Conditions: Ulcerative Colitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 131
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of oral deucravacitinib in participants with moderate to severe ulcerative colitis (UC).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BMS-986165 intervention 2: Placebo
Intervention descriptions: intervention 1: Specified Dose on Specified Days intervention 2: Specified Dose on Specified Days

Protocol document:
Prot_SAP_000.pdf: 
Protocol for 
 
Official Title of Study 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of the Safety and 
Efficacy of BMS-986165 in Subjects with Moderate to Severe Ulcerative Colitis 
NCT03934216 
April 14, 2021 


Page:
1
Protocol Number:
IM011024
Date; Version:
14-Apr-2021, Protocol Amendment 03
CLINICAL PROTOCOL IM011024
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of 
BMS-986165 in Subjects with Moderate to Severe Ulcerative Colitis
Short Title: Safety and Efficacy of BMS-986165 in Subjects with Moderate to Severe 
Ulcerative Colitis
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1328, Japan
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
2
REGULATORY AGENCY IDENTIFIER NUMBER(S)
EUDRACT Number: 2018-004694-27
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).
Approved
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
3
DOCUMENT HISTORY
Document
Date of Issue
Approver(s)
Summary of Changes
Protocol
Amendment 03
(Global Revised 
Protocol 12_v4.0) 
im011024-
protamend03
14-Apr-2021
•
Added information, instructions,
and measures to be taken related
to SARS-CoV-2 infection/
COVID-19, including the
following:
o
Amended exclusion
criterion 5)l
o
Added diagnostic test at
screening
•
Removed fasting requirement for
blood tests at screening
•
Amended wording of note from
Administrative Letter 1 regarding
consistent endoscopy procedures
•
Updated study endpoints and
endpoint definitions
•
Clarified that study data may be
used for additional analyses
related to UC and other
inflammatory diseases
•
Updated text in multiple sections 
of the protocol due to changes in
BMS protocol standards
Revised 
Protocol 02a
France-specific
(Revised Protocol 
11a)
im011024-
revprot02a-fr-
specific
22-Jun-2020
This country-specific revised protocol 
applies to all subjects enrolled in 
France. It encompasses the removal of 
the first bullet point of inclusion 
criterion 2)h) and modification 
of APPENDIX 5, which 
allowed subjects with only an 
inadequate response, loss of response, 
or intolerance to a standard course of 
oral 5-aminosalicylates (5-ASAs) to 
be included in the trial.
Administrative 
Letter 1
16-Jan-2020
Includes clarifications and minor 
typographical error corrections.
Amendment 10
v3.0
(Japan)
08-Jan-2020
This country-specific amendment 
applies to all subjects enrolled in 
Japan. 
Modifications include: 
•
Changes made in Global Revised
Protocol v3.0
•
Revisions based on the updated
Japan hepatitis guideline
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
4
Document
Date of Issue
Approver(s)
Summary of Changes
Revised Protocol 09
v3.0
(Germany)
19-Dec-2019
This country-specific revised protocol 
applies to all subjects enrolled in 
Germany. The purpose of this revised 
protocol is to incorporate the changes 
from Revised Protocol 06 (global 
version 3.0) into the Germany-
specific Revised Protocol 05 (global 
version 2.0). Additionally, a new 
exclusion criterion was added to 
Section 5.2 to exclude subjects with 
hereditary galactose intolerance, total 
lactase deficiency, or glucose-
galactose malabsorption.
Revised Protocol 08
v3.0
(Czech Republic)
19-Dec-2019
This country-specific revised protocol 
applies to all subjects enrolled in the 
Czech Republic. The purpose of this 
revised protocol is to incorporate the 
changes from Revised Protocol 06 
(global version 3.0) into the Czech 
Republic–specific Revised Protocol 
04 (global version 2.0).  
Revised Protocol 07
v3.0
(South Korea)
18-Dec-2019
This country-specific revised protocol 
applies to all subjects enrolled in 
South Korea. The purpose of this 
revised protocol is to incorporate the 
changes from Revised Protocol 06 
(global version 3.0) into the South 
Korea-specific Revised Protocol 03 
(global version 2.0). Additionally, 
new language regarding biopsy 
sampling was added to reflect South 
Korea–specific endoscopic 
procedures.
Global Revised 
Protocol 06
v3.0
28-Oct-2019
Includes the following modifications:
•
Add a 52-week open-label
extension period to provide the
option of additional treatment to
subjects deriving clinical benefit
at Week 52;
•
Modify the type and/or frequency
of various study assessments to
improve subject safety and
minimize subject burden; provide
additional detail for each of the
study periods, including clear
guidance for management of
Week 12 responders and
nonresponders in the
maintenance period and
additional hepatitis B Virus
(HBV) and hepatitis C Virus
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
5
Document
Date of Issue
Approver(s)
Summary of Changes
(HCV) screening and monitoring 
information;
•
Modify several inclusion and
exclusion criteria to increase
subject eligibility, and add
specific randomization criteria to
aid in final determination of
eligibility;
•
Incorporate several elements
from the South Korea and
Germany specific v2.0
amendments regarding age of
majority, and follow-up after
discontinuation and adverse
events;
•
Revise or clarify the definitions
of key study terms and endpoints;
•
Revise or clarify the following
study elements: prohibited and
restricted treatments; use and
tapering of corticosteroids during
all study periods; criteria defining
treatment failure; criteria leading
to discontinuation; and criteria
defining inadequate response,
loss of response, and intolerance
to previous biologic therapy;
•
Clarify sample size calculation
;
•
Remove or modify several
contraception requirements to
reflect recent toxicology data
consistent with these changes;
•
Implement other revisions
including modification of text
regarding safety reporting
requirements; and addition of
several new appendices to
evaluate UC disease activity
Amendment 05
(Germany)
v2.0
29-Aug-2019
This country-specific amendment 
applies to all subjects enrolled in 
Germany. Modifications include: 
•
Exclusion Criterion 7)a) has been
revised to exclude prisoners or
Approved
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
6
Document
Date of Issue
Approver(s)
Summary of Changes
subjects who are involuntarily 
incarcerated from trial 
participation. 
•
Section 7.1.1 (Post-Study
Treatment Follow-up) has been
revised to state that participants
who discontinue study treatment
will be followed for 28 days or
longer, as required, and in line
with Section 8.2.3.
•
Section 8.2.1 and APPENDIX 3
have been revised to state that
serious adverse events (AEs)
need to be reported
‘immediately’ to Sponsor or
designee but no later than 24
hours after awareness of the
event.
•
Section 8.2.5 (Pregnancy) has
been revised to state that study
drug treatment must be
discontinued immediately in case
of pregnancy and that the
pregnancy must be reported
within 24 hours of awareness of
the pregnancy.
•
APPENDIX 3 has been revised to
state that nonserious AEs that
cause interruption or
discontinuation of study
treatment must be followed to
resolution or stabilization.
Amendment 04
(Czech Republic)
v2.0
01-Aug-2019
This country-specific amendment 
applies to all subjects enrolled in the 
Czech Republic. The purpose of this 
Amendment is to adjust the maximum 
age of subjects from 80 to 70 years of 
age, and to align Section 8.2.5 
Pregnancy with local regulatory 
requirements for Czech Republic 
sites.
Amendment 03
(South Korea)
v2.0
31-Jul-2019
Adding “or age of majority” to 
inclusion criterion to align with local 
regulatory requirements for South 
Korean sites
Approved
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Protocol Amendment No.: 03
Date: 14-Apr-2021
BMS Confidential
7
Document
Date of Issue
Approver(s)
Summary of Changes
Amendment 02
(Japan)
v2.0
09-Apr-2019
This country-specific amendment 
applies to all subjects enrolled in 
Japan. The purpose of this 
Amendment is to incorporate local 
regulatory requirements for Japanese 
sites.
Global Revision 01
v2.0
26-Mar-2019
Includes modifications to the 
Schedule of Activities
 
added new 
Section 8.1.1 and language 
throughout protocol regarding central 
read versus local read of endoscopy; 
clarified corticosteroid use as a rescue 
medication; and added 
discontinuation criteria and study 
stopping rule
 
Original Global 
Protocol v1.0
17-Dec-2018
Not applicable
a Document naming conventions have been updated. Legacy 
numbering is provided for consistency.
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
OVERALL RATIONALE FOR GLOBAL PROTOCOL AMENDMENT 03
The primary purpose of this revised protocol is to include the following updates:
•
Addition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic
testing, as well as an exclusion criterion and study procedures pertaining to SARS-CoV-2
infection
•
Inclusion of coronavirus disease 2019 (COVID-19) benefit-risk information and vaccination
guidelines
•
Update to study endpoints prior to database lock for primary endpoint analysis
The revised protocol will be implemented after the Investigator receives all appropriate agency 
and IRB/EC approvals.
Generally, only major additions and deletions are provided in this summary of changes document, 
and all minor grammatical, formatting, rephrasing, stylistic changes, or clarifications, as well as 
organizational changes are not included. All changes applied to the protocol body were applied to 
the protocol synopsis, as necessary; synopsis changes are not included in the summary of key 
changes table. 
The rationale for the change to this Revised Protocol is provided in the summary of key changes 
table, as shown below:
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
2 Schedule of Activities, Tables 1-4
3.3 Benefit/Risk Assessment
6.2 Exclusion Criteria, 5) Immune and 
Infectious Disease Exclusion Criteria
7.7.1 Prohibited and/or Restricted 
Treatments
8.2.1 Temporary Discontinuation (new 
section)
9.8 SARS-CoV-2 Testing (new section)
Appendix 19 COVID-19 Vaccines 
(new appendix)
Added information, instructions, 
and measures to be taken related 
to SARS-CoV-2 infection/
COVID-19, including the 
following:
Amended exclusion criterion 5)l
Added diagnostic test at 
screening
 
Provides guidance to investigators 
related to SARS-CoV-2 
2 Schedule of Assessments, Table 1
Removed fasting requirement for 
blood tests at screening 
Reduces subject burden
Protocol Amendment No.: 03
Date: 14-Apr-2021
8
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
2 Schedule of Assessments, Tables 2-4
Amended wording of note from 
Administrative Letter 1
regarding consistent endoscopy 
procedures
Clarified aim of previously added 
text
4 Objectives and Endpoints, Tables 5-7
Updated study endpoints and 
endpoint definitions
Adds histologic and histologic-
endoscopic endpoints and 
definitions to reflect consensus 
guidelines on the measure of 
efficacy in UC. Due to the study’s 
small sample size we do not wish 
to add additional multiplicity-
controlled endpoints and therefore 
find histologic improvement as a 
better measure of efficacy than 
endoscopic remission
9 Study Assessments and Procedures
Clarified that study data may be 
used for additional analyses 
related to UC and other 
inflammatory diseases
Clarifies potential future analyses
Study Acknowledgment/Disclosure
6.5 Screen Failures
7.3.2 Circumstances for Unblinding
7.8 Treatment After the End of the 
Study
9.2.1 Time Period and Frequency for 
Collecting AE and SAE Information
9.2.5 Pregnancy
Appendix 2 Study Governance 
Considerations
Appendix 3 Adverse Events and 
Serious Adverse Events: Definitions 
and Procedures for Recording, 
Evaluating, Follow-up and Reporting
Appendix 4 Women of Childbearing 
Potential
Updated text in multiple sections 
of the protocol due to changes in 
BMS protocol standards
Reflects current BMS procedures, 
policies, and guidelines
Protocol Amendment No.: 03
Date: 14-Apr-2021
9
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v
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5.1.1 Screening Period ...................................................................................... 
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5.1.6 Treatment Failure .................................................................................... 
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of the Safety 
and Efficacy of BMS-986165 in Subjects with Moderate to Severe Ulcerative Colitis
Short Title: Safety and Efficacy of BMS-986165 in Subjects with Moderate to Severe Ulcerative 
Colitis
Study Phase: 2
Rationale: Study IM011024 is a Phase 2 randomized, double-blind study to assess the safety and 
efficacy of oral (PO) BMS-986165 6 mg twice daily (BID) in subjects with moderate to severe 
ulcerative colitis (UC). BMS 986165 will be compared to placebo to evaluate its effect on clinical 
remission of UC following 12 weeks of study treatment.
UC is a chronic inflammatory disease of the gastrointestinal tract that causes significant morbidity, 
impact on quality of life, and healthcare expenditures. Outcomes for patients with UC have 
improved significantly over the last several years due to better treatment strategies and the 
emergence of highly targeted biological therapies, yet significant therapeutic challenges still 
remain with this and other inflammatory bowel diseases (IBDs).
Tyrosine kinase 2 (TYK2) is an intracellular signaling kinase that mediates cytokine-driven 
immune and proinflammatory signaling pathways that are critical in the cycle of chronic 
inflammation central to a number of immune-mediated diseases. TYK2 inhibition selectively 
blocks interleukin (IL)-23, IL-12, and Type I interferon-driven responses but not cytokine 
responses mediated by other Janus kinases (JAK), such as IL-6, hematopoietic growth factors, and 
the IL-2 family. TYK2-dependent pathways and the cytokine networks they modulate have been 
implicated in the pathophysiology of multiple immune-mediated diseases, including UC, Crohn’s 
disease 
(CD), 
psoriasis, 
psoriatic 
arthritis, 
systemic 
lupus 
erythematosus, 
and 
spondyloarthropathies.
BMS-986165 is an orally administered selective TYK2 inhibitor with a unique mechanism of 
action distinct from other JAK inhibitors and has the potential to treat a wide spectrum of immune-
mediated diseases. Inhibition of TYK2 is expected to provide therapeutic benefit for patients with 
UC for multiple reasons: 1) IL-12 and IL-23 have been implicated in the pathogenesis of
UC; 2) Biologic agents targeting IL-23p19 and IL-12/IL-23p40 cytokines have been shown to be 
efficacious in UC and CD, and ustekinumab targeting IL-12/IL-23p40 has been approved for the 
treatment of CD and UC; and 3) BMS-986165 has been shown to be efficacious in psoriasis, an 
IL-23-mediated disease, in a recent Phase 2 study.
Study Population: Key inclusion criteria (Section 6.1) include:
•
Male and female subjects, 18 years (or age of majority) to 80 years of age, inclusive, at the
time of screening
•
Documented diagnosis (endoscopic and histological) of UC of at least 3 months’ duration prior
to screening
Protocol Amendment No.: 03
Date: 14-Apr-2021
14
Approved
1.0
v
Approved
1.0
v


Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
•
Active moderate to severe UC, defined by a modified Mayo score of 5 to 9 points, inclusive 
(modified Mayo score range = 0 to 9 points), which includes all of the following subscore 
values:
o
A stool frequency (SF) subscore of ≥ 2, and
o
A rectal bleeding (RB) subscore ≥ 1, and
o
An endoscopic (ES) subscore of ≥ 2 (screening endoscopy)
•
Active UC extending ≥15 cm from the anal verge and confirmed by a screening/baseline 
colonoscopy/sigmoidoscopy prior to the randomization visit
•
Documentation of an inadequate response, loss of response, or intolerance to a treatment course 
of 1 or more of the following standard of care medications; specific criteria and dosing details 
are in APPENDIX 5:
•
Oral 5-aminosalicylic acids (5-ASAs) (eg, mesalamine, sulfasalazine, olsalazine, or 
balsalazide)
•
Corticosteroids (eg, prednisone [or equivalent] or budesonide [or equivalent])
•
Immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or 
methotrexate [MTX])
•
Anti-tumor necrosis factor-alpha (TNF-α) agents (eg, infliximab, adalimumab, or 
golimumab)
•
Integrin inhibitors (eg, vedolizumab)
•
Anti-IL-12/IL-23p40 antibodies (eg, ustekinumab); subjects can only be included if 
they were intolerant to treatment. Inadequate response or loss of response is 
exclusionary.
Key exclusion criteria (Section 6.2) are as follows:
•
Previous/current documented diagnosis of CD, indeterminate colitis, ischemic colitis, or 
pseudomembranous colitis (other than associated with Clostridium difficile [C. difficile])
•
Stool positive for C. difficile toxin at screening visit; subjects may be rescreened 30 days after 
completion of an institutional standard of care course with antibiotics, and subsequent negative 
testing for C. difficile stool toxin and a C. difficile nucleic acid amplification test
•
Current or recent (within 12 weeks prior to the randomization visit) evidence of fulminant 
colitis, abdominal abscess, toxic megacolon, or bowel perforation
•
History or evidence of any extensive colonic resection, subtotal or total colectomy, with or 
without presence of a stoma or ileoanal pouch. Current need for, or anticipated need for, 
surgical intervention for UC during the study
•
History of diverticulitis within 60 days prior to the randomization visit. (Previous diverticulitis 
that has been successfully treated with a local standard course of antimicrobial therapy is 
permitted; however, the course of antimicrobial therapy must be completed at least 60 days 
prior to the randomization visit.)
•
Current colonic adenomas, dysplasia, or past confirmed colonic dysplasia that has not been 
eradicated (subjects who have had UC > 8 years should have had a colonoscopy to screen for 
dysplasia within 1 year prior to the randomization visit, or this can be performed as part of 
screening colonoscopy). A subject with prior history of adenomatous polyps will be eligible if 
Protocol Amendment No.: 03
Date: 14-Apr-2021
15
Approved
1.0
v
Approved
1.0
v


Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
the polyps have been completely removed (documented), and the subject is free of polyps and 
without evidence of dysplasia on histology at randomization. 
•
Prior exposure to treatment with TYK2 inhibitors
•
Inadequate response or loss of response to medications that target the same pathway as 
BMS-986165, such as anti-IL-12/IL-23p40 antibodies (eg, ustekinumab, briakinumab) or 
anti-IL-23p19 antibodies (eg, guselkumab, risankizumab, tildrakizumab, brazikumab 
[MEDI2070], and mirikizumab [LY3074828]). 
o
Subjects who have been exposed to the medications listed above, but who have not had a 
treatment failure (ie, an inadequate response or loss of response) may be eligible for 
inclusion. 
o
Subjects who have experienced intolerance to the medications listed above (eg, an infusion 
reaction) without a treatment failure may be eligible for inclusion.
•
Failure or loss of response to JAK inhibitors, such as tofacitinib. Prior exposure is not 
exclusionary.
•
Use of other investigational agents within 4 weeks or 5 half-lives, whichever is longer, prior 
to randomization
•
Use of immunomodulators (AZA, 6-MP, or MTX) within 4 weeks prior to randomization
•
Use of a biologic agent within the minimum washout period prior to randomization 
(APPENDIX 7)
o
Fecal transplant is considered an "investigational” biologic agent and the washout period 
must be ≥4 weeks prior to randomization
•
Use of topical rectal treatment with 5-ASA or corticosteroid within 2 weeks prior to 
randomization
•
Current use of corticosteroid at a dose of > 20 mg/day for prednisone (or equivalent) or 
> 9 mg/day for budesonide (Multi-Matrix System [MMX®] colonic-release technology; eg, 
Uceris® or equivalent)
Protocol Amendment No.: 03
Date: 14-Apr-2021
16
Approved
1.0
v
Approved
1.0
v


Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Objectives and Endpoints:
Efficacy (primary and secondary) and safety objectives and endpoints (Section 4) are summarized
below:
Objectives
Endpoints
Efficacy
Primary
•
To assess the effect of BMS-986165 on 
clinical remission at the end of the 
induction period
•
Clinical 
remission 
(modified 
Mayo 
scorea)b at Week 12 
Secondary
•
To assess the effect of BMS-986165 on 
clinical response at the end of the induction 
period
•
Clinical responsec at Week 12 
•
To assess the effect of BMS-986165 on 
endoscopic response at the end of the 
induction period
•
Endoscopic responsed at Week 12 
•
To assess the effect of BMS-986165 on 
histologic improvement at the end of the 
induction period
•
Histologic improvemente at Week 12 
Safety
•
To assess the safety and tolerability of 
BMS-986165 in subjects with moderate to 
severe UC 
•
Number and proportion of subjects 
experiencing AEs, SAEs, AEs leading to 
study discontinuation, and AEs of interest 
(AEIs)
•
Number and proportion of subjects 
experiencing abnormalities in laboratory 
testing, ECG, physical examination, and 
vital sign parameters over time
AE = adverse event; AEI = adverse event of interest; ECG = electrocardiogram; SAE = serious adverse event; 
UC = ulcerative colitis
a Modified Mayo Score (0 to 9 points) is the sum of 3 components: stool frequency (SF) (0 to 3), rectal bleeding
(RB) (0 to 3), and endoscopic (ES) (0 to 3) subscores.
b Clinical remission is defined as: Mayo SF subscore ≤1, with ≥1-point decrease from baseline, and Mayo RB
subscore = 0, and Mayo ES subscore ≤1 (obtained from centrally read endoscopy; modified, excludes friability).
c Clinical response is defined as: A decrease from baseline in the modified Mayo score of ≥2 points, and a decrease 
from baseline in the modified Mayo score ≥30%, and a decrease in Mayo RB subscore of ≥1 point or absolute 
RB subscore ≤1.
d Endoscopic response is defined as: Mayo ES subscore ≤1 (obtained from centrally read endoscopy)
e Histologic improvement is defined as: Geboes score ≤3.1
Protocol Amendment No.: 03
Date: 14-Apr-2021
17
Approved
1.0
v
Approved
1.0
v


Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Overall Design:
•
Study design: Parallel, placebo controlled, multicenter, proof of concept
•
Blinding: Double-blind, matching placebo oral tablets
•
Treatment assignment method/stratification: 
o
Subjects who have completed screening procedures (up to 28 days duration) and met 
inclusion/exclusion criteria will be randomized on Week 0 (Day 1) of the induction period.
o
Subjects will be randomized in a 2:1 ratio using interactive response technology (IRT) to 
receive oral BMS-986165 6 mg BID or placebo BID during the induction period of 
12 weeks.
o
Randomization will be stratified based on corticosteroid use (yes/no) and prior exposure to 
biologics indicated for the treatment of UC (ie, no prior exposure, exposure to 1 biologic, 
or exposure to > 1 biologic). JAK inhibitors are considered as a biologic for stratification 
purposes. (Note: Failure or loss of response to JAK inhibitors is exclusionary, but prior 
exposure is not exclusionary.)
•
Study periods: 
o
Screening: up to 4 weeks (28 days)
o
Induction: 12 weeks (84 days)
o
Maintenance: 40 weeks (280 days)
o
Open-label extension: 52 weeks (364 days)
o
Post-treatment follow-up: 4 weeks (28 days) 
•
Study assessments:
o
Endoscopic (colonoscopy/sigmoidoscopy) evaluations and collection of colonic tissue 
biopsies will be performed during the screening period, at the end of the induction period 
(Week 12), at the end of the maintenance period (Week 52), and at the end of the open-
label extension period (Week 104). Endoscopy should also be performed at unscheduled 
visits (if clinically indicated). Endoscopy is required at early termination (ET) visits that 
occur between Week 4 and Week 12. Endoscopy is recommended for ET visits occurring 
from Week 16 through Week 52 and Week 56 through Week 104. Endoscopic procedures
will be video recorded and scored for disease activity by a blinded central reader. 
Histologic scoring of gastrointestinal tissue specimens will also be performed by a blinded 
central reader. 
o
At Week 12, local assessment of the endoscopy will be utilized to derive the ES subscore 
of the modified Mayo score used for determination of treatment assignment during the 
maintenance period. The central read of the endoscopy will be used for efficacy analysis 
at all time points (Section 2 and APPENDIX 9).
o
Electronic diaries will be maintained by subjects throughout the study to collect daily stool 
frequency and rectal bleeding data; this will enable Mayo score calculations used in the 
determination of the primary and secondary efficacy endpoints (APPENDIX 9).
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o
Assessment of adverse events (AEs), physical examinations, vital sign measurements, 
12-lead electrocardiogram (ECG), and clinical laboratory evaluations will be performed at 
selected times throughout the study (Section 2). 
o
Disease worsening will be assessed at each visit during the maintenance period using SF
and RB subscores as defined in Table 5.
•
Corticosteroid use and tapering:
o
Induction period: Prednisone or colonic-release budesonide are allowed, provided the dose 
is stable for 2 weeks prior to randomization, and thereafter stable during the induction 
period. Corticosteroid tapering is not allowed during the induction period.
o
Maintenance period: Subjects receiving corticosteroids during the induction period must 
initiate a corticosteroid taper. This is described in Section 5.1.5 for different treatment 
arms.
•
Treatment failure: Subjects who require corticosteroid rescue therapy due to increased UC 
activity, fail to taper corticosteroids, or require an alternative, efficacious therapy for UC will 
be defined as a treatment failure (Section 5.1.6). 
•
Discontinuation from the study: Subjects who discontinue study treatment will remain in the 
study and are required to continue to be followed for protocol-specified post-treatment follow-
up procedures. The only exception to this is when a subject specifically withdraws consent for 
any further contact with him/her or persons previously authorized by the subject to provide 
this information.
•
An independent Data Monitoring Committee (DMC) will be instituted to perform safety 
monitoring by unblinded treatment group (Section 5.1.7).
Number of Subjects: Approximately 120 subjects are planned to be randomized in a 2:1 ratio to 
receive BMS-986165 6 mg BID (80 subjects) or placebo (40 subjects) during the induction period 
of 12 weeks.
Treatment Arms and Duration: 
Induction Period: On Week 0 (Day 1) of the 12-week, double-blind induction period, subjects will 
be randomized to receive 1 of the following study treatments:
•
BMS-986165 6 mg BID
•
Placebo
Maintenance Period: At Week 12, all subjects who complete the induction period will be eligible 
to enter the 40-week maintenance period; the treatment assignment will be based on their clinical 
response (assessed using the modified Mayo score with a locally read endoscopy). 
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Subjects who achieve clinical response at Week 12 will be categorized as a responder at Week 12, 
and they will enter 1 of the following study treatment arms:
•
Responders at Week 12 continuing blinded treatment:
o
BMS-986165 6 mg BID → BMS-986165 6 mg BID
o
Placebo → Placebo
Subjects who do not achieve clinical response at Week 12 will be categorized as a nonresponder 
at Week 12, and they will enter 1 of the following study treatment arms (or they will be 
discontinued from the study per investigator discretion):
•
Nonresponders at Week 12 continuing open-label treatment:
o
BMS-986165 6 mg BID → BMS-986165 6 mg BID
o
Placebo → BMS-986165 6 mg BID
Open-label Extension Period: After Week 52, subjects who continue to safely derive clinical 
benefit (as judged by the investigator) and receive open-label treatment during the 52-week, 
open-label extension period of the study will enter 1 of the following study treatment arms: 
•
Responders at Week 12, clinical benefit at Week 52 continuing open-label treatment:
o
BMS-986165 6 mg BID → BMS-986165 6 mg BID→ BMS-986165 6 mg BID
o
Placebo → Placebo→ BMS-986165 6 mg BID
•
Nonresponders at Week 12, clinical benefit at Week 52 continuing open-label treatment:
o
BMS-986165 6 mg BID → BMS-986165 6 mg BID→ BMS-986165 6 mg BID
o
Placebo → BMS-986165 6 mg BID → BMS-986165 6 mg BID
The total duration of study participation is approximately 112 weeks (784 days) in 5 periods.
Study Treatment:
Study Treatment for IM011024
Study Treatment
Potency/Dose
Blinded or 
Open label
IP/Non-IP
BMS-986165 oral tablet
6 mg
Blinded
IP
Placebo matching BMS-986165 oral 
tablet
Not applicable
Blinded
IP
BMS-986165 oral tablet
6 mg
Open-label
IP
IP = investigational product
Statistical Methods: Approximately 120 subjects will be randomized in a 2:1 ratio to 
BMS-986165 6 mg BID or placebo, respectively (80 subjects on BMS-986165 and 40 on placebo). 
In this proof of concept study, if the observed response rates are the same as the assumed rates 
reported in current UC investigative trials, the total number of 120 subjects will provide 
approximately 82% power to detect a 15% treatment difference in clinical remission at Week 12 
with a 1-sided 0.1 level of significance.
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Categorical data will be summarized as frequency counts and percentages. Continuous data will 
be summarized using n, mean, standard deviation, median, minimum, and maximum, unless 
otherwise specified.
Efficacy data will be summarized using the full analysis set population, unless otherwise stated, 
and listed by study period and treatment group.
The primary efficacy analysis model for clinical remission (responder/nonresponder) will be 
analyzed at Week 12 using a stratified Cochran-Mantel-Haenszel test stratified by corticosteroid 
use (yes/no) and prior exposure to biologics (0, 1, > 1). JAK inhibitors are considered as a biologic 
for stratification purposes. If expected cell counts are not sufficient for each strata level, then strata 
levels will be combined for analysis. The assessment of statistical significance will be based upon 
a 1-sided, 0.1 alpha, which is in alignment with the sample size calculation. The odds ratio and 
corresponding 2-sided 95% confidence interval (CI) will be provided for descriptive purposes.
Supportive analyses using logistic regression may be performed to incorporate additional 
covariates of interest and to confirm primary analysis results. The model will include treatment, 
geographic region, corticosteroid use (yes/no), prior exposure to biologics (0, 1, > 1), as well as 
other covariates as applicable. The odds ratio and the corresponding 2-sided 95% CI will also be 
provided.
Statistical analysis of the secondary endpoints will use the same approach as the primary endpoint 
analysis with missing data being imputed as nonresponders. Testing strategy of secondary 
endpoints will be performed in a hierarchical fashion to control for Type I error rate inflation. The 
statistical testing of the primary endpoint will be the serial gatekeeper for proceeding to the testing 
of the secondary endpoints. Each secondary endpoint will be tested sequentially in a 
fixed-sequence order using a 1-sided alpha = 0.1 for significance testing. No further testing will 
be performed once a test fails to show significance at the alpha level stated above.
Safety endpoint analyses will be descriptive in nature.
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1.2
Schema
The study design schematic for the induction and maintenance periods is presented below:
BID = twice daily; OL = open-label; OLE = open-label extension; R = randomization
At Week 12, clinical response is determined using the modified Mayo score (see Table 5 and Section 9.1.1). Subjects who achieve clinical response at Week 12 
and continue into the maintenance period will continue to receive their double-blind treatment from the induction period. Subjects who subsequently experience 
disease worsening (Table 5) can enter the Week 12 responder open-label arm at any time from Week 13 through Week 52. 
Subjects who do not achieve clinical response at Week 12 are eligible to enter the Week 12 nonresponder open-label arm. 
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The study design schematic for the open-label extension period is presented below:
BID = twice daily; IP = investigational product; OL = open-label
a Subjects in this arm are those who achieved clinical response at Week 12 of the induction period, but they subsequently lost clinical response to IP between 
Week 13 and Week 52 of the maintenance period and switched to the Week 12 responder open-label arm (Section 5.1.3.2). 
b Subjects in this arm are those who did not achieve clinical response at Week 12 of the induction period and switched to the Week 12 nonresponder open-label 
arm.
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2
SCHEDULE OF ACTIVITIES 
The schedules of procedures are described in Table 1 for the screening period, Table 2 for the 
induction period, Table 3 for the maintenance period, and Table 4 for the open-label extension
period.
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2.1
Screening Period Activities and Assessments
Table 1
Screening Procedural Outline (IM011024)
Procedure
Screening
Visit 
Day -28 to -1
Notes
Eligibility and Disease 
Assessments
Informed Consent
X
A subject will be considered enrolled only when the ICF is signed.
Enroll subject
X
Obtain number from IRT; contact IRT to screen fail those not eligible.
Inclusion/Exclusion criteria 
X
Section 6
Medical history
X
Include any toxicities or allergy related to previous treatments.
Ulcerative colitis (UC) disease 
history
X
Dispense electronic subject diary
X
Subject diary training
X
Includes training for entry of stool frequency (SF) and rectal bleeding (RB) assessments into the 
electronic subject diary. Instructions for recording the number of stools and worst rectal bleeding (each 
over a 24-hour period) are in Table 26 (APPENDIX 9). 
Baseline SF 
X
Establish the baseline SF. This is determined based on the number of stools a subject has in a 24-hour 
period when in remission from UC symptoms; or if a subject has not been in remission, he/she should 
be asked to identify the number of stools he/she had in a 24-hour period before initial onset of signs and 
symptoms of UC (APPENDIX 9).
Enter SF and RB subscores for 
baseline Mayo score calculations
X
SF and RB subscores are calculated using the electronic subject diary and entered into the eCRF 
(APPENDIX 9). 
Endoscopy 
(colonoscopy/sigmoidoscopy)
X
Colonoscopy/sigmoidoscopy examination must be performed within Day - 21 and Day - 1 of the 
screening period and should be scheduled as close as possible to the Week 0 (Day 1) visit. 
The Week 0 (Day 1) visit must occur within 14 days of the screening endoscopy. 
Instructions for review of SF and RB diary entries to assess if a subject is likely to meet inclusion 
criteria and should continue screening prior to commencing bowel preparation for the endoscopy are in 
APPENDIX 9.
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Table 1
Screening Procedural Outline (IM011024)
Procedure
Screening
Visit 
Day -28 to -1
Notes
At the screening endoscopy, collection of colonic tissue biopsies will be performed as described in the 
rows below. Full colonoscopy will be required in these situations:
•
If normal margins are not apparent from sigmoidoscopy or if proximal colonic involvement is 
suspected
•
In subjects with a history of UC ≥8 years, if one was not performed in the prior 12 months
Colon histology
 
X
Two biopsy samples will be obtained from each of the 4 colonic segments (rectum, descending 
colon/sigmoid, transverse colon, ascending colon) if colonoscopy is performed or from each of the 
2 segments (rectum, descending colon/sigmoid) if sigmoidoscopy is performed for the histologic 
assessments (Section 9.1) 
 
. 
 
Baseline modified Mayo score 
calculation
X
The modified Mayo score is used to determine subject eligibility. A score of 5 to 9 points, inclusive, is 
required at screening, and it must include all of the following subscores:
•
A stool frequency (SF) subscore of ≥ 2 and
•
A rectal bleeding (RB) subscore of ≥ 1, and  
•
A screening endoscopic (ES) subscore (central read) of ≥2
Instructions for calculating the modified Mayo score for eligibility are provided in APPENDIX 9. 
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Table 1
Screening Procedural Outline (IM011024)
Procedure
Screening
Visit 
Day -28 to -1
Notes
Confirm washout of prohibited 
medication and dose stabilization 
of allowed medication (if 
applicable)
X
Prohibited medications are described in Section 7.7.1. Washout periods for specific immunomodulatory 
and biologic agents required before a participant can be randomized are in APPENDIX 7; the use of 
therapeutic drug monitoring (TDM) to confirm washout is also described in APPENDIX 7.
Note: The washout periods shown in APPENDIX 7 may be longer than the 4-week screening period. 
This needs to be considered at enrollment. Prednisone dose stabilization requirements are described in 
Section 5.1.5.1. The dose equivalents to prednisone of commonly used corticosteroids are provided in 
APPENDIX 6.
Tobacco use history
X
Prior and current concomitant 
medications
X
Section 7.7
Safety Assessments
Physical examination
X
General, head, eyes, ears, nose, throat, neck, cardiovascular, lungs, abdominal, extremities, neurologic, 
skin, musculoskeletal. If the screening physical examination is performed within 7 days prior to dosing 
on Week 0 (Day 1), then a single exam may count as both the screening and predose evaluation.
Physical measurements
X
Height and weight
Vital signs
X
Body temperature, respiratory rate, and seated blood pressure, and heart rate. Blood pressure and heart 
rate should be measured after the subject has been resting quietly for at least 5 minutes. 
Electrocardiogram
X
Single 12-lead ECG reading recorded after the subject has been supine for at least 5 minutes 
Chest x-ray
X
Also acceptable within 6 months of the screening visit with documentation on file
Diagnostic testing for 
SARS-CoV-2
X
To be performed locally, as close as possible to randomization. Diagnostic testing for SARS-CoV-2 
infection refers to a molecular test (eg, PCR or NAAT) or antigen test. PCR testing is preferred 
(Section 9.8).
Monitor for SAEs or nonserious 
AEs
X
SAE reporting begins at the time of signing of the ICF; nonserious AEs are collected starting with the 
initiation of study treatment (Section 9.2 and APPENDIX 3). 
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Table 1
Screening Procedural Outline (IM011024)
Procedure
Screening
Visit 
Day -28 to -1
Notes
However, all AEs related to SARS-CoV-2 infection should be collected from time of signing the ICF.
Breast and cervical cancer 
screening 
X
Investigators are encouraged to confirm if screening is up-to-date according to local guidelines (women 
only). Screening for cervical and breast cancer prior to randomization is encouraged as per local 
guidelines due to the small inherent risk of increased malignancy with immunomodulatory agents, but 
this screening is at the investigator’s discretion.
Laboratory Tests
Hematology, chemistry, 
urinalysis, and coagulation 
X
Blood and urine samples (must be repeated and verified to ensure that subjects meet study inclusion 
criteria and no exclusion criteria if performed more than 28 days prior to randomization) (Section 
9.4.3).
Serology
X
Hepatitis B Virus (HBV): HBsAg, HBsAb, HBcAb with reflex to HBV DNA in subjects with HBsAg 
negative, HBcAb positive serology. (APPENDIX 8) 
Hepatitis C Virus (HCV): Anti-HCV; if positive or indeterminate, HCV RNA testing will be performed 
using a separate blood draw (APPENDIX 8). 
Human Immunodeficiency Virus (HIV): HIV-1 and -2 antibody (Section 6.2); HIV-1 and -2 serology 
may be performed centrally, or locally in regions where central laboratory testing for HIV is not 
available.
Tuberculosis screening
X
In accordance with standard testing (details are provided in Section 6.2 and 9.4.2)
Pregnancy test (urine or serum)
X
WOCBP only (APPENDIX 4). If the urine pregnancy test is positive, a serum pregnancy test should be 
done for confirmation prior to enrolling the subject. Study treatment should not be administered until 
the results of the confirmatory test are known.
Follicle-stimulating hormone 
(FSH)
X
Postmenopausal women only to confirm status (APPENDIX 4)
Stool culture (performed locally)
X
If a subject is positive for enteric pathogens (not including flora that are considered commensal within a 
study region), he/she can be rescreened 30 days after completing a full course of standard treatment for 
bacterial enterocolitis and being deemed clinically improved by the investigator. 
Stool C. difficile toxin 
(performed centrally)
X
If a subject is positive for C. difficile toxin, he/she can be rescreened as described in Section 6.5.1.
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IM011024
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Table 1
Screening Procedural Outline (IM011024)
Procedure
Screening
Visit 
Day -28 to -1
Notes
Therapeutic drug monitoring 
(TDM)
X
Optional test for subjects who recently received infliximab, adalimumab, golimumab, vedolizumab 
(> 14 weeks treatment duration), or ustekinumab (> 12 weeks treatment duration) and are subject to a 
washout period for those medications (APPENDIX 7). This washout period will be waived for subjects 
who have an undetectable drug level for that specific medication on TDM testing at screening or prior 
to screening.
AE = adverse event; anti-HCV = hepatitis C virus antibody; C. difficile = Clostridium difficile; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
eCRF = electronic case report form; ES = endoscopic; FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HIV-1 and -2 = human immunodeficiency virus -1 and -2; ICF = informed consent form; 
 IRT = interactive response technology; NAAT = nucleic acid amplification test; PCR = polymerase chain reaction; RB = rectal 
bleeding; RNA = ribonucleic acid; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SF = stool frequency; TDM = 
therapeutic drug monitoring; UC = ulcerative colitis; WOCBP = women of childbearing potential
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2.1.1
Induction Period Activities and Assessments
Table 2
Induction Period On-treatment Procedural Outline Up to Week 12 (Day 85) (IM011024)
Procedure/Visit Weeks (Days)
0 
(1) a
2
(15)
4 
(29)
8 
(57)
12 
(85)
Notes
Visit window (± n days)
0
3
3
3
3
Study Treatment
Eligibility/randomization criteria
X
Confirm eligibility criteria (Section 6.1and Section 6.2) and assess 
randomization criteria (Section 6.3). All procedures to be completed 
before dosing unless otherwise specified.
Dispense clinical drug supplies 
(blinded)
X
X
X
X
Subjects are to receive blinded IP twice daily PO (Section 5.1.2). 
See Section 5.1.3.1 and 5.1.3.2 regarding IP based on clinical response 
at Week 12.
Study treatment (blinded)
X-----------------------------------------------X
Review study drug compliance
X
X
X
X
Section 7.6
Safety Assessments
Physical examination
X
Xb
General, head, eyes, ears, nose, throat, neck, cardiovascular, lungs, 
abdominal, extremities, neurologic, skin, musculoskeletal. 
Physical measurement
X
Xb
Weight only
Vital signs
X
X
X
X
Xb
See Note in the screening period procedures (Table 1).
Electrocardiogram
Xb
Single 12-lead ECG should be recorded after the subject has been 
supine for at least 5 minutes.
Concomitant medication use
X
X
X
X
X
Section 7.7
Tobacco use
X
X
X
X
X
Monitor AEs
X
X
X
X
X
Monitoring for AEs will occur at every study visit (Section 9.2). 
Monitor SAEs
X
X
X
X
X
Monitoring for SAEs will occur at every study visit (Section 9.2). All 
SAEs will be followed until resolution, until the condition stabilizes, 
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Table 2
Induction Period On-treatment Procedural Outline Up to Week 12 (Day 85) (IM011024)
Procedure/Visit Weeks (Days)
0 
(1) a
2
(15)
4 
(29)
8 
(57)
12 
(85)
Notes
until the event is otherwise explained, or until the subject is lost to 
follow-up (Section 8.3). 
Laboratory Tests
Hematology, chemistry, 
urinalysis, and coagulation
X
X
X
X
Xb
HBV DNA
X
X
Xb
To be performed only in subjects with the following HBV serology at 
screening: HBsAg negative, HBcAb positive, HBV DNA undetectable 
(APPENDIX 8)
Serum Igs
X
X
Xb
IgG, IgM, IgA, and IgE
TBNK panel
X
X
Xb
Serum hsCRP 
X
X
X
X
Xb
Fasting lipid panel
X
Xb
Subjects are required to fast for ≥10 hours prior to the collection of 
specimens for the fasting lipid panel.
Fasting glucose
X
Xb
Subjects are required to fast for ≥10 hours prior to the collection of 
specimens for the fasting glucose evaluation.
Pregnancy test (urine or serum)
X
X
X
X
X
WOCBP only (APPENDIX 4). If the urine pregnancy test is positive, a 
serum pregnancy test should be done for confirmation prior to 
discontinuing the subject. Study treatment should not be administered 
until the results of the confirmatory test are known. 
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Table 2
Induction Period On-treatment Procedural Outline Up to Week 12 (Day 85) (IM011024)
Procedure/Visit Weeks (Days)
0 
(1) a
2
(15)
4 
(29)
8 
(57)
12 
(85)
Notes
Efficacy Assessments
Review subject diary for SF and 
RB values
X
X
X
X
X
Prior to each scheduled visit, review subject diary to ensure SF and RB 
data have been entered daily. 
Prior to each scheduled visit at which Mayo scores are to be calculated, 
ascertain whether an adequate number of days of diary entries have 
been made (APPENDIX 9). If adequate entries have not been made, the 
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Table 2
Induction Period On-treatment Procedural Outline Up to Week 12 (Day 85) (IM011024)
Procedure/Visit Weeks (Days)
0 
(1) a
2
(15)
4 
(29)
8 
(57)
12 
(85)
Notes
site should contact the subject to reschedule the visit, and the subject 
should be counseled about proper study procedures. 
Enter SF and RB subscores for 
Mayo score calculation 
X
APPENDIX 9
Endoscopy 
(colonoscopy/sigmoidoscopy) 
X
After bowel preparation, endoscopic examination will be performed 
within a 7-day window prior to the Week 12 (Day 85) visit.
Endoscopy is required at ET visits that occur between Week 4 and 
Week 12.
If colonoscopy is conducted at screening assessment, every effort 
should be made to ensure colonoscopy is done at subsequent 
assessment. Screening and surveillance as per local guidelines may be 
completed during study related colonoscopy.
Colon histology
 
X
Two biopsy samples will be obtained from each of the 4 colonic 
segments (rectum, descending colon/sigmoid, transverse colon, 
ascending colon ) if colonoscopy is performed or from each of the 
2 segments (rectum, descending colon/sigmoid) if sigmoidoscopy is 
performed for the histologic assessments (Section 9.1) 
 
.
Efficacy/Mayo Scoring
Modified Mayo score
X
Composite score of ES (central read), SF, and RB subscores. SF and 
RB subscores will be calculated using electronic subject diary data. 
See Section 9.1 and APPENDIX 9.
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Table 2
Induction Period On-treatment Procedural Outline Up to Week 12 (Day 85) (IM011024)
Procedure/Visit Weeks (Days)
0 
(1) a
2
(15)
4 
(29)
8 
(57)
12 
(85)
Notes
a Week 0/Day 1/Randomization Visit
b This assessment can be performed at either the Week 12 endoscopy visit or the Week 12 visit. NOTE: All other assessments are to be performed only at the 
Week 12 visit, except for the endoscopy and related procedures, which are to be performed within a 7-day window prior to the Week 12 (Day 85) visit.
AE = adverse event; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
 ES = endoscopic; ET = early 
termination; HBcAb = hepatitis B virus core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; hsCRP = high-sensitivity C-reactive protein; 
IBD = inflammatory bowel disease; 
 Ig = immunoglobulin; IgA = immunoglobulin A; IgE = immunoglobulin 
E; IgG = immunoglobulin G; IgM = immunoglobulin mu; 
 IP = investigational product; 
 
 PO = oral; 
 RB = rectal bleeding; 
 SAE = serious adverse event; 
 
 SF = stool frequency; TBNK = T cells, B cells, and natural killer cells; UC = ulcerative colitis; WOCBP = women of 
childbearing potential; 
In the event multiple procedures are required at a single time point, the ECG may be obtained up to 20 minutes earlier, vital signs may 
be obtained up to 20 minutes earlier or later, and clinical laboratory sample may be obtained up to 10 minutes earlier than the nominal 
time poin
.
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
2.1.2
Maintenance Period Activities and Assessments
Table 3
Maintenance Period On-treatment Procedural Outline Up to Week 52 (IM011024)
Procedure/Visit Weeks (Days) 
16 
(113)
20 
(141) 
24 
(169)
32 
(225)
40 
(281)
52 
(365)
Notes
Visit window (± n days)
3
3
3
3
3
3
Study Treatment
Dispense clinical drug supplies 
(blinded)* 
X
X
X
X
X
Section 5.1.3
*At Week 52, open-label IP will be dispensed to subjects who 
enter the OLE period.  
Dispense clinical drug supplies 
(open-label)
X
X
X
X
X
X
Open-label IP will only be dispensed to subjects who have 
entered an open-label treatment arm during the maintenance 
period. Blinded IP must be dispensed to all other subjects 
(Section 5.1.3).
At Week 52, open-label IP will only be dispensed to subjects 
who enter the OLE period.
Study treatment 
(blinded or open-label)
X----------------------------------------------------------X
See Notes above in “Dispense Clinical Drug Supplies.”
Review study treatment 
compliance
X
X
X
X
X
X
Section 7.6
Safety Assessments
Physical examination
X
X
X
X
X
X
General, head, eyes, ears, nose, throat, neck, cardiovascular, 
lungs, abdominal, extremities, neurologic, skin, 
musculoskeletal 
Physical measurement
X
X
Weight only
Vital signs
X
X
X
X
X
X
See Notes in the screening period procedures (Table 1).
Electrocardiogram
X
See Notes in the induction period procedures (Table 2).
Concomitant medication use
X
X
X
X
X
X
Tobacco use
X
X
X
X
X
X
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 3
Maintenance Period On-treatment Procedural Outline Up to Week 52 (IM011024)
Procedure/Visit Weeks (Days) 
16 
(113)
20 
(141) 
24 
(169)
32 
(225)
40 
(281)
52 
(365)
Notes
Visit window (± n days)
3
3
3
3
3
3
Monitor AEs
X
X
X
X
X
X
Monitoring for AEs will occur at every study visit 
(Section 9.2).
Monitor SAEs
X
X
X
X
X
X
Monitoring for SAEs will occur at every study visit 
(Section 9.2). All SAEs will be followed until resolution, until 
the condition stabilizes, until the event is otherwise explained, 
or until the subject is lost to follow-up (Section 8.3).
Laboratory Tests
Hematology, chemistry, 
urinalysis, and coagulation
X
X
X
X
X
X
HBV DNA 
(Week 12 responder arms)
X
X
X
For subjects with the following HBV serology at screening: 
HBsAg negative, HBcAb positive, HBV DNA undetectable 
(APPENDIX 8)
HBV DNA 
(Week 12 responder arms, with 
subsequent disease worsening and 
entry to the open-label treatment 
arm)
See Note 
For subjects with the following HBV serology at screening: 
HBsAg negative, HBcAb positive, HBV DNA undetectable. 
Subjects who have a clinical response at Week 12 and who 
subsequently experience disease worsening and enter the 
open-label treatment arm: Obtain HBV DNA at the following 
3 study visits, and thereafter according to the schedule for the 
Week 12 responder arm (see above). (APPENDIX 8)
HBV DNA 
(Week 12 nonresponder arm)
X
X
X
X
X
For subjects with the following HBV serology at screening: 
HBsAg negative, HBcAb positive, HBV DNA undetectable 
(APPENDIX 8)
Serum Igs
X
X
X
X
X
IgG, IgM, IgA, and IgE
TBNK panel
X
X
Serum hsCRP 
X
X
X
X
X
X
Fasting lipid panel
X
X
X
See Notes in the induction period procedures (Table 2).
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 3
Maintenance Period On-treatment Procedural Outline Up to Week 52 (IM011024)
Procedure/Visit Weeks (Days) 
16 
(113)
20 
(141) 
24 
(169)
32 
(225)
40 
(281)
52 
(365)
Notes
Visit window (± n days)
3
3
3
3
3
3
Fasting glucose
X
X
X
See Notes in the induction period procedures (Table 2).
Pregnancy test (urine or serum)
X
X
X
X
X
X
WOCBP only (APPENDIX 4). If the urine pregnancy test is 
positive, a serum pregnancy test should be done for 
confirmation prior to discontinuing the subject. Study 
treatment should not be administered until the results of the 
confirmatory test are known.
Efficacy Assessments
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 3
Maintenance Period On-treatment Procedural Outline Up to Week 52 (IM011024)
Procedure/Visit Weeks (Days) 
16 
(113)
20 
(141) 
24 
(169)
32 
(225)
40 
(281)
52 
(365)
Notes
Visit window (± n days)
3
3
3
3
3
3
Review subject diary for 
SF and RB values
X
X
X
X
X
X
Prior to each scheduled visit, review subject diary to ensure 
SF and RB data have been entered daily. 
Prior to each scheduled visit at which Mayo scores are to be 
calculated, ascertain whether an adequate number of days of 
diary entries have been made (APPENDIX 9). If adequate 
entries have not been made, the site should contact the subject 
to reschedule the visit, and the subject should be counseled 
about proper study procedures.
Enter SF and RB subscores for 
Mayo score calculation 
X
APPENDIX 9
Enter SF and RB subscores for 
disease worsening 
X
X
X
X
X
X
Disease worsening is defined as an increase of the sum of the 
SF and RB subscores ≥2 compared to Week 12 (Table 5 and 
Sections 5.1.3.2 and 5.1.3.3)
Endoscopy 
(colonoscopy/sigmoidoscopy)
X
After bowel preparation, endoscopic examination will be 
performed within a 7-day window of the Week 52 (Day 365) 
visit.
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 3
Maintenance Period On-treatment Procedural Outline Up to Week 52 (IM011024)
Procedure/Visit Weeks (Days) 
16 
(113)
20 
(141) 
24 
(169)
32 
(225)
40 
(281)
52 
(365)
Notes
Visit window (± n days)
3
3
3
3
3
3
Endoscopy is recommended at ET visits that occur between 
Weeks 16 and 52.  
If colonoscopy is conducted at screening assessment, every 
effort should be made to ensure colonoscopy is done at 
subsequent assessment. Screening and surveillance as per 
local guidelines may be completed during study related 
colonoscopy.
Colon histology
 
 
X
See Notes in the induction period procedures (Table 2). 
 
Efficacy/Mayo Scoring
Modified Mayo score
X
Composite score of ES (central read), SF, and RB subscores. 
SF and RB subscores will be calculated using electronic 
subject diary data. 
See Section 9.1 and APPENDIX 9.
AE = adverse event; DNA = deoxyribonucleic acid; ES = endoscopic; ET = early termination; 
 
HBcAb = hepatitis B virus core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; hsCRP = high-sensitivity C-reactive protein; 
IBD = inflammatory bowel disease; 
 Ig = immunoglobulin; IgA = immunoglobulin A; IgE = immunoglobulin 
E; IgG = immunoglobulin G; IgM = immunoglobulin mu; 
 IP = investigational product; OLE = open-label extension; 
 
 
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
 RB = rectal bleeding; 
 SAE 
= serious adverse event; 
 SF = stool frequency; TBNK = T cells, B cells, and natural killer cells; 
UC = ulcerative colitis; WOCBP = women of childbearing potential; 
In the event multiple procedures are required at a single time point, the ECG may be obtained up to 20 minutes earlier, vital signs may 
be obtained up to 20 minutes earlier or later, and clinical laboratory sample may be obtained up to 10 minutes earlier than the nominal 
time poin
.
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Date: 14-Apr-2021
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
2.1.3
Open-label Extension Period Activities and Assessments
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Study Treatment
Dispense clinical drug 
supplies (open-label) 
X
X
X
X
X
Study treatment 
X--------------------------------------------------X
Review study treatment 
compliance
X
X
X
X
X
X
X
Section 7.6
Safety Assessments
Physical examination
X
X
X
X
X
X
X
X
General, head, eyes, ears, nose, throat, neck, 
cardiovascular, lungs, abdominal, 
extremities, neurologic, skin, 
musculoskeletal 
Physical measurement
X
X
X
Weight only
Vital signs
X
X
X
X
X
X
X
X
See Notes in the screening period 
procedures (Table 1).
Electrocardiograms 
X
X
See Notes in the induction period 
procedures (Table 2).
Concomitant medication 
use
X
X
X
X
X
X
X
X
Tobacco use
X
X
X
X
X
X
X
Monitor for AEs
X
X
X
X
X
X
X
X
Monitoring for AEs will occur at every 
study visit (Section 9.2). 
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Monitor for SAEs
X
X
X
X
X
X
X
X
Monitoring for SAEs will occur at every 
study visit (Section 9.2). All SAEs will be 
followed until resolution, until the condition 
stabilizes, until the event is otherwise 
explained, or until the subject is lost to 
follow-up (Section 8.3). 
Laboratory Tests
See notes in the screening period 
procedures (Table 1) and Section 9.4.3.
Hematology, chemistry, 
urinalysis, and 
coagulation*
X
X
X
X
X
X
X
X
*Coagulation is to be collected at Week 56 
only. 
HBV DNA
X
X
X
X
X
X
X
For subjects with the following HBV 
serology at screening: HBsAg negative, 
HBcAb positive, HBV DNA undetectable 
(APPENDIX 8)
Tuberculosis testing
X
X
In accordance with standard testing (details 
are provided in Section 5.2 4) and 
Section 9.4.2)
Serum Igs 
X
X
X
IgG, IgM, IgA, and IgE
TBNK panel
X
X
X
Serum hsCRP 
X
X
X
X
X
X
X
Fasting lipid panel
X
X
X
Subjects are required to fast for ≥10 hours 
prior to the collection of specimens for the 
fasting lipid panel.
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Fasting glucose
X
X
X
Subjects are required to fast for ≥10 hours 
prior to the collection of specimens for the 
fasting glucose panel.
Pregnancy test (urine or 
serum)
X
X
X
X
X
X
X
X
WOCBP only (APPENDIX 4). If the urine 
pregnancy test is positive, a serum 
pregnancy test should be done for 
confirmation prior to discontinuing the 
subject. Study treatment should not be 
administered until the results of the 
confirmatory test are known
Protocol Amendment No.: 03
Date: 14-Apr-2021
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Efficacy Assessments
Review subject diary for 
SF and RB values
X
X
X
X
X
X
Prior to each scheduled visit, review subject 
diary to ensure SF and RB data have been 
entered daily. 
Prior to each scheduled visit at which Mayo 
scores are to be calculated, ascertain 
whether an adequate number of days of 
diary entries have been made ( APPENDIX 
9.). If adequate entries have not been made, 
the site should contact the subject to 
reschedule the visit, and the subject should 
be counseled about proper study 
procedures.
Enter SF and RB 
subscores for Mayo score 
calculation
X
See APPENDIX 9
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Enter SF and RB 
subscores for disease 
worsening
X
X
X
X
X
X
Disease worsening is defined as an increase 
of the sum of the SF and RB subscores ≥2 
compared to Week 12 (Table 5)
Endoscopy 
(colonoscopy/
sigmoidoscopy)
X
After bowel preparation, endoscopic 
examination will be performed within a 
7-day window of the Week 104 (Day 729) 
visit.
Endoscopy is recommended at ET visits 
that occur between Weeks 56 and 104.
If colonoscopy is conducted at screening 
assessment, every effort should be made to 
ensure colonoscopy is done at subsequent 
assessment. Screening and surveillance as 
per local guidelines may be completed 
during study related colonoscopy.
Colon histolog
 
 
X
See Notes in the induction period 
procedures (Table 2). 
 
Efficacy/Mayo Scoring
Protocol Amendment No.: 03
Date: 14-Apr-2021
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
Table 4
Open-label Extension Period On-treatment Procedural Outline Up to Week 104 (IM011024)
Procedure/Visit Weeks 
(Days)
56
(393)
60
(421)
64
(449)
78
(547)
90
(631)
104
(729)/E
T
108 (757) 
or Post-
treatment 
Follow-up
Unschedule
d Visit a
Notes
Visit Window (± n 
days)
3
3
3
3
3
3
Modified Mayo score
X
Composite score of ES (central read), SF, 
and RB subscores. SF and RB subscores 
will be calculated using electronic subject 
diary data. See Section 9.1 and APPENDIX 
9.
a Additional procedures/assessments will be done per investigator’s discretion
AE = adverse event; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
 EOT = end of treatment; 
ES = endoscopic; ET = early termination; HBcAb = hepatitis B virus core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; hsCRP = high-
sensitivity C-reactive protein; IBD = inflammatory bowel disease; 
 Ig = immunoglobulin; 
IgA = immunoglobulin A; IgE = immunoglobulin E; IgG = immunoglobulin G; IgM = immunoglobulin M; 
 
RB = rectal bleeding; 
 SAE = serious adverse event; 
 SF = stool frequency; TBNK = T cells, 
B cells, and natural killer cells; 
 WOCBP = women of childbearing potential
In the event multiple procedures are required at a single time point, the ECG may be obtained up to 20 minutes earlier, vital signs may 
be obtained up to 20 minutes earlier or later, and clinical laboratory sample may be obtained up to 10 minutes earlier than the nominal 
time poin
.
Protocol Amendment No.: 03
Date: 14-Apr-2021
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
3
INTRODUCTION
3.1
Study Rationale
Study IM011024 is a Phase 2 randomized, double-blind study designed to assess the safety and 
efficacy of oral (PO) BMS-986165 6 mg twice daily (BID) in subjects with moderate to severe 
ulcerative colitis (UC). The primary objective is to assess the effect of BMS-986165 on the primary 
endpoint of clinical remission, which is defined as a modified Mayo score with the following 
subscores: stool frequency (SF) subscore ≤1 with ≥1 point decrease from baseline, rectal bleeding 
(RB) subscore = 0, and endoscopic (ES) subscore ≤1 (modified, excludes friability); at the end of 
the induction period (Week 12).
3.2
Background
Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract that causes 
significant morbidity, impact on quality of life, and healthcare expenditures. Outcomes for patients 
with UC have improved significantly over the last several years due to better treatment strategies 
and the emergence of highly targeted biological therapies, yet significant therapeutic challenges 
still remain with this and other inflammatory bowel diseases (IBDs). The current treatment 
regimens often fail, induce only a partial response, or are poorly tolerated. For example, studies 
with tumor necrosis factor inhibitors (TNFi) report 10% to 30% of subjects do not respond to their 
first treatment and 23% to 46% of subjects lose their response over time.1 Therefore, there is still 
a critical unmet need for novel, safe, well-tolerated, and orally administered therapies with a 
different mechanism of action that can effectively modify the disease course.
Tyrosine kinase 2 (TYK2) is a protein involved in interleukin (IL)-12, IL-23, and Type I interferon 
(IFN) signaling, and it is required for the activation of downstream signaling pathways.2 TYK2 is 
a widely expressed, non-receptor tyrosine kinase that catalyzes the phosphorylation of signal 
transducer and activator of transcription (STAT) proteins downstream of the receptors for the p40-
containing cytokines IL-12 and IL-23, as well as the Type I IFN receptor. This results in the 
activation of STAT-dependent transcription and functional responses specific for these cytokines.3, 
4, 5 TYK2-dependent cytokines (eg, IL-12, IL-23 and Type I IFNs) are distinct from those 
dependent on closely related Janus kinase (JAK) family members JAK1, JAK3 (eg, IL-2, IL-15, 
IL-7, IL-6) or JAK2 (eg, erythropoietin, thrombopoietin, and granulocyte-monocyte colony-
stimulating factor). Consequently, a TYK2 inhibitor is expected to have a highly differentiated 
profile from inhibitors of other JAK family kinases. TYK2 dependent pathways and the cytokine 
networks they modulate (eg, IL-23, IL-17, IFNα) have been implicated in the pathophysiology of 
multiple immune-mediated diseases, including UC, Crohn’s disease (CD), psoriasis, psoriatic 
arthritis, systemic lupus erythematosus (SLE) and spondyloarthropathies.
BMS-986165 is an orally administered selective TYK2 inhibitor. A comprehensive in vitro and in 
vivo characterization of BMS-986165 has been established and supports the development of this 
compound in humans.6, 7 Inhibition of TYK2 is expected to provide therapeutic benefit for patients 
with UC for multiple reasons: 1) IL-12 and IL-23 have been implicated in the pathogenesis of 
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
UC8, 9, 10, 11; 2) Biologic agents targeting IL-23p19 and IL-12/IL-23p40 cytokines have been 
shown to be efficacious in UC and CD, and ustekinumab targeting IL-12/IL-23p40 has been 
approved for the treatment of CD12 and UC13; and 3) BMS-986165 has been shown to be 
efficacious in psoriasis, an IL-23-mediated disease, in a recent Phase 2 study.14
This Phase 2 study (IM011024) will provide safety and efficacy data for BMS-986165 in subjects 
with moderate to severe UC. Approximately 120 subjects will be randomized in this study. After 
a 28-day screening period, eligible subjects will be randomized in a 2:1 ratio to receive oral 
BMS-986165 6 mg BID or placebo BID during the induction period of 12 weeks. Randomization 
will be stratified based on corticosteroid use (yes/no) and prior exposure to biologics indicated for 
the treatment of UC (ie, no prior exposure, exposure to 1 biologic, or exposure to > 1 biologic). 
JAK inhibitors are considered as a biologic for stratification purposes. (Note: Failure or loss of 
response to JAK inhibitors is exclusionary, but prior exposure is not exclusionary.) The induction 
period lasts from Week 0 through Week 12. The primary outcome for the study will be assessed 
at Week 12 (Day 85).
The maintenance period lasts from Week 12 through Week 52. This study has a treat-through study 
design. Subjects who achieve clinical response at Week 12 (Day 85), with an appropriate safety 
profile, are eligible to continue into the maintenance period, during which they will continue to 
receive the same blinded study treatment regimen (BMS-986165 6 mg BID or placebo BID) that 
they received during the induction period. An open-label study arm is available within the 
maintenance period for subjects who do not achieve a clinical response at Week 12 and for subjects 
in the treat-through study arms who experience disease worsening between Week 13 and Week 52. 
The open-label extension period lasts from Week 52 through Week 104 and is available to subjects 
who complete per protocol assessments and who continue to derive clinical benefit from the 
investigational product (IP), as judged by the investigator, at that time.
A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986165 is 
provided in the Investigator’s Brochure (IB).15
3.2.1
Nonclinical Toxicology
The projected systemic exposure multiples presented in this section are expressed relative to the 
highest anticipated mean steady-state systemic exposure in human following oral dosing at 
6 mg BID (mean AUC[0-24h] = 857 ng•h/mL) and were calculated as animal sex-combined mean 
AUC ÷ human sex-combined mean AUC at the no-observed-adverse-effect level (NOAEL) or 
level associated with adverse findings in the pivotal toxicology studies.
In single-dose oral toxicity studies, BMS-986165 was well tolerated up to the highest administered 
doses of 75, 100, and 30 mg/kg in rats, dogs, and monkeys, respectively. 
In repeat-dose oral toxicity studies in rats, BMS-986165 was tolerated at all doses (5, 15, or 
75 mg/kg/day for 1 month; 2, 5, or 15 mg/kg/day for 3 months; and 5, 15, or 50 mg/kg/day for 
6 months). All doses were associated with on-target pharmacodynamic (PD) effects. Systemic 
exposures to BMS-986165 increased approximately dose proportionally, with no substantial sex 
differences, accumulation, or loss of exposure in all studies. In the 6-month rat toxicity study with 
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Clinical Protocol
IM011024
BMS-986165
TYK2 Inhibitor
2-month postdose recovery period, BMS-986165 was tolerated by rats for 6 months at oral doses 
≤50 mg/kg/day (mean sex-combined AUC[0-24h] ≤117 μg•h/mL; ≤137-fold AUC multiple). 
Consistent with BMS-986165-mediated pharmacologic immunomodulation, the primary findings 
at ≥5 mg/kg/day were decreased peripheral blood lymphocyte counts, lymphoid cellularity in 
lymph nodes and spleen, and/or suppression of T-cell dependent antibody response (TDAR) to 
keyhole limpet hemocyanin (KLH) immunogen. No BMS-986165-related infections were noted. 
Additional BMS-986165-related findings considered adverse at ≥15 mg/kg/day (mean 
sex-combined AUC[0-24h] ≥19.7 μg•h/mL; ≥23-fold AUC multiple) included decreased mean 
body weights and body weight gains, decreased red blood cell (RBC) mass parameters, 
reticulocytes, platelets, and bone marrow cellularity. All BMS-986165-related changes were 
reversible except for the decreased food consumption and body weights, decreased spleen weights, 
and nonadverse increased incidence of macrophage aggregation in the lung. In conclusion, based 
on the absence of adverse findings, the NOAEL was considered to be 5 mg/kg/day (mean sex-
combined AUC[0-24h] 4.31 μg•h/mL; 5-fold AUC multiple).
In repeat dose (≤3 months) oral toxicity studies in monkeys, BMS-986165 was well tolerated at 
all doses (0.5, 1.5, or 5 mg/kg/day for 1 month; 0.75, 1.5, or 5 mg/kg/day for 3 months). All doses 
were associated with on-target PD effects. Exposures to BMS-986165 increased approximately 
dose proportionally, with no substantial sex differences, loss of exposure or accumulation noted. 
There were no BMS-986165-related mortalities at any dose during any monkey toxicity studies. 
In the 9-month monkey toxicity study (doses of 0, 1, 3, or 10 mg/kg/day; the 10-mg/kg dose was 
changed to 5 mg/kg due to observed toxicity) with 2 month postdose recovery period, the principal 
BMS-986165-related findings at all doses included generally dose-dependent skin changes, which 
were likely infectious in etiology, and secondary to BMS 986165-mediated pharmacologic 
immunomodulation. The various skin changes (swollen, dry, lesion, flaking, papule, red, white, 
scab) were located throughout the body, and could be seen as early as Week 1 in some monkeys. 
The skin changes were noted at necropsy as abrasions, discoloration, foci, nodule, scab, scale, 
and/or thick, and correlated with microscopic findings in the epidermis (hyperkeratosis, erosion, 
and/or crusts) and/or dermis (mixed cell infiltrates and/or subacute inflammation). Although no 
definitive microbial pathogens were confirmed as the causative agents, the skin changes were 
considered likely infectious in etiology, as they improved following antibiotic and antiseptic 
treatments, and were present in the context of BMS-986165 mediated immunomodulation. 
Additional findings at all doses included transient slight to severe liquid feces, which improved 
clinically with veterinary treatments, dose-dependent decreased RBC mass parameters, and 
suppression of TDAR to KLH, and at ≥3 mg/kg/day (mean sex-combined AUC[0-24h] 
≥15.4 μg•h/mL; ≥18-fold AUC multiple) decreased activity, hunched posture, pale gums, and 
increased body temperature, with decreased platelets and occult blood in urine at 10 followed by 
5 mg/kg/day (mean sex-combined AUC[0-24h] 30.7 μg•h/mL; 36-fold AUC multiple). Following 
the 2-month recovery period, all BMS-986165-related findings were partially or fully reversible. 
The NOAEL was not identified due to the presence of adverse skin findings at doses ≥1 mg/kg/day 
(mean sex-combined AUC[0-24h] ≥3.38 μg•h/mL; ≥4-fold AUC multiple). Although the 
NOAEL was not determined in this study, the skin findings did not result in any unscheduled 
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euthanasia or preterminal deaths, were clinically monitorable, manageable with veterinary 
treatments, and trended toward reversibility during the 2-month post-dose recovery.
The totality of the toxicity assessments demonstrates that BMS-986165, at doses associated with 
robust PD effects, has a favorable dose-related safety profile in both rodents and nonrodents, 
toxicological findings that are either fully reversible or trending toward recovery, and are clinically 
monitorable and manageable. 
Additional details regarding the nonclinical toxicology results are provided in the current IB.15
3.2.2
Early Clinical Experience
BMS-986165 has a favorable pharmacokinetic (PK) profile characterized by consistent oral 
absorption, dose-related increase in exposure and no evident time-dependency. The oral absorption 
is rapid with maximal plasma concentrations achieved in 1 to 2 hours and a high absolute 
bioavailability (approximately 99% with a 12 mg oral dose). No significant interaction was 
observed when BMS-986165 was administered with food (high fat/high calorie meal) or with pH-
modulating agents like famotidine. A study is currently underway to evaluate the effect of 
rabeprazole on BMS-986165. BMS-986165 is moderately bound to plasma proteins and is 
therefore unlikely to be displaced by drugs that have a greater binding affinity. 
The terminal half-life of BMS-986165 is ~10 to 15 hours and that of the active metabolite 
(BMT-153261) is ~12 hours. BMS-986165 accumulates ~1.5-fold with repeated administration. 
BMS-986165 is eliminated via multiple well-balanced mechanisms including Phase I and II 
metabolism along with direct renal and possibly fecal elimination. Additionally, multiple enzymes 
(CYP1A2, CES2, and UGT1A9) are involved in its elimination. The active metabolite, 
BMT-153261, whose whole blood potency is 50% of the parent, is formed via CYP1A2 
metabolism. The formation of the BMT-334616 metabolite is mediated by UGT1A9. The 
formation of the BMT-158170 metabolite is mediated by CES2.
The clinical data available to date supporting the safety, PK, and PD of BMS-986165 are from 
8 Phase 1 studies of BMS-986165 in healthy volunteers (IM011002, IM011015, IM011016, 
IM011025, IM011031, IM011039, IM011048 and IM011071) and a Phase 2 study in adult 
subjects with moderate to severe plaque psoriasis (IM011011). In addition to the current study, 
Phase 2 studies in CD (IM011023), psoriatic arthritis (IM011084), SLE (IM011021, IM011074), 
and lupus nephritis (IM011073), and Phase 3 studies in psoriasis (IM011046, IM011047, 
IM011065, IM011066, IM011075) are currently ongoing.
Study IM011002 (Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, 
PK, and PD of BMS-986165 in Healthy Subjects) used 1, 3, 10, 20, and 40 mg doses for the 
single-dose part, and 2, 4, 6, or 12 mg BID or 12 mg every day (QD) for 14 days for the multiple 
ascending dose part. All reported adverse events (AEs) were mild or moderate in severity, and 
approximately half of subjects overall had at least 1 AE that was considered potentially related to 
study treatment. The most frequently reported AEs with single dosing were headache and 
dyspepsia. The most frequently reported AEs with multiple dosing were headache, skin rash and 
acne, and upper respiratory tract infection. Dose-limiting AEs in the form of skin rashes and 
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acneiform lesions were observed. These observations were largely reported for subjects in the 
24 mg/day (12 mg BID) group and were reported for most subjects dosed at this level. These AEs 
were mild or moderate in nature and resolved with topical treatments (corticosteroid applications, 
benzoyl peroxide cream, clindamycin solution, chlorhexidine ointment). All events requiring 
treatment responded appropriately, and rarely resulted in discontinuation of study drug. Overall, 
BMS-986165 was found to have an acceptable safety profile in healthy volunteers, and the 
acneiform lesions that were seen at the highest doses were manageable with topical treatments, 
were reversible, and were not serious or severe.
The study to evaluate the cardiodynamic effects of BMS-986165 was conducted at 12 mg and 
36 mg, and included a positive control (moxifloxacin) and placebo. The study demonstrated that 
BMS-986165 at these doses does not have a clinically relevant effect on electrocardiogram (ECG)
parameters. Using concentration-QTc analysis, a QTcF effect (∆∆QTcF) exceeding 10 msec can 
be excluded up to BMS-986165 plasma concentrations of ~500 ng/mL. Assay sensitivity was 
demonstrated by the QT effect of moxifloxacin with a statistically significant slope of the 
concentration-ΔΔQTc relationship and the lower bound of the 2-sided 90% confidence interval 
(CI) of the predicted effect at the observed geometric Cmax above 5 msec. The study therefore 
constitutes a negative TQT study.
Study IM011011 was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel group Phase 2 study to evaluate the clinical efficacy, safety, and PD of BMS-986165 after 
12 weeks of treatment with 4 weeks’ follow-up in 267 subjects with moderate to severe plaque 
psoriasis.14 The study met its primary and secondary efficacy endpoints of clinically relevant 
improvement in Psoriasis Activity and Severity Index (PASI) and static Physician Global 
Assessment (PGA) scores for 4 of the 5 doses investigated (only the 3 mg every other day dose 
did not meet the primary endpoint). Treatment with BMS-986165 at doses of > 3 mg once daily 
were associated with significantly greater clinical responses compared with placebo at Week 12, 
as measured by a ≥75% reduction in the Psoriasis Area and Severity Index (PASI 75) score. At 
Week 12, the percentage of patients with a PASI 75 response was 7% (3 of 45 patients) with 
placebo, 39% (17 of 44 patients) with 3 mg QD, 69% (31 of 45 patients) with 3 mg BID, 67% 
(30 of 45 patients) with 6 mg BID, and 75% (33 of 44 patients) with 12 mg QD (P value < 0.001 
for each comparison). Treatment with BMS-986165 at doses > 3 mg BID was also associated with 
a numerically greater proportion of patients achieving ≥90% reduction in PASI score (PASI 90), 
compared with placebo at Week 12. The most common AEs reported overall were nasopharyngitis, 
upper respiratory tract infection, diarrhea, and nausea. The majority of the AEs reported in the 
study were mild or moderate in intensity. AEs of acneiform dermatitis were observed in a few 
subjects that appeared to be dose-related, and most were reported for subjects at the 2 highest dose 
groups. Most of the lesions were completely resolved (a few were almost completely resolved) 
with topical treatments and did not result in discontinuation of the study treatment. In summary, 
BMS-986165 has demonstrated promising clinical efficacy in the treatment of subjects with 
moderate to severe plaque psoriasis.14
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3.3
Benefit/Risk Assessment
BMS-986165 is being developed as an oral treatment for UC, CD, psoriasis, psoriatic arthritis, 
SLE, and lupus nephritis. Based on its mechanism of action as an inhibitor of TYK2-mediated 
signaling pathways downstream of well-characterized pharmaceutical targets for the treatment of 
UC, the IL-12/TH1 and IL-23/TH17 axis, it is predicted that subjects with UC may benefit from 
treatment with BMS-986165. Further, the first-in-human (FIH) study of BMS-986165 
(Study IM011002) in healthy subjects demonstrated IL-12 signaling inhibition by BMS-986165. 
These data suggest that subjects with UC are likely to derive clinical benefit after treatment with 
BMS-986165.
The effects of TYK2 inhibition by BMS-986165 have been documented in pharmacology studies, 
and the potential for benefit in UC is supported through in vivo studies showing BMS-986165 is 
efficacious in murine models for lupus, colitis, and psoriasis. In all models, efficacy was observed 
at doses providing continuous coverage of the mouse whole blood half-maximal inhibitor 
concentration (IC50) value over the dosing interval. 
The proposed dosing regimen reflects implementation of appropriate safety margins and is within 
the range of doses tested in the FIH study and within exposure margins based on comparisons of 
systemic exposure and body surface area. The dose of BMS-986165 6 mg BID is also being 
investigated in clinical trials for other indications.
BMS-986165 was safe when investigated in the FIH study IM011002 with healthy subjects at 
single doses up to 40 mg and multiple doses of 24 mg/day (12 mg BID) for 14 days. However, 
BMS-986165 did elicit dose-dependent, mild-to-moderate acneiform skin reactions particularly 
after multiple doses of 24 mg/day (12 mg BID). Importantly, all skin-related AEs were mild or 
moderate, with no signs or symptoms of circulatory impairment or respiratory distress in these 
subjects; required topical treatment in only a few cases, responded quickly and appropriately when 
treatment was required, and rarely required discontinuation of study drug. Based on these findings, 
the highest proposed dose for the Phase 2 study IM011024 in subjects with UC will be 6 mg BID. 
In case of the occurrence of skin-related events, subjects may receive treatment per standard 
practice according to investigator’s discretion and followed until resolution. 
The risk for PK drug-drug interactions (DDIs) with BMS-986165 was assessed using Food and 
Drug Administration (FDA) and European Medicines Agency guidance documents for DDI 
assessments. At the maximum concentrations expected in this study (in portal vein or systemic 
circulation, as appropriate), the potential for DDIs involving cytochrome P450 (CYP450) enzymes 
and most transporters is low. BMS-986165 has low turnover in in vitro metabolism studies, and a 
number of enzymes are involved in its metabolism. Additionally, BMS-986165 is not an inhibitor 
or inducer of CYP450 enzymes at the expected clinical concentrations. Therefore, the potential for 
DDIs resulting from CYP450 inhibition or induction is low. BMS-986165 is a breast cancer 
resistance protein (BCRP) inhibitor with an in vitro IC50 = 0.31 μM. However, due to overlapping 
substrate specificity between BCRP and other transporters not affected by BMS-986165 at the 
expected concentrations, the impact of BMS-986165 on the exposures of potential comedications 
that are BCRP substrates, such as rosuvastatin, was expected to be low. Based on data from 
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IM011015 DDI study, co-administration of 12 mg QD BMS-986165 and 10 mg rosuvastatin had 
no impact on the exposure of rosuvastatin. Data from a study evaluating the impact of 
BMS-986165 in women taking oral contraceptives found no impact on exposure of ethinyl 
estradiol or norethindrone.
Because BMS-986165 is a potential immunomodulator and in line with standard practice for 
immunosuppressive therapies, this study has been designed with study visits that allow for close 
monitoring and with inclusion/exclusion criteria aimed at minimizing the risk for serious infections 
and malignancies.
Additionally, the current study (Study IM011024) has been designed to closely monitor study 
subjects’ safety throughout the duration of the study. At the investigator’s discretion, rescue 
therapy can be initiated (Section 5.1.5), or dosing of study medication can be discontinued at any 
time during the study (Section 8.1). In addition to a comprehensive monitoring of safety with 
oversight by the investigators, medical monitors from both BMS and the partner organization, 
 and the BMS Safety Physician, the safety of subjects will also be monitored 
by an independent Data Monitoring Committee (DMC). 
In summary, existing preclinical data and clinical experience in healthy subjects in combination 
with the design and dose selected for this Phase 2 study indicate an overall favorable benefit-risk 
assessment of investigating BMS-986165 as an oral treatment for subjects with UC.
Additional detailed information on the known and expected benefits and risks and reasonably 
anticipated AEs of BMS-986165 is provided in the IB.15
The global coronavirus disease 2019 (COVID-19) pandemic has been identified as a potential risk 
to clinical trial subjects in general, and it may particularly affect individuals with underlying 
chronic diseases. The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection in participants taking BMS-986165 is unknown. The individual benefit-risk 
considerations regarding COVID-19 infection remains the responsibility of the investigator.
BMS-986165 is an immunomodulatory IP. The inclusion (Section 6.1) and exclusion (Section 6.2) 
criteria have been designed to exclude people with active infections and people at higher risk of 
malignancies. In order to reduce the risk of asymptomatic SARS-CoV-2 at baseline, subjects will 
be tested for SARS-CoV-2 during the screening period, as close as possible prior to randomization 
(refer to Section 9.8).
The study has been designed with study visits that allow for close monitoring of study subjects’ 
safety throughout the study, and additional data collection will be triggered if AEs of interest 
(AEIs) are observed in this study. Each study visit will include a clinical assessment for signs 
and/or symptoms of intercurrent illness, including COVID-19 and other infections. Subjects will 
also be encouraged to contact the investigator if they develop an intercurrent illness between study 
visits.
The Sponsor has developed guidance for investigators on how to manage a subject with a clinical 
suspicion of, or a diagnosis of, COVID-19. This includes criteria for temporary discontinuation of 
IP in the context of clinical suspicion of COVID-19, or a positive diagnostic test for SARS-CoV-2. 
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This also includes criteria for potentially recommencing IP upon complete resolution of a 
COVID-19 infection, confirmed by a negative diagnostic test (Section 8.2.1).
The study captures treatment-emergent AEs (occurring after randomization). In order to facilitate 
enhanced reporting of SARS-CoV-2–related AEs that occur during the study, these AEs (and 
SAEs) must be reported from the time of consent (Section 9.2.1). 
4
OBJECTIVES AND ENDPOINTS
Primary and secondary endpoints and related study terms are defined in Table 5.
Table 5
Primary and Secondary Endpoint and Related Study Term 
Definitions
Endpoint
Definition
Primary
Clinical remission
(modified Mayo score)
A modified Mayo scorea with the following:
•
SF subscore ≤1, with ≥1 point decrease from 
baseline, and
•
RB subscore = 0, and
•
ES subscoreb ≤1 (modified, excludes friability)
Secondary
Clinical responsec
•
A decrease from baseline in the modified Mayo scorea
of ≥2 points, and
•
A decrease from baseline in the modified Mayo scorea
≥30%, and
•
A decrease in RB subscore of ≥1 point or absolute 
RB subscore ≤1
Endoscopic response
Mayo ES subscoreb ≤1
Histologic improvement
Geboes score ≤3.1
Study Term
Definition
Disease worsening
An increase of the sum of the SF and RB subscores 
≥2 compared to Week 12
ES = endoscopic; RB = rectal bleeding; SF = stool frequency
a The modified Mayo score (0 to 9 points) is the sum of 3 components: the SF, RB, and ES subscores (see Section 9.1
and APPENDIX 9).
b Obtained from centrally read endoscopy (Section 9.1.1)
c Efficacy analyses will use the modified Mayo score calculated with centrally read endoscopy. At Week 12, 
treatment assignment in the maintenance period will be determined using clinical response based on the modified 
Mayo score calculated with a locally read endoscopy (Section 9.1.1).
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The study objectives and endpoints are in Table 7. 
Additional endpoints and analyses will be described in the statistical analysis plan (SAP), the 
Endoscopy Image Review Charter or the Histopathology Image Review Charter.
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
Efficacy
Primary
•
To assess the effect of BMS-986165 on 
clinical remission at the end of the 
induction period
•
Clinical remission (modified Mayo score) 
at Week 12 
Secondary
•
To assess the effect of BMS-986165 on 
clinical response at the end of the induction 
period
•
Clinical response at Week 12 
•
To assess the effect of BMS-986165 on 
endoscopic response at the end of the 
induction period
•
Endoscopic response at Week 12 
•
To assess the effect of BMS-986165 on 
histologic improvement at the end of the 
induction period
•
Histologic improvement at Week 12 
Safety
•
To assess the safety and tolerability of 
BMS-986165 in subjects with moderate to 
severe UC 
•
Number and proportion of subjects 
experiencing AEs, SