutinib, vecabrutinib, zanibrutinib, ARQ-531, 
GDC-0853, or others) at any time.
q) Prior exposure to S1PR modulators (eg, fingolimod, etrasimod, ozanimod, etc.) at any 
time.
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r)
Use of any immunomodulator or investigational drug not listed above within the longer of 
5 PK half-lives, 5 PD half-lives, or 6 months of randomization.
5) Laboratory Test and Procedural Findings
a) The following test findings at Screening or Baseline
i)
WBC count < 3000/μL or > 14,000/μL
ii) ANC < the lower of: lower limit of normal (LLN) or 1500/μL 
iii) ALC < 1000/μL 
iv) Platelet count < 100,000/μL
v) Serum creatinine > 2 mg/dL
vi) Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 as calculated using 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation110:
eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] -- where Scr is serum creatinine, κ is 0.7 for females and 0.9 for 
males, α is -0.329 for females and -0.411 for males, min indicates the minimum of 
Scr/κor 1, and max indicates the maximum of Scr/κ or 1.
vii)AST or ALT >1.5x ULN
viii)
Total bilirubin > 2 mg/dL (34 μmol/L)
ix) Hemoglobin <10 g/dL
x) ECG: HR < 55 bpm; PR ≥ 210 msec; QRS ≥ 120 msec; QTcF >450 msec males, > 
470 msec females, or any clinically significant heart conduction abnormality (eg, left 
bundle branch block, atrial fibrillation).
xi) Abnormality on posteroanterior + lateral chest radiograph, taken during the Screening 
period that is relevant to safe conduct of this study.
xii)Abnormality on optical coherence tomography (OCT) testing suggestive of macular 
or choroidal pathology beyond that expected for a healthy person of the participant’s 
age.
xiii)
Heart rate < 55 bpm or > 95 bpm at rest
xiv)
Blood pressure > Grade 1 hypertension (> 159 mmHg systolic and > 99 mmHg 
diastolic) according to the 2018 European Society of Cardiology/European Society of 
Hypertension guidelines for the management of arterial hypertension111
xv) Any other clinically significant laboratory or procedure abnormalities that, in the 
opinion of the investigator, might pose unacceptable risk to the participant during the 
study.
6) Other Exclusion Criteria
a) Use of a tanning booth/parlor or significant change in sun exposure within 4 weeks of the 
Screening visit.
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b) Onset of a new exercise routine or major change to a previous exercise routine within 
2 weeks prior to randomization.
c) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and participant to local law a person who has been imprisoned after 
enrollment may be permitted to continue as a participant. Strict conditions apply and 
Bristol Myers Squibb approval is required.)
d) Employment by the Sponsor, clinical research organizations, or study site.
e) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
f)
Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in 
DSM-5, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 7)
g) Inability to comply with restrictions as listed in Section 6.3 and prohibited/restricted 
treatments in Section 7.7.1. 
h) Inability to tolerate oral medication.
i)
Inability to be venipunctured and/or tolerate venous access.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Lifestyle restrictions are listed below.
6.3.1
Meals and Dietary Restrictions
With the exception of the 8-hour fasting requirement prior to blood sample collection for safety 
and PK testing on Day 1 and Day 85, no meal or dietary restrictions are required for this study. A 
light meal/snack may be provided after the 2-hour PK sample and/or ECG collection insofar as to 
not interfere with obtaining either.
However, participants are advised to abstain from excessive consumption of quinine (tonic water), 
grapefruit and Seville oranges. 
St. John’s wort and herbal medications are not allowed.
6.3.2
Caffeine, Alcohol, and Tobacco
With the exception of prohibited alcohol abuse as defined by the diagnostic criteria for Drug and 
Alcohol Abuse defined in the DSM-5 (Appendix 7) within six months prior to randomization, 
there are no restrictions on caffeine, alcohol, or tobacco use for this study. However, participants 
who use tobacco or alcohol should be counseled for potential contraindications with non-study 
treatments as appropriate, and continued study participation should be based on investigator 
judgment.
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6.3.3
Activity
The use of contraceptives during sexual activity is mandatory as stated in Section 6.1.
Use of tanning beds is prohibited during the study.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, 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 serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
been treated) due to an issue that is transient. If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted one time (in addition to any parameters that require a 
confirmatory value).The most current result prior to Randomization is the value by which study 
inclusion will be assessed, as it represents the participant’s most current, clinical state.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo 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 standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study Treatments for IM018005
Product Description / Class 
and Dosage Form
Potency
IP
Blinded or Open 
Label
Packaging 
Storage Conditions
(per label)
BMS-986166-04 capsule
0.25 mg
IP
Blinded
Bottle
Refer to the label on the 
container
Branebrutinib capsule
(BMS-986195-01)
3 mg
IP
Blinded
Bottle
Refer to the label on the 
container
Placebo capsule
NA
IP
Blinded
Bottle
Refer to the label on the 
container
Abbreviations: IP = investigational product; NA = not applicable 
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows.
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s) /
Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
BMS-986166 
0.25 mg / 0.25 mg
QD
Oral
BMS-986166 
0.25 mg / 0.50 mg 
QD
Oral
BMS-986166 
0.25 mg / 0.75 mg 
QD
Oral
Branebrutinib
3 mg / 9 mg
QD
Oral
Placebo
NA
QD
Oral
Abbreviations: NA = not applicable; QD = once daily
Participants will be randomized to one of the following dose levels of BMS-986166 or 
branebrutinib or placebo in blinded fashion: 

BMS-986166 0.25 mg PO QD 

BMS-986166 0.50 mg PO QD

BMS-986166 0.75 mg PO QD

Branebrutinib 9 mg PO QD

Placebo PO QD
•
The first dose of double-blind study medication (BMS-986166 or branebrutinib or placebo) 
will be taken in the morning on Day 1 after fasting for at least 8 hours. 
•
Study medication should be taken at approximately the same time each day.
•
Participants will take 3 capsules each day, one from each of 3 distinct bottle.
The actual IP taken by each participant is summarized in Table 7.1-2.
Table 7.1-2:
Investigational Product: as Dispensed to Participants
Treatment 
Group
Double-blind 
Kit
Bottle A
Bottle B
Bottle C
Placebo
Each kit 
contains 
Bottle A, 
Bottle B,
Bottle C
Placebo capsule
Placebo capsule
Placebo capsule
`166 0.25 mg QD
`166 capsule, 0.25 mg
Placebo capsule
Placebo capsule
`166 0.5 mg QD
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg
Placebo capsule
`166 0.75 mg QD
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg
`166 capsule, 0.25 mg 
BRA 9 mg QD
BRA capsule, 3 mg
BRA capsule, 3 mg
BRA capsule, 3 mg
Abbreviations: ‘166 = BMS-986166-04; BRA = branebrutinib; QD = daily
Note: all capsules are identical (size 0).
In the morning on Day 1, after fasting for at least 8 hours, each participant will receive an oral 
dose of BMS-986166 or branebrutinib or placebo, each consisting of 3 capsules. At the time of 
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dosing, 240 mL of water will be administered to the participant along with his/her dose of study 
drug. The time of dose administration will be called “0” hour. A light meal/snack may be provided 
after the 2-hour PK sample and/or ECG collection insofar as to not interfere with obtaining either.
Storage of investigational product will be according to the label on the container and/or packaging.
Restrictions related to food and fluid intake are described in Section 6.3.
7.2
Method of Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be entered into the study via the IRT to obtain a participant number. Specific 
instructions for using the IRT will be provided to the investigational site in a separate document.  
The investigator or designee will register the participant for screening by following the screening 
procedures established by BMS.
Once it is determined that the participant meets the eligibility criteria following screening,  
participant will be centrally randomized through the IRT.
The study will not allow participant replacement due to an AE.
7.3
Blinding
This is a randomized double-blinded study. Access to treatment codes will be restricted from all 
participants, and site and BMS personnel prior to database lock, with exceptions as specified 
below.
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 participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
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 actual task of unblinding can be delegated by the investigator to a designee 
assigned the task on the Delegation of Authority. The Principal Investigator or appointed designee 
should only call in for emergency unblinding AFTER the decision to unblind the participant has 
been documented.
For this study, the method of unblinding for emergency purposes is through the IRT system. In 
case of an emergency, the investigator has unrestricted access to randomization information via
IRT and can break 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. The 
method of unblinding for emergency purposes is described in the IRT Manual. Participant and 
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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).
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor.
Designated staff of Bristol Myers Squibb Company may be unblinded (obtain the randomization 
codes) prior to database lock to facilitate the bioanalytical analysis of pharmacokinetic samples 
and immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of Bristol 
Myers Squibb 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.
7.4
Dosage Modification
There is no provision for dose modification of study treatment. If a participant interrupts treatment 
due to an AE, study treatment can be restarted in consultation with the Medical Monitor.
A Pharmacy Manual will not be provided for studies with oral dose formulations.
Dose reductions or dose escalations are not permitted. All dose modification rules apply to all arms 
given the blinded nature of this study.
7.5
Preparation/Handling/Storage/Accountability
The investigational product 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 Participants. The investigational product 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 contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product 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.  
7.5.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
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7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability (Section 2). 
Drug accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit. 
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study participants.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to or during the study (up through Study 
Day 149) are described below. Medications taken within 4 weeks prior to Screening must be 
recorded on the eCRF.
1) Use of Class Ia and class III antiarrhythmic agents.
2) Table 7.7.1-1 presents prohibited and/or restricted potential medications.
Table 7.7.1-1:
Prohibited and Restricted Medications
Type of Medication
Examples
(not exhaustive)
Restriction
Required Washout
Allergen 
immunotherapy
various intradermal or 
sublingual
Prohibited during the study
4 months prior to 
randomization
Anticoagulants or 
antiplatelet agents
aspirin, clopidogrel, 
ticlopidine, warfarin, 
heparin, apixaban, etc.
Prohibited during the study
2 weeks or effective post-
discontinuation PD 
duration (whichever is 
longer) prior to 
randomization
Antihistamines -
except fexofenadine
Diphenhydramine, 
loratadine
Stable dose during the 
screening period; consistent 
use through the treatment 
period
Not applicable
Biologics
Belimumab, dupilumab, 
or omalizumab 
Prohibited during the study
6 months prior to 
randomization
Abatacept
Prohibited during the study
6 months prior to 
randomization
Other biologics, 
including tocilizumab, 
anakinra
Prohibited during the study
8 weeks prior to screening
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Table 7.7.1-1:
Prohibited and Restricted Medications
Type of Medication
Examples
(not exhaustive)
Restriction
Required Washout
Intravenous 
Immunoglobulin
Prohibited during the study
8 weeks prior to screening
Bronchodilators
-inhaled
Albuterol, salmeterol, 
ipratropium bromide
Stable dose during screening 
and through treatment period
Not applicable
BTK inhibitors
Marketed drugs, eg, 
ibrutinib, acalabrutinib
Experimental drugs, eg, 
tirabrutinib, 
vecabrutinib, 
zanibrutinib, ARQ-531, 
GDC-0853, and any 
others
Prohibited lifetime use
Not applicable
Calcineurin-inhibitor
-Topical
cyclosporine, tacrolimus
Prohibited during the study 
4 weeks prior to 
randomization
Corticosteroid
-Inhaled, oral non-
absorbable or 
modified-release
Budesonide, fluticasone
Must follow stable regimen 
throughout study; cannot be 
used on as-needed basis
Not applicable
Corticosteroid
-Systemic
IM, IA, intrabursal, IV
Prednisone, 
dexamethasone 
Prohibited during the study
4 weeks prior to 
randomization
Corticosteroid
-Topical
Fluocinolone, 
hydrocortisone
As rescue therapy until Week 
4 as detailed in Section 7.7.2
3 weeks prior to 
randomization
CYP2C8 and CYP3A4
-Strong or moderate 
inhibitors 
clopidogrel, gemfibrozil, 
clarithromycin, 
itraconazole
Prohibited during the study
5 PK half-lives or 14 days 
of randomization
CYP2C8 and CYP3A4
-Strong or moderate 
inducers
rifampin, phenytoin
Prohibited during the study
3 weeks of the 
randomization
CYP2C8 or P-gp
Sensitive 
substrates with 
narrow therapeutic 
indices
Repaglinide, dabigatran, 
fexofenadine
Prohibited during the study 
(digoxin allowed under 
limited/urgent circumstances; 
see below)
5 PK half-lives or 14 days 
of randomization
Immunization
against agents other 
than influenza or 
SARS-CoV-2
Live vaccines
Prohibited during the study
90 days before and 60 days 
after EOT
Nonlive vaccines 
unassociated with 
influenza or SARS-
CoV-2
30 days before and 60 days 
after EOT
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Table 7.7.1-1:
Prohibited and Restricted Medications
Type of Medication
Examples
(not exhaustive)
Restriction
Required Washout
Immunization for 
influenza or SARS-
CoV-2
Live vaccines
Prohibited during the study
90 days before and 60 days 
after EOT
Nonlive vaccines for 
influenza or SARS-CoV-
2
14 days prior to screening
and 60 days after EOT
Immunosuppressants
-systemic or 
oral preparations 
of herbal 
immunomodulator
y medications
Mycophenolate-mofetil, 
azathioprine, 
methotrexate
Prohibited during the study
8 weeks prior to 
randomization
JAK inhibitors
Tofacitinib, baricitinib, 
filgotinib, and 
upadacitinib
Prohibited during the study
8 weeks prior to 
randomization
Leukotriene inhibitors
montelukast
Prohibited during the study
4 weeks prior to 
randomization
Monoamine Oxidase 
Inhibitors
Selegiline, phenelzine
Prohibited during the study
2 weeks prior to 
randomization
Narcotic analgesics
Oxycodone and, 
hydrocodone
Prohibited during the study
Not applicable
Non-narcotic 
analgesics
Acetaminophen
Brief courses for up to 7 days 
allowed
Not applicable
Phosphodiesterase 
Inhibitor
Apremilast, crisaborole
Prohibited during the study
3 weeks prior to 
randomization
Phototherapy 
UVB, UVA
Prohibited during the study
4 weeks prior to 
randomization
S1P Receptor 
Modulators
Fingolimod, ozanimod, 
siponimod, etrasimod
Prohibited lifetime use
Not applicable
rosiglitazone
Dose up to 4 mg can be used, 
monitor glucose closely
Not applicable
Treatments to be 
restricted or suspended 
during the study
torasemide
Dose up to 10 mg can be 
used
Not applicable
digoxin
For acute use only, exclude 
at baseline; limit highest 
dose and monitor trough 
concentrations; stop 
treatment with IP during 
treatment with digoxin and 
for 3 days afterwards
Not applicable
Treatments
-Other
Diquafosol, rebamipide
Prohibited during the study
4 weeks prior to
randomization
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No 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, along with the reason for its administration.
The investigator should contact and confirm agreement with the BMS medical monitor (and 
acknowledgement from the contract research organization medical monitor) prior to the 
administration of any concomitant medications, excepting those needed for urgent/emergent 
treatment for which there is insufficient time for such contact.
7.7.2
Rescue Therapy
Participants having intolerable symptoms within the first 4 weeks of treatment may use the below 
topical agents (according to their respective label instructions) as rescue therapy up until Week 4 
according to the investigator’s judgement. 
•
Fluocinolone acetonide 0.025% 
•
Hydrocortisone butyrate 0.1%
•
Mometasone furoate 0.1%
•
Triamcinolone acetonide 0.1%
Participants requiring and completing ≤ 7 days of topical rescue therapy within the first 4 weeks 
of IP treatment initiation, will remain eligible to be counted as responders for categorical efficacy 
endpoints; their numerical endpoints will also be counted as if they did not receive rescue therapy.
Participants either (1) requiring topical rescue therapy after 4 weeks of IP treatment, or for more 
than 7 days, or (2) requiring systemic corticosteroid/immunosuppression or phototherapy will 
discontinue from study treatment and be considered treatment failures for categorical endpoints.
Participants who discontinue study treatment are to remain in the study and complete all study 
visits and assessments unless they withdraw consent (Section 8.2).
Statistical handling of data from participants requiring rescue medication appears in 
Section 10.3.1.
7.7.3
Use of Concomitant Emollient
Application of fixed doses of an additive-free, basic bland emollient twice-daily for ≥ 7 days before 
baseline visit and for the duration of the study is required.
Note: On study visit days, showering or bathing is permitted prior to attending the study visit, but 
participants must not moisturize or apply emollient. The additive-free, basic bland emollient is 
allowed after the visit.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
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BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of the study treatment 
is terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. 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
•
Any clinical adverse event (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 participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
•
Asthma or COPD that requires systemic glucocorticoid or biologic treatment, or inhaled 
budesonide or equivalent at >1200 μg/day or fluticasone propionate at > 880 μg/day along with 
another anti-asthma/COPD drug such as a long-acting beta-agonist.
•
Systemic or photo-based rescue therapy for AD (Section 7.7.2),
•
Replication-competent (live) vaccine 
•
Grade 4 lymphopenia (ALC < 200) with repeat testing within 7 days(according to the Common 
Toxicity Criteria for Adverse Events [CTCAE] version 5.0)
•
Elevation of ALT or AST > 5x ULN or concurrent elevations of ALT or AST > 3x ULN and 
bilirubin > 2x ULN
•
Decline in PFT values (FEV1 and/or FVC) below 30% of the baseline values
•
Diagnosis of macular edema, retinal or choroidal disease or syndrome
•
Grade 2 or higher cardiac or bone marrow adverse events (with exception of ALC) according 
to the CTCAE version 5.0.
•
Grade 3 for other system adverse events (according to the CTCAE version 5.0)
•
Missed dose of ≥ 3 consecutive days or overall compliance < 85% over a period of > 30 days 
starting from study Day 1.
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Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS 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 participant safety). Refer to Section 9.2.5 Pregnancy. 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
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).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (eCRF) page.
8.1.1
Post Study Treatment Study Follow-up
In this study, efficacy as measured by EASI is a key endpoint of the study. Post study follow-up 
is of critical importance and is essential to preserving participant safety and the integrity of the 
study. Participants who discontinue study treatment must continue to be followed (in this study or 
a rollover study) for collection of outcome and/or survival follow-up data as required and in line 
with Section 2 until death or the conclusion of the study.
If a patient withdraws before completion, every effort should be made to complete the assessments 
of the Follow-up Visits.
8.2
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. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate eCRF page.
•
In the event that vital status (whether the participant 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.
•
If the participant 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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8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
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 participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Efficacy assessments completed by the investigator include vIGA-AD, Eczema Area and Severity 
Index (EASI), and % Body Surface Area (BSA) worksheet. Every effort should be made to ensure 
that the same assessor conducts the assessments at all study visits for a given participant.
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9.1.1
Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-
AD)
The vIGA-AD is a static 5-point assessment intended to assess the global severities of key acute 
clinical signs of AD, including erythema, induration/papulation, and oozing/crusting 
(lichenification excluded).112 The rating of cleared (0), almost cleared (1), mild (2), moderate (3), 
and severe (4) will be assessed at each scheduled visit, and at unscheduled clinic visits, if 
applicable. Refer to Appendix 8.
The vIGA-AD will be collected prior to the EASI.
9.1.2
Eczema Area and Severity Index (EASI)
The EASI is a validated, composite scoring system assessed by the investigator based on the extent 
of each of the 4 body regions (head and neck, upper limbs, lower limbs, and trunk) affected with 
AD and the intensity of each of 4 key signs of AD (erythema, induration/papulation, excoriation, 
and lichenification) and is based on a 4-point scale of 0 (absent), 1 (mild), 2 (moderate), and 3 
(severe).113 For each of the 4 body regions, the mean intensity of inflamed lesions for each of the 
4 signs is recorded. Xerosis, scaling, urticaria, or post-inflammatory pigmentation changes are not 
included. The total EASI score ranges from 0 to 72. The EASI will be collected at each scheduled 
and unscheduled clinic visit, if applicable. Further details of the evaluation and calculation of the 
EASI score are provided in Appendix 9.
9.1.3
Body Surface Area (BSA)
A widely used method of measuring BSA involvement by AD, is the rule of nines in which for 
each section of the body (the possible highest score for each region is: head and neck [9%], anterior 
trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], genitals [1%]) and will be 
reported as a percentage of all major body sections combined.114,115 Participants will undergo this 
assessment at each scheduled and unscheduled clinic visit, if applicable. Refer to Appendix 10.
9.1.4
Pruritus and Sleep Quality Numerical Rating Scale (NRS)
Participants will complete a daily diary recording the intensity of their pruritus and the average 
quality of sleep they experienced during the preceding 24 hours. The intensity of pruritus will be 
assessed using a validated 11-point NRS, ranging from 0 (“no itching”) to 10 (“the worst itching 
imaginable”). The quality of sleep will be assessed using a validated 11-point NRS ranging from 
0 (“the best possible sleep”) to 10 (“the worst possible sleep) provided in Appendix 11.116,117
9.1.5
Dermatology Life Quality Index (DLQI)
The DLQI is a 10-item, easy-to-use, self-administered, assessment of the participants’ perception 
of the impact of their skin disease on different aspects of their Quality of Life (QOL) over the 
previous week. The DLQI score ranges from 0 (no effect on the participant’s life) to 30 (extremely 
large effect on the participant’s life). For each item, the scale is rated as follows: 0 =’not at all’/’not 
relevant’; 1=’a little’; 2=’a lot’; 3=’very much’/’yes’ in question 7, with an overall scoring system 
of 0 to 30; a high score is indicative of a poor QOL.118 The DLQI will be assessed at every 
scheduled and unscheduled clinic visit, if applicable. Refer to Appendix 12.
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9.1.6
Patient Oriented Eczema Measure (POEM)
The POEM is a validated tool used for monitoring atopic eczema severity. It is a 7-item 
questionnaire completed by the subject to assess the severity of eczema over the last week and 
evaluates itch, sleep disturbance, skin bleeding, skin weeping or oozing, skin cracking, skin 
flaking, and skin dryness. Each item has the following response options: 0 = No Days, 1 = 1-2
Days, 2 = 3-4 Days, 3 = 5-6 Days and 4 = Every Day. A total score is calculated by summing each 
item and results in a score ranging from 0-28. The subject will complete the questionnaire onsite 
at study visits. Refer to Appendix 13.
9.1.7
Patient Global Impression of Change (PGI-C)
The PGI-C is a global rating anchor scale and has been used across different therapeutic categories 
to interpret the scores from participant-reported outcome measurements. The PGI-C will be used 
in this study to confirm the threshold for meaningful change on other patient reported outcomes 
instruments in the target patient population. Participants will be asked the following question as 
per the schedule of assessments: “Compared to the beginning of the study, before you started the 
study treatment, which of the following best describes the skin symptoms of your atopic dermatitis 
today?” The response choices will be as follows: much improved, moderately improved, a little 
improved, the same, a little worse, moderately worse, or much worse. Refer to Appendix 14.
9.1.8
Patient Global Impression of Severity (PGI-S)
The PGI-S is a global rating anchor scale and has been used across different therapeutic categories 
to interpret the scores from participant-reported outcome measurements. The PGI-S will be used 
in this clinical trial to confirm the threshold for meaningful change on other PRO instruments in 
the target population. The PGI-S is not subject to recall error and can be also used to assess change 
from baseline data. Participants will be asked the following question as per the schedule of 
assessments, “Which of the following best describes the severity of the skin symptoms of your 
atopic dermatitis over the past 7 days?” The response choices will be as follows: none, mild, 
moderate, severe, or very severe. Refer to Appendix 15.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (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 participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
Adverse events of interest (AEIs) are described in Section 9.2.8.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Appendix 1 in the Investigator’s Brochure (IB) represent the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting.
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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.
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 (eg, a follow-up skin biopsy).
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
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 participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
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.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
•
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.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs 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 participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of interest (as defined in Section 9)
will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
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9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
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 Investigator’s Brochure 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 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least for 
3 months after study product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. 
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 participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
If any sexual activity (eg, vaginal, anal, oral) has occurred between a male participant and a 
pregnant partner(s) without the use of a condom during and at least for 3 months, after study 
product administration, the information should be reported to the Sponsor or designee, even if the 
male participant has undergone a successful vasectomy.
In order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner(s) must sign an informed consent form for disclosure of this 
information. Information on the pregnancy will be collected on the Pregnancy Surveillance Form.
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S1P Receptor Modulator and Branebrutinib
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
Clinically significant changes, in the judgment of the investigator, in laboratory parameters 
(abnormalities) will be recorded as AEs. During the treatment period, all total WBC and WBC 
differential results will be blinded. Reductions in ALC levels is a known PD effect of 
BMS-986166. If any of the following results are observed, the investigator will be notified and 
asked to repeat the laboratory tests within approximately 7 days:
•
Absolute lymphocyte count [ALC] < 200 cells/μL
•
Absolute neutrophil count [ANC] < 1000 cells/μL
•
Total WBC > 20,000 cells/μL
If the repeat values also exceed these limits, the investigator will be informed that the patient’s 
results for the abnormal parameter have fallen below the acceptable threshold. 
If ANC or total WBC counts are confirmed below the acceptable limits, the Medical Monitor will 
contact the treating investigator to request close monitoring for risk of serious infection and 
appropriate follow-up, at the discretion of the investigator.
If the ALC is confirmed < 200 cells/μL, the investigator will discontinue investigational drug and 
then consult with the Medical Monitor. Laboratory testing will be repeated weekly until ALC is 
> 500 cells/μL.
If participants have elevations in ALT and/or AST ≥ 3x the upper limit of normal (ULN), a retest 
should be performed as soon as possible but not later than 4 days after the original test. If the 
abnormality is confirmed, twice-weekly testing should occur until ALT and AST are < 3x ULN. 
If the ALT and/or AST stabilizes at a level > 3x ULN, the Medical Monitor may agree to less 
frequent testing. Other liver-related laboratory testing, including international normalized ratio 
(INR), alkaline phosphatase (AP), gamma-glutamyl transferase (GGT), hepatitis serologies, and 
other tests as deemed necessary by the investigator should be performed to better understand the 
observation.
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S1P Receptor Modulator and Branebrutinib
The investigator should establish causality. In addition, the confirmed elevation > 3x ULN is an 
AEI (see Section 9.2.8) and should be reported by the investigator. At any time, if any of the 
following occur and there are no apparent alternative causes for the finding, the investigational 
drug must be permanently discontinued:
•
ALT or AST > 8x ULN or
•
ALT or AST > 5x ULN with confirmation, within 2 weeks or
•
ALT or AST > 3x ULN and (total bilirubin > 2x ULN or INR > 1.5) or
•
ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
The investigator should establish causality. After discontinuation due to elevation of ALT or AST 
> 5x ULN or concurrent elevations of ALT or AST > 3x ULN and bilirubin > 2x ULN, further 
liver function evaluation should be performed (for example, coagulation panel and alkaline 
phosphatase) in consultation with the Medical Monitor.
9.2.7
Potential Drug Induced Liver Injury (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 9 and Appendix 3 for reporting details).
Potential drug induced liver injury is defined as: 
•
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND
•
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) AND
•
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Monitoring of Participants with Adverse Events of Interest (AEIs)
Adverse events 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 addition to the 
conventional safety monitoring employed in the study. 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.
Potential AEs of interest that may be a consequence of S1PR1 modulation will therefore be 
monitored in the IM018005 study. These AEs include:
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S1P Receptor Modulator and Branebrutinib
•
Bradycardia and heart conduction abnormalities:
Dose-related transient, reversible bradycardia and first-degree atrioventricular block were 
reported primarily as first dose effects in fingolimod studies. The HR reduction observed with 
S1PR1 agonists is an expected effect of S1PR modulation and appears to be conducted through 
the same pathway as vagus nerve stimulation. In addition, these negative chronotropic effects 
of S1PR1 agonists appear to attenuate over time secondary to S1PR desensitization and 
internalization on cardiac myocytes.119 Because of its biased ligand properties, both 
nonclinical and clinical data suggest that this effect is less with BMS-986166 (Section 3.2 and
IB). 
Nevertheless, ECG assessment predose and at 1, 2, 4, and 6 hours post-dose will be obtained; 
in addition to hourly monitoring of the HR and blood pressure on Day 1. Standard 12-lead 
ECG will be collected and reviewed with every subsequent visit. 
Clinicians should be particularly mindful of participants who have a low HR at baseline 
(spontaneously or through drug-induced ß-receptor blockade), prior to administration of the 
investigational drug. Atropine IV is recommended as the first-line treatment of bradycardia, 
up to a maximum daily dose of 3 mg. Furthermore, the common guidelines for treatment of 
bradycardia (eg, Advanced Cardiac Life Support [ACLS] guidelines) should be followed as 
appropriate.
•
Pulmonary effects:
An initial sharp decrease followed by a slow progressive decline over time in FEV1 was 
observed in fingolimod clinical studies. Nonclinical toxicity studies however with 
BMS-986166 have not revealed the potential for pulmonary toxicity at doses considerably 
higher than the pharmacologically active dose. PFTs including FEV1, FVC, and diffusion 
capacity of carbon monoxide (DLCO), will be measured in all participants. Every participant 
whose PFTs are abnormal will be followed until such time as resolution is confirmed or no 
further improvement is expected by the investigator.
Any condition that might affect the outcome of pulmonary function testing including infection, 
respiratory symptoms, occupational exposures (including asbestos) and cigarette smoking 
needs to be collected before PFT testing and transcribed to the PFTs eCRF page. If participants 
experience a decline in PFT values (FEV1 and/or FVC) below 30% of the baseline values, 
treatment should be discontinued.
If a participant discontinues due to a respiratory AE, the investigator should ensure that the 
patient has adequate evaluations as clinically indicated by a pulmonologist for the AE. Further 
evaluations will be conducted until such time as resolution is confirmed or no further 
improvement is expected by the investigator (based on a follow-up period of not less than 3 
months).
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BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
•
Hepatotoxicity:
Fingolimod caused frequent, reversible liver enzyme elevations greater than 3-fold above the 
ULN in up to 12% of patients; this was a significant cause of cessation of therapy. In this study, 
clinical blood chemistry analyses to assess liver function tests (LFTs) will be performed. Every 
patient whose LFTs are abnormal will be followed until values return to baseline.
Refer to Section 9.2.6 and Section 9.2.7 for instructions regarding hepatotoxicity.
•
Macular edema:
Instances of serious macular edema were reported in fingolimod renal transplant studies, and 
a 0.8% incidence was reported as an SAE in fingolimod (1.25 mg dose) MS clinical studies. 
Nonclinical studies with BMS-986166 have not revealed eye-related toxicities. In this study, 
visual acuity (VA) testing and OCT will be performed in all participants at screening and the 
end of study visits or early termination. In addition, participants will be questioned about visual 
signs or symptoms at each study visit and instructed to inform the investigator if they develop 
symptoms between visits. For participants with visual symptoms suggestive of macular edema, 
OCT and ophthalmologic examination, including visual acuity testing and dilated 
ophthalmoscopy, will also be performed. Every participant whose ophthalmic evaluations 
reveal abnormalities will be followed until values return to baseline.
Study drug must be discontinued in any participant who has a diagnosis of macular edema. 
Participants with a diagnosis of macular edema must be followed up monthly or more 
frequently if needed based on the ophthalmologist’s judgment. Further ophthalmological 
evaluations will be conducted until such time as resolution is confirmed or no further 
improvement is expected by the ophthalmologist (based on a follow-up period of not less than 
3 months). If the participant does not show definite signs of improvement on examination 6 to 
8 weeks after discontinuation of investigational drug, then therapy for macular edema in 
conjunction with an ophthalmologist experienced in the management of this condition should 
be initiated.
•
Opportunistic or serious infections:
TB, serious bacterial infections, systemic fungal infections, viral infections such as herpes 
infections (including herpes zoster and disseminated herpes simplex), and protozoal infections 
should be reported as AEIs and treated accordingly.
Malignancies
Malignancies such as melanoma, basal cell carcinoma, breast cancer, lymphoma  (cutaneous 
T-cell lymphoproliferative disorders or diffuse B-cell lymphoma), and seminoma have also 
been reported for the class of S1P receptor modulators. Malignancy should be reported as AEIs 
and referred accordingly to the appropriate specialist.
Progressive multifocal leukoencephalopathy (PML)
PML is an opportunistic viral infection of the brain caused by the John Cunningham virus 
(JCV) that typically occurs in patients who are immunocompromised and may lead to death or 
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BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
severe disability. JCV infection resulting in PML has been observed in patients treated with 
immunomodulatory therapies for MS and has been associated with some risk factors (eg, 
polytherapy with immunosuppressants, severely immunocompromised patients). Typical 
symptoms associated with PML vary, progress over days to weeks, and include progressive 
weakness on 1 side of the body or clumsiness of limbs, disturbance of vision, and changes in 
thinking, memory, and orientation leading to confusion and personality changes.
Investigators should be vigilant for clinical symptoms or other findings that may be suggestive 
of PML. If PML is suspected, a neurologist consultation should be obtained and magnetic 
resonance imaging (MRI) should be requested and treatment should be discontinued.
Posterior reversible encephalopathy syndrome (PRES)
PRES is a syndrome characterized by sudden onset of severe headache, confusion, seizures,
and visual loss. If a participant develops any unexpected neurological or psychiatric 
symptoms/signs (eg, cognitive deficits, behavioral changes, cortical visual disturbances, or any 
other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of 
intracranial pressure, or accelerated neurological deterioration, the physician should promptly 
schedule a complete physical and neurological examination and should consider an MRI. If 
PRES is suspected, treatment should be discontinued.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
For this study, any dose of BMS-986166 or branebrutinib greater than 2 daily doses of study 
treatment within a 24-hour time period will be considered an overdose. See Section 9 for AE 
assessment and reporting procedures regarding suspected overdose and intentional overdose.
Based on the IB, there has been no clinical experience nor known specific antidote for overdose 
with either BMS-986166 or branebrutinib.38,47
In the event of an overdose, the investigator should:
1) Contact the Medical Monitor immediately.
2) Closely monitor the participant 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.
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 participant.
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BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
9.4
Safety
An external, independent DMC will be empaneled to review safety on a prescheduled and ad-hoc 
basis, in addition to contemporaneous safety monitoring by the study team. Planned time points 
for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
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, or a 
laboratory abnormality. Refer to the Schedule of Activities (Section 2).The examination includes 
examination of the abdomen, conjunctival mucosae, heart, lungs, lymph nodes, oral mucosa, skin, 
and any sites deemed necessary by the investigators based on symptoms or other findings.
9.4.2
Vital signs
Refer to the Schedule of Activities (Section 2).
9.4.3
Electrocardiograms
12-lead ECG will be performed at the visits indicated in the Schedule of Activities (Section 2). 
The participant 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. 
9.4.4
TB Screening and Chest Imaging
A participant 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 
participants will have a screening interferon-gamma release assay (IGRA; eg, QuantiFERON®-
TB Gold) performed centrally. If unable to obtain central laboratory results, an IGRA test could 
be obtained locally, after consultation with the BMS Medical Monitor. A participant with an 
indeterminate IGRA test result must be retested for confirmation. If the second result is again 
indeterminate, the participant will be excluded from the study. If the second result is positive, the 
participant should be considered as having LTBI provided there are no signs or symptoms of active 
TB. If the second result is negative, the participant may be eligible provided no other exclusion 
criterion for TB is met. A chest x-ray is also required during Screening.
9.4.5
Pulmonary Function Tests
Pulmonary findings in animals and humans are associated with full-agonist S1PR1 modulators 
such as fingolimod.120,121 It is hypothesized that the differentiated biased-ligand properties of 
BMS-986166 (Section 3.2.1.1) obviates this phenomenon and its downstream consequences such 
as pulmonary effects and macular edema in animals and humans; this hypothesis is supported by 
observations in nonclinical models.38
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BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
•
In both Studies IM018001122 and IM018003,123 there was no apparent effect of BMS-986166 
on pulmonary function including FVC, FEV1, or DLCO. Participants underwent frequent 
safety assessments while in the clinic and during an extended follow-up period to monitor for 
AEs. Decline in PFT values (FEV1 and/or FVC) below 30% of the baseline values during 
treatment in this study (IM018005) will result in discontinuation from further study drug 
administration.
To monitor the potential pulmonary effects of BMS-986166, FEV1, FVC, and DLCO 
measurements will be performed as indicated the Schedule of Activities (Section 2).These tests 
will be performed at a qualified pulmonary function laboratory or respiratory department. Please 
refer to the American Thoracic Society/European Respiratory Society guidelines for 
standardization of spirometry and single breath determination of carbon monoxide uptake in the 
lung.124,125,126
9.4.6
Neurological Safety
Preclinical toxicity data in conjunction with large systemic exposure (AUC-based) margins 
suggest a low safety concern for likely neurological effects in human participants.
Consistent with the nonclinical results, comprehensive neurological examination and nerve 
conduction velocity results for participants in Study IM018001101 or IM018003102 demonstrated 
no concerning treatment-emergent neurological findings following dosing with BMS-986166. 
Specific monitoring for neurologic toxicity, beyond standard safety measures, is not planned in 
Study IM018005.
9.4.7
Ophthalmological Examination
Full-agonist S1PR1 modulators such as fingolimod are associated with potential macular 
edema.127 Accordingly VA and OCT will be performed at scheduled times as indicated in the 
Schedule of Activities (Section 2). Diagnosis of macular edema, retinal or choroidal disease, or 
syndrome during treatment will result in discontinuation from further study drug administration.
9.4.8
Male Sex Hormones
For the purposes of monitoring the preclinical testicular finding, participants with history of 
significant testicular or epididymal disease will be excluded, and male sex hormones 
(follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone) will be 
assessed at baseline and selected time points throughout the treatment period and until study 
discharge.38
9.4.9
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
A central laboratory will perform the analyses and will provide reference ranges for these tests. 
WBC counts and lymphocyte counts will be monitored centrally and will not be provided to the 
site to prevent potential unblinding of the investigator.
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
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S1P Receptor Modulator and Branebrutinib
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Coagulation Panel
Prothrombin time/International normalized ratio (PT/INR)- screening only
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Uric acid
Fasting glucose
Cholesterol & Lipid Panel
Testosterone
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Magnesium
Creatine phosphokinase
eGFR calculation
Hemoglobin A1c
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Screening Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, hepatitis B core antibody, HIV-1 
and -2 antibody (screening only)
Other Analyses
Test for drugs of abuse (urine or serum), (screening and predose on Day 1)
Pregnancy test (WOCBP only).
Follicle stimulating hormone (FSH) (screening only for select women only)
QuantiFERON-TB Gold test (or equivalent if not available; screening only)
SARS-CoV-2 serology test
SARS-CoV-2: RT-PCR Test or Antigen test
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S1P Receptor Modulator and Branebrutinib
9.5
Pharmacokinetics
Pharmacokinetics of BMS-986166 and its major metabolites (BMS-986166-P) will be derived 
from blood concentration. Pharmacokinetics of branebrutinib will be derived from plasma 
concentration. Blood (BMS-986166 and its major metabolite [BMS-986166-P]) and plasma 
(branebrutinib) samples will be analyzed by validated assays. Samples collected from participants 
who receive placebo will not be analyzed. In addition, blood and plasma samples will be archived 
for potential additional metabolites analysis, if the need arises and to the extent possible. Detailed 
instructions for PK blood collection, labeling, processing, storage, and shipping will be provided 
to the sites.The pharmacokinetic parameters to be assessed include:
Cmax
Maximum observed blood concentration for BMS-986166 and its major 
metabolite BMS-986166-P 
Maximum observed plasma concentration for branebrutinib
Tmax
Time of maximum observed blood or plasma concentration
AUC(0-T)
Area under the blood or plasma concentration-time curve from time zero 
to time of last measured concentration wherever applicable
Ctrough
Trough observed blood or plasma concentration wherever applicable
AUC(TAU)
Area under the concentration-time curve in one dosing interval wherever 
applicable
Individual participant pharmacokinetic parameter values will be derived by non-compartmental 
methods by a validated pharmacokinetic analysis program. Actual times will be used for the 
analyses.
9.5.1
Sampling Schedule
The sampling schedule for the assessment of PK is provided in Table 9.5.1-1. Predose samples 
must be drawn before the dose on visit days, and after a fast of at least 8 hours for the Day 1and 
Day 85 visits. As described in Section 2, Schedule of Activities, the timing of other procedures at 
a given visit can be adjusted so that PK sampling can be performed at the scheduled time. If 
possible, PK samples should be collected from participants who discontinue treatment due to an 
AE. Further details of blood collection and processing will be provided to sites.
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BMS-986166 and BMS-986195
S1P Receptor Modulator and Branebrutinib
Table 9.5.1-1:
Pharmacokinetic Sampling Schedule for All Participants 
(IM018005)
Study Day of 
Sample Collection
Event
Time Relative to 
BMS-986166 or 
Branebrutinib Dose (hr:min)
BMS-986166 + 
BMS-986166-P
Blood Sample 
Branebrutinib 
Plasma 
Sample 
Day 1 (Week 0) 
(Randomization)a
Predose
0:00
X
X
0:30
X
X
1:00
X
X
2:00
X
X
4:00
X
X
6:00
X
X
12:00b
X
Day 29 (Week 4)
Predose
0:00
X
Day 57 (Week 8)
Predose
0:00
X
Day 85 (Week 12)a
Predose
0:00
X
X
0:30
X
X
1:00
X
X
2:00
X
X
4:00
X
X
6:00
X
X
12:00b
X
Day 113 (Week 16)
Post Dose
24:00
X
Abbreviations: hr = hour; min = minute
a Participant is required to fast for 8 hours. A light meal/snack may be provided after the 2-hour PK collection insofar 
as to not interfere with obtaining PK sample.
b Samples collected from consenting participants at selected sites and will be analyzed for BMS-986166 and 
BMS-986166-P only.
It is expected that every effort will be made to collect PK samples at the times indicated. 
At selected sites, participants will be asked to complete an additional blood draw 12 hours 
post-dose on Days 1 and 85. They will be required to sign a separate ICF before collection of the 
samples. All samples should be collected using the time point labels provided, even if they are 
outside of the scheduled sampling time. Actual sample times must be recorded. If samples cannot 
be taken within the specified time, then every effort should be made to take a sample as soon as 
possible. 
9.6
Pharmacodynamics
Pharmacodynamic blood sampling should be performed at the nominal time(s) specified in this 
clinical protocol. All actual PD blood sample collection times will be recorded in the source 
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documents and eCRF. Explanation should be provided in the source documents and eCRF for 
missed or mishandled samples and for samples collected outside the following time windows 
(applicable to all parts of the study, as appropriate).
Exploratory analyses may not be conducted in all cohorts or at all timepoints in each cohort. The 
exact analyses and time points for each cohort will be communicated to the clinical site 
prospectively. For some exploratory analyses, samples will be collected and banked. Select banked 
samples may be analyzed based on emerging PD and/or PK data.
The sampling schedule for all biomarkers, including PD biomarkers, is outlined in Table 9.8-1. 
All samples will be collected predose.
9.6.1
Blood Collection for Immunocyte Profiling
Blood samples will be collected and measured by flow cytometry or other methods for quantitating 
immune cell populations including, but not limited to   Th1, Th2, Th17, Tem, Tcm, Temra, B-cells 
subsets, basophils, eosinophils, and DCs by panels comprised of appropriate surface markers.
On days when IP is administered, samples will be collected prior to dosing.
9.6.2
Blood Collection for Plasma Cytokines
Blood samples will be collected to explore the in vivo effects of BMS-986166 and branebrutinib 
on cytokines and other circulating proteins. Cytokines measured may include, but not limited to 
TSLP, IFN-Ț, IL-1Ș, IL-1ș, IL-6, IL-17A, IL-17F, IL-31, IL-33, TNF-Ș, CRP, CXCL10, and 
CXCL13.
On days when IP is administered samples will be collected prior to dosing.
9.6.3
Blood Collection for Gene Expression
Blood samples will be collected to explore the effects of BMS-986166 and branebrutinib on gene 
expression from total cells in whole blood or from purified cell types. Samples will be collected 
and mRNA isolated for assessment of expression levels of genes encoding proteins including, but 
not limited to TSLP, IFN-Ț, IL-1Ș, IL-1ș, IL-6, IL-17A, IL-17F, IL-31, IL-33, TNF-Ș, CRP, 
CXCL10, CXCL13, and Th, B-cell, pDC, and eosinophil associated genes. Whole blood RNA will 
be analyzed pending efficacy results and may not be assessed for all time points and treatment 
arms.
On days when IP is administered samples will be collected prior to dosing.
9.7
Pharmacogenomics
Whole-genome sequencing or single-nucleotide polymorphism (SNP) analysis of DNA may be 
performed to determine if there is a genetic basis associated with the response to BMS-986166 
and/or branebrutinib. Variants examined will include, but are not limited to, genes with known 
relevance to small-molecule drug distribution and metabolism, and to AD pathogenesis such as 
filaggrin (FLG), human leukocyte antigen analyses, and mutations/SNPs in disease relevant 
pathways such as genes involved in type I IFN signaling and the JAK/ signal transducer and 
activator of transcription pathway. Epigenetic analyses of DNA may also be performed.
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9.7.1
ADME Sampling
A 6-mL whole blood sample will be drawn at baseline (Day 1, as indicated in Section 2 Schedule 
of Activities and Table 9.8-1) for potential analysis of DNA variants in ADME-related genes (see 
Appendix 16 which contains the lists of ADME-related genes from http://pharmaadme.org, 
analyses will likely include these genes but may not be limited to them). Further details of blood 
collection and processing will be provided to the site in the procedure manual.
9.8
Biomarkers
The objectives of the biomarker work are to confirm target engagement for BMS-986166 (S1PR) 
and branebrutinib (BTK), and to understand the biological consequences of blocking these 
pathways in AD participants. 
 
 
 
Samples may also be used to build or improve assays related 
to the above questions. The biomarker approaches for this study are discussed in the following 
subsections in greater detail, and will focus on leukocyte counts and inflammatory signaling 
molecules in blood (eg, Th2 cells and eosinophils in whole blood, RAST, Serum IgE, and 
cytokines), gene expression analysis in blood and tissue, pathologic analyses of skin biopsies (eg, 
histology, lymphocyte and neutrophil infiltration, eosinophils, mast cells), and proteomic/gene 
expression analyses of skin tape stripping samples. Where possible, blood and tissue samples will 
be collected at multiple timepoints to facilitate longitudinal analyses.
The collection of the stratum corneum, the uppermost layer of the epidermis, by tape-stripping 
offers the advantage of obtaining skin samples in a simple and noninvasive manner. This technique 
has been used to determine different skin biomarkers such as interleukin (IL)-1 cytokines, 
enzymes, lipids, and filaggrin degradation products. Details on the use of tape stripping procedures 
in AD patients as well as the downstream biomarker analyses128,129,130,131 will be provided in the 
Study Laboratory Manual. 
Measurements may also include, but are not limited to, assessments of SARS-CoV-2 serologic 
status. Serum will be collected at baseline and end of study for optional measurements of SARS-
CoV-2 serology (anti-SARS-CoV-2 IgM and/or IgG and/or IgA). Further details of sample 
collection and processing for blood, serum, and skin biopsies will be provided to the site in the 
Study Laboratory Manual.
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Table 9.8-1:
Biomarker Sampling Schedule All Participants (IM018005)
Study Day of 
Sample 
Collection
Serum 
Biomarkersa
Whole 
Blood for 
BTK 
Occupancy
Whole 
Blood 
Total 
BTK 
pBTK
Whole 
Blood 
DNA
Whole 
Blood 
Epigenetic 
Analysesb
Whole 
Blood RNA 
(PAXgene)c
Flow 
Cytometry
Skin 
Tape 
Stripping
Skin 
Biopsy 
(optional)
SARS-
CoV-2 
Serology
Day 1
X
X
X
X
X
X
X
X
X
X
Day 8
X
X
X
X
Day 29
X
X
X
X
X
X
X
Day 85
X
X
X
X
Day 113 / 
EOT
X
X
X
X
X
X
X
X
Follow Up -
Day 127
X
X
X
X
X
X
Follow Up -
Day 169
X
X
X
X
X
X
X
Study 
Withdrawal
X
Abbreviations: BTK = Bruton Tyrosine Kinase; DNA = deoxyribonucleic acid; EOT = end of treatment: RNA = ribonucleic acid
a Serum analyses on Day 8 and Day 85 will be performed if deemed necessary based on efficacy and other biomarker results.
b Epigenetic samples will be stored for later analysis.
c Whole blood for all RNAseq (RNA sequencing) time points will be stored, and analyses will be performed if warranted based on efficacy and other biomarker 
results.
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9.8.1
Pathway Engagement Assays
As one of the primary biological roles of S1P signaling is regulation of tissue/blood leukocyte 
trafficking.132 S1P target and pathway engagement will be assessed by absolute lymphocyte count 
(ALC) in blood and tissue assessments of lymphocyte infiltration in AD lesions. 
Blood and tissue analyses of other immune cell populations will be assessed in parallel to 
determine if any effects seen are global or specific to subsets of leukocytes.
Branebrutinib target engagement will be assessed by a mass-spectrometric based BTK occupancy 
assay and measurement of total BTK in whole blood. 
9.8.2
Additional Exploratory Biomarkers
As current scientific literature and internal BMS research suggests that BTK and S1P signaling 
may impact many overlapping, complementary immunological processes and immune cell types, 
exploratory analyses will be performed with the goal of producing the same data outputs whenever 
possible. This approach will maximize the translational value of the dataset, ensuring that this 
study will advance understanding of the field regardless of the efficacy seen in this study, and thus 
provide value to the AD patient community.
Cellular analyses will include, but may not be limited to, skin and blood analysis of Th2 cells and 
other T-cells subsets, B-cells, eosinophils, basophils, mast cells, neutrophils, myeloid cells, and 
innate lymphoid cells. A combination of techniques including gene expression analyses, ELISA 
or other protein measurements for serum IgE and cytokines, proteomic/gene expression analyses 
of skin tape stripping samples, autoantibodies, and clinical chemistry tests such as RAST and 
serum surrogates of mast cell activation will be used to build a comprehensive picture of the 
response of AD participants to BTK and S1P inhibition. Genetic analyses will include, but are not 
limited to mutations in the Filaggrin gene (FLG), with FLG potentially informing on disease 
mechanisms relevant to pediatric vs. adult AD in particular.24,133
Skin punch biopsies will be optional but strongly encouraged, with a minimum goal of 12 biopsies 
per group, since they are critical to a full understanding of response to these therapies in AD 
participants. Looking to future studies, having as many skin samples as possible will also allow 
for greater understanding of which tissue measures may have viable blood/serum surrogates and 
what can only be assessed accurately from biopsies. Immune cell trafficking, expected to be one 
of the major phenomena affected by BMS-986166, is expected to fall into the category of those 
requiring tissue assessment. Skin punch biopsies will be taken at baseline and at end of treatment, 
and either frozen, placed in formalin, or sent into an equivalent process as appropriate for the 
experimental end use of the material (ie, separate processing for RNA extraction). Details for the 
biopsy procedures will be provided in the Study Laboratory Manual. 
Extra serum, plasma and whole blood for DNA and RNA will be taken to explore pathways 
impacted by branebrutinib and BMS-986166 and pathophysiological aspects of AD. RNA may be 
analyzed by any common technique, including RNA sequencing, to enable broad or directed 
profiling of gene expression.
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Biomarker samples will be collected in the appropriate collection tubes or devices at the times 
indicated in Table 9.8-1.
Allowed windows of biomarker assessments will be detailed in the lab manual. 
Biomarker samples will be shipped to a central and contracted laboratories for the analytical 
assessments for the measurement of the following exploratory biomarkers: 
•
Target engagement assay, mass-spectrometric BTK occupancy assay (branebrutinib), or ALC 
(BMS-986166) 
•
Pathway engagement: ALC / assessment of immune cell infiltrate in AD skin lesions 
(BMS-986166) 
•
Immune cell counts from whole blood
•
Leukocyte profiling from whole blood
•
Eosinophil and basophil profiling from whole blood
•
Serum cytokines, inflammatory markers, and soluble proteins 
•
Clinical chemistry measures of mast cell activity in serum (eg, serum histamine) 
•
Extra serum (explore pathway, disease and drug effects) 
•
Extra plasma (explore pathway, disease and drug effects) 
•
RNA from whole blood
•
DNA from whole blood
•
RNA and cytokine analyses 
•
Skin tape stripping samples for proteomic / gene expression analyses
•
Skin biopsy (optional)
•
Pathologic analyses of skin and immune cell populations in punch biopsies (optional) 
•
Gene expression and cytokine analyses in skin biopsies (optional)
Details for collection, processing, storing, and shipping these samples will be provided in the Study 
Laboratory Manual.
9.8.3
Additional Research Collection
This protocol will include sample collection and/or residual sample storage for additional research 
(AR).
For All US sites:
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees, or academic/institutional requirements. Where one or more of these exceptions 
occurs, participation in the additional research should be encouraged but will not be a condition of 
overall study participation.
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•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study.
•
If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right participants. This may also include genetic/genomic exploration aimed at exploring 
disease pathways, progression and response to treatment etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
•
Prospective samples of serum, whole blood, and plasma will be collected at selected time 
points (see Table 9.8.3-1)
•
Residual samples of all types from all test collections (see Table 9.8.3-2) will also be retained 
for additional research purposes
Samples kept for future research will be stored at the BMS Biorepository in New Jersey, USA or
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be participant to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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Table 9.8.3-1:
Prospective Additional Research Sampling Schedule
Study Day
Time 
(Event)
Hour
Time 
(Relative To 
Dosing)
Hour: Min
Blood Sample
Serum 
Sample
Plasma 
Sample
Day 1
0 (predose)
00:00
X
X
X
Day 8
0 (predose)
00:00
X
X
X
Day 15
0 (predose)
00:00
X
X
X
Day 29
0 (predose)
00:00
X
X
X
Day 57
0 (predose)
00:00
X
X
X
Day 85
0 (predose)
00:00
X
X
X
Day 113/EOT
0 (predose)
X
X
X
Day 127/Final 
Follow-up Visit
0
X
X
X
Day 169
0
X
X
X
Abbreviations: EOT = end of treatment: min = minute
Table 9.8.3-2:
Residual Sample Retention for Additional Research Schedule
Sample Type
Timepoints for which residual samples will be retained
Plasma
All
Whole Blood
All
Serum
All
Skin Biopsy
All
9.9
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.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
The sample size calculation is driven by the power to compare mean percentage change from 
baseline in EASI score at Week 16 between BMS-986166 or branebrutinib versus placebo. 
Thirty participants per group will provide 84% power to detect a treatment difference (versus 
placebo) of 30 % at the type I error of α = 0.05 (1-sided), assuming a common standard deviation 
of 43%. The assumed treatment difference of 30% is similar to the mean difference observed from 
historical data on approved drugs across different mechanism of actions. No adjustment will be 
made for multiplicity.
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Assuming a 15% dropout rate (ie, the fraction of participants not completing Week 16 assessment), 
25 participants per group will still provide 78% power to detect a treatment difference of 30%.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Randomized
All participants who are randomized to a treatment
Treated
All participants who take at least 1 dose of study treatment
modified Intent-To-Treat 
(mITT)
All participants who are randomized and received at least one dose 
of study treatment
Safety
All randomized participants who take at least 1 dose of double-
blind study treatment. Participants will be included in the 
treatment group they were randomized to, except in the following 
cases:
•
If a participant received the same incorrect treatment 
throughout the study, then the participant will be analyzed 
based on the treatment received.
•
If a participant received study drug from more than one 
treatment group, and none of the administrations were 
consistent with the assigned randomized treatment group, then 
the participant will be analyzed based on the first non-placebo 
treatment received.
•
If a participant is randomized to placebo treatment and 
receives non-placebo treatment, then the participant will be 
analyzed based on the first non-placebo treatment received.
Pharmacokinetic
All participants who received any corresponding study drug and 
have any available concentration-time data
Biomarker
All participants that received any study treatment and have any 
available biomarker measurement
Safety analysis will be based on Safety population, participants will be analyzed as per actual 
treatment received. Efficacy analysis will be based on mITT population, participants will be 
analyzed as per randomized treatment.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will include 
a more technical and detailed description of the statistical analyses described in this section. This 
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section is a summary of planned statistical analyses of the most important endpoints including 
primary and secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender and race.
10.3.1
Efficacy Analyses
10.3.1.1
Primary Endpoint
The primary efficacy endpoint is mean percent change from baseline in EASI score at Week 16.
A mixed effect model will be fit with treatment, visit and treatment-by visit interaction as the fixed 
effects and measurements within each participant as the repeated measurements. Adjusted mean 
% change (LSMEAN) and unadjusted mean % change with corresponding 95% CI per treatment 
group will be provided. The difference in adjusted means and corresponding 95% CIs will be 
provided for the difference between active treatment groups and placebo group at different visits 
(week 16 for primary endpoints). P-value will be provided for difference at Week 16. 
10.3.1.2
Secondary Endpoint
The secondary efficacy endpoints are: 
•
Proportion of participants exhibiting a vIGA-AD score of 0 (cleared) or 1 (almost cleared) 
AND a ≥2 point reduction from Baseline at Week 16; 
•
Proportions of participants exhibiting a ≥ 50% (EASI-50) reduction from baseline in EASI 
score at Week 16
•
Proportion of participants exhibiting a ≥ 4 point improvement from baseline in Pruritus NRS 
at Week 16.
•
Mean percentage change from baseline in Pruritus NRS at Week 16
•
Mean change from baseline in percentage of affected BSA at Week 16
For categorical (proportion) endpoints, the estimate and its corresponding 95% CI of each 
treatment group will be estimated using Clopper-Pearson method. The difference of the proportion 
between active treatments and the placebo will be estimated and their corresponding 95% CI will 
be calculated.
All participants discontinuing prematurely prior to Week 16, regardless of reason, will be counted 
as non-responders at subsequent visits. 
For continuous (percent change from baseline and change from baseline) endpoints, the similar 
mixed effect model (as used in Section 10.3.1.1) will be fit with treatment, visit, and treatment-by 
visit interaction as the fixed effects and measurements within each participant as the repeated 
measurements. The baseline value will be added into the model as a covariate if necessary, for 
change from baseline endpoints. Adjusted mean % change (LSMEAN) and unadjusted mean % 
change with corresponding 95% CI per treatment group will be provided. The difference in 
adjusted means and corresponding 95% CIs will be provided for the difference between active 
treatment groups and placebo group at specific visits (eg, week 16 for secondary endpoints).
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For participants requiring topical rescue therapy after the first 4 weeks of treatment or for more 
than 7 days, efficacy assessment after administration of rescue therapy will be considered as 
missing for continuous endpoints and considered as non-responder for categorical endpoints.
10.3.2
Safety Analyses
All adverse event will be listed and tabulated by system organ class, preferred term and treatment. 
Vital signs and clinical laboratory test results will be listed and summarized by treatment. Any 
significant clinical laboratory results will be listed. ECG readings will be evaluated by the 
investigator and abnormalities, if present, will be listed. 
10.3.3
Other Analyses
PK, PD/biomarker and additionally efficacy exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population PK analysis and PD analyses will be 
presented separately from the main clinical study report. 
10.3.4
Interim Analyses
When approximately 50% of the participants reached Week 16 or discontinued, an interim analysis 
(IA) for safety and efficacy will be performed to accelerate internal decision making. The safety 
analysis will focus on incidence and severity of AE, and SAE. The efficacy analysis will focus on 
percent change from baseline in EASI score and proportion of participants with ≥ 4 point 
improvement from baseline in Pruritus NRS at Week 16. The probability of treatment difference 
greater than certain value will be calculated using a Bayesian method. The interim analysis will be 
performed by individuals or vendor independent of the study team. The study team will remain 
blinded during interim analysis. The interim analysis results will be reviewed by an unblinded 
sponsor team to facilitate internal decision making related to the development of this asset. This 
unblinded sponsor team will not be involved in the study conduct.
The Statistical Analysis Plan will further describe the planned interim analyses.
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11
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59 BMS-986195: 6-month oral toxicity study in rats, with a 5-week recovery period (Study 
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AD
atopic dermatitis
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AEI
adverse event of interest
AF
atrial fibrillation
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
additional research
AST
aspartate aminotransferase
AT
aminotransferase
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
AV
atrioventricular
AZA
azathioprine
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BMS
Bristol Myers Squibb
bpm
beats per minute
BRA
Branebrutinib
BSA
body surface area
BTK
Bruton’s tyrosine kinase
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation
CFR
Code of Federal Regulations 
CHO
Chinese hamster ovary
CI
confidence interval
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Term
Definition
Cmax, CMAX
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CRF
Case Report Form, paper or electronic
CRP
C-reactive protein
CTCAE
Common Toxicity Criteria for Adverse Events
Ctrough
Trough observed plasma concentration
CXCL13
chemokine ligand 13,
CXR
chest X-ray
CYP
cytochrome p-450
DC
dendritic cell
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DLCO
Diffusion capacity of carbon monoxide
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EASI
Eczema Area and Severity Index
EC50
half maximal effective concentration
ECG
electrocardiogram
eCRF
electronic Case Report Form
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate 
EGFR
epidermal growth factor receptor
EHT
electronic health record
EMR
electronic medical record
EO
enzyme occupancy
EOS
end of study
EOT
end of treatment
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Term
Definition
ERK
extracellular signal-related kinase
FDA
Food and Drug Administration
FEV
forced expiratory volume
FIH
first in human
FITC
fluorescein isothiocyanate
FLG
filaggrin
FSH
follicle stimulating hormone
FTY-720
fingolimod
FTY-P
fingolimod phosphate
FVC
forced vital capacity
GALT
gut associated lymphoid tissue
GLP
good laboratory practice
GTP
guanosine triphosphate
H / hr
hour
HBsAg
hepatitis B surface antigen
HBcAb
hepatitis B core antibody
HCG
human chorionic gonadotrophin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s brochure
IC50
half maximal inhibitory concentration
IC
Immune complexes
ICF
Informed consent form
IDEC
inflammatory dendritic epidermal cell
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon
IGA
Investigators’ Global Assessment
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Term
Definition
IgA
Immunoglobulin A
IgE
immunoglobulin E
IgG
immunoglobulin G
IgM
immunoglobulin M
IGRA
interferon gamma release assay
IL
interleukins
ILC2
type 2 innate lymphoid cell
ILC
innate lymphoid cell
IMP
Investigational Medicinal Products
INF
infinity
INR
International Normalized Ratio
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-To-Treat
IU/L
International units per liter
IV
intravenous
JAK
Janus kinase
JCV
John Cunningham virus
KLH
keyhole limpet hemocyanin
LC
Langerhans cell
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
LFT
liver function test
LH
luteinizing hormone
LTBI
latent TB infection
MAD
multiple ascending dose
mg
milligram
min
minute
mL
milliliter
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Term
Definition
MMF
mycophenolate mofetil
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MS
multiple sclerosis
MTD
maximum tolerated dose
MTX
methotrexate
μg
microgram
N
number of subjects or observations
NA
not applicable
NCV
nerve conduction velocity
ng
nanogram
NOAEL
no-observed-adverse-effect-level
NRS
numerical rating scale
NSAID
nonsteroidal anti-inflammatory drug
NSVT
nonsustained ventricular tachycardia
NYHA
New York Heart Association
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OCT
optical coherence tomography
PA
posteroanterior
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PDE4
phosphodiesterase 4
PFT
pulmonary function test
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
P-gp
P-glycoprotein
PI
Principle investigator
PID
patient identification number
PK
pharmacokinetics
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Term
Definition
PML
progressive multifocal leukoencephalopathy
PO
taken orally
POEM
Patient Oriented Eczema Measure
PPE
personal protective equipment
PRES
posterior reversible encephalopathy syndrome
PVC
premature ventricular contraction
PT
prothrombin time
QD
once daily
QOL
quality of life
QRS
Quick-Reaction Spare
QTc
QT interval corrected for heart rate
RA
rheumatoid arthritis
RAST
radioallergosorbent test
RNA
ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction
SAD
single ascending doses
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SNP
Single nucleotide polymorphisms
SUSAR
Serious Adverse Reactions
S1P
sphingosine-1-phosphate 
S1P-1R
sphingosine-1-phosphate-1 receptor
TB
tuberculosis
TDAR
T-cell-dependent antibody response
TEAE
treatment-emergent adverse events
Th
helper T-cell
Th1
type 1 helper T-lymphocytes
Th2
type 2 helper T-lymphocytes
T-HALF
mean half-life
TK
toxicokinetics
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Term
Definition
Tmax
time to maximum concentration
TNF
tumor necrosis factor
Trm
Resident memory T-cell
TSLP
thymic stromal lymphopoietin
UA
urinalysis
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
UV
ultraviolet
VA
visual acuity testing
vIGA-AD
Validated Investigator Global Assessment scale for Atopic Dermatitis
VZV
Varicella Zoster virus 
W
week
WBC
white blood cell
WNOCBP
women not of childbearing potential
WOCBP
women of childbearing potential
XLA
X-linked agammaglobulinemia
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. Typically, the term “participant” is used in the protocol and the term 
“subject” is used in the Case Report Form (CRF).
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines, 
•
Applicable International Council on Harmonisation (ICH), Good Clinical Practice (GCP)
•
Applicable laws, regulations and requirements.
The study will be conducted in compliance with the protocol. The protocol and any 
revisions/amendments and the participant informed consent form (ICF) 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 the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the rights, physical safety or mental 
integrity of one or more participants; (2) the scientific value of the clinical trial (eg, reliability and
robustness of generated data). Items (1) or (2) can be associated with either GCP regulation(s) or 
trial protocol(s).
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, Investigator’s Brochure, product labeling information, ICF,
participant recruitment materials (eg, advertisements), and any other written information to be 
provided to participants. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, administrative letters)  annually, or more 
frequently, in accordance with regulatory requirements or institution procedures.
The investigator is responsible for providing oversight of the conduct of the study at the site and 
adherence to requirements of the following where applicable:
•
ICH guidelines, 
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•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
•
European Regulation 536/2014 for clinical studies (if applicable), 
•
European Medical Device Regulation 2017/745 for clinical device research (if applicable),
•
the IRB/IEC
•
and all other applicable local regulations.
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 the local health authority) except where necessary to eliminate an immediate 
hazard(s) to study participants. 
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:
•
IRB/IEC
•
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 the local health authority must be sent to Bristol-Myers 
Squibb (BMS).
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the ICF 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 participants 
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 participants prior to enrollment.
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with  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 participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
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The Sponsor or designee will provide the investigator with an appropriate  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.
The investigator or his/her representative must:
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Explain the nature of the study to the participant and answer all questions regarding the study.
•
Inform participant that his/her participation is voluntary. Participant will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/IEC or study center.
•
Allow time necessary for participant to inquire about the details of the study.
•
Obtain an ICF signed and personally dated by the participant and by the person who conducted 
the informed consent discussion. 
•
Include a statement in participant’s medical record that written informed consent was obtained 
before participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
•
Re-consent participant to the most current version of the ICF(s) during his/her participation in 
the study, as applicable.
Revise the ICF whenever important new information becomes available that is relevant to the 
participant's consent. The investigator, or a person designated by the investigator, should fully 
inform the participant of all pertinent aspects of the study and of any new information relevant to 
the participant’s willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participants’ signed 
ICF and, in the US, the participants’ signed HIPAA Authorization.
The ICF must also include a statement that BMS and regulatory authorities have direct access to 
participant records. 
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
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•
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
•
Definitions of what constitutes source data can be found in systems that may include, but are 
not limited to, electronic medical/health records (EMRs/EHTs), adverse event (AE) 
tracking/reporting, protocol required assessments, and/or drug accountability records).
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are handwritten 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 trial 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 records/electronic health 
records , adverse event (AE) tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of an 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 INTERVENTION RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study intervention 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:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
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 IP 
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment 
integrity in accordance with requirements applicable 
under 
law 
and 
the 
standard 
operating 
procedures/standards of the sourcing pharmacy.
BMS or its 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 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 (EDC) tool, eCRFs 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 electronic 
SAE form is not available, a paper SAE form can be used. 
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The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
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, 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 eCRFs, review and approval/signature is completed electronically through the BMS EDC
tool. The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing eCRFs must meet Sponsor or designee training 
requirements and must only access the BMS EDC tool using the unique user account provided by 
the 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. Monitoring details 
describing strategy, including definition of study critical data items and processes (eg, risk-based 
initiatives in operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities, and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan.
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 the 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 the 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 its 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.
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BMS or its 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 its designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, or 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 interventions 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).
Partially used study interventions and/or 
empty containers may be destroyed after 
proper reconciliation and documentation. But 
unused IMP must be reconciled by site 
monitor/Clinical Research Associate prior to 
destruction.
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 sites 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 of study interventions, 
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:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
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•
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.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, 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.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial 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 non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
STUDY AND SITE START AND CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
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in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR). 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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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 
pre-existing medical condition in a clinical investigation participant administered study 
treatment  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 treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, electrocardiograms, 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.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
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/serious adverse event (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
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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.
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SERIOUS ADVERSE EVENTS
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at 
any dose:
Results in death.
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which 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 Bristol-Myers Squibb (BMS) clinical 
studies: 
•
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).
•
Elective surgery, planned prior to signing consent.
•
Admissions as per protocol for a planned medical/surgical procedure.
•
Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy).
•
Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases.
•
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).
•
Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols).
Results in persistent or significant disability/incapacity.
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 participant or may require intervention [e.g., 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 
home for allergic bronchospasm and 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 9.2.7 for the definition of potential DILI.) 
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Pregnancy and DILI must follow the same transmission timing and processes to BMS as used for 
SAEs (see Section 9.2.5 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
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, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying 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.
•
The investigator will also consult the Investigator’s Brochure  and/or product information 
for marketed products, in his/her assessment.
•
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.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
•
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
•
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
•
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.
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An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
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 treatment 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 treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the electronic case report form 
(eCRF).
−
The paper SAE Report Form is  intended only as a back-up option when the electronic 
data capture  system is unavailable/not functioning for transmission of the eCRF) to BMS 
(or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on  paper Pregnancy Surveillance Forms and transmitted via 
email or confirmed facsimile transmission 
SAE Email Address: worldwide.safety@BMS.com.
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by local 
site monitor.
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Women of Childbearing 
Potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
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.
•
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. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels. 
•
1-week minimum for vaginal hormonal products (rings, creams, gels)
•
4-week minimum for transdermal products
•
8-week minimum for oral products
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.
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End of Relevant Systemic Exposure
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have 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  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
•
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 participants in studies where hormonal contraception is permitted by the study 
protocol)b 
−
Oral (birth control pills)
−
Intravaginal (rings)
−
Transdermal 
•
Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy
•
Progestogen-only hormonal contraception associated with inhibition of ovulation. (This 
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol.)b 
−
Oral 
−
Injectable 
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation. (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol.)b
•
Intrauterine device 
•
Intrauterine hormone-releasing system (IUS). (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol.) b,c
•
Bilateral tubal occlusion.
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•
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.
A vasectomy is a highly effective contraception method provided that the participant is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the 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.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participant chooses to forego complete abstinence.
•
Periodic abstinence (including but not limited to calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and 
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants 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. For information specific to this study regarding permissibility of 
hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 7.7.1 PROHIBITED AND/OR 
RESTRICTED TREATMENTS of the protocol.
c IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone 
exposures from intrauterine devices do not alter contraception effectiveness. For information specific to this 
study regarding permissibility of hormonal contraception, refer to Sections 6.1 INCLUSION CRITERIA and 
7.7.1 PROHIBITED AND/OR RESTRICTED TREATMENTS of the protocol.
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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.
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously.
•
Diaphragm with spermicide.
•
Cervical cap with spermicide.
•
Vaginal Sponge with spermicide.
•
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 
participants in studies where hormonal contraception is prohibited).
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, postovulation methods).
•
Withdrawal (coitus interruptus).
•
Spermicide only.
•
LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and Appendix 3.
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APPENDIX 5
DIAGNOSTIC CRITERIA FOR ATOPIC DERMATITIS
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APPENDIX 6
NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION 
OF CARDIOVASCULAR DISABILITY
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels, 9th ed, Little, Brown & Co, Boston 1994. 
p.253.
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APPENDIX 7
DSM-5 DIAGNOSTIC CRITERIA FOR SUBSTANCE USE 
DISORDER
DSM-5 diagnostic criteria for substance use disorder are described below:
A problematic pattern of use leading to clinically significant impairment or distress is manifested 
by two or more of the following within a 12-month period:
1. Often taken in larger amounts or over a longer period than was intended.
2. A persistent desire or unsuccessful efforts to cut down or control use.
3. A great deal of time is spent in activities necessary to obtain, use, or recover from the 
substance’s effects.
4. Craving or a strong desire or urge to use the substance.
5. Recurrent use resulting in a failure to fulfill major role obligations at work, school, or home.
6. Continued use despite having persistent or recurrent social or interpersonal problems caused 
or exacerbated by its effects.
7. Important social, occupational, or recreational activities are given up or reduced because of 
use.
8. Recurrent use in situations in which it is physically hazardous.
9. Continued use despite knowledge of having a persistent or recurrent physical or psychological 
problem that is likely to have been caused or exacerbated by the substance.
10. Tolerance.
11. Withdrawal.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013
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APPENDIX 8
VALIDATED INVESTIGATOR GLOBAL ASSESSMENT SCALE 
FOR ATOPIC DERMATITIS (VIGA-ADTM)
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Body Surface Area Estimate Work Sheet (Continued)
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APPENDIX 11
PRURITUS AND SLEEP QUALITY NUMERICAL RATING 
SCALES (NRS)
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APPENDIX 12
DERMATOLOGY LIFE QUALITY INDEX (DLQI)
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APPENDIX 13
PATIENT ORIENTED ECZEMA MEASURE (POEM)
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APPENDIX 14
PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C)
Compared to the beginning of the study, before you started the study treatment, which of the 
following best describes the skin symptoms of your atopic dermatitis today?
1
Much improved 
2
Moderately improved
3
A little improved
4
The same
5
A little worse
6 
Moderately worse
7 
Much worse
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APPENDIX 15
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S)
Which of the following best describes the severity of the skin symptoms of your atopic dermatitis 
over the past 7 days?
1
None 
2
Mild
3
Moderate 
4
Severe
5
Very Severe
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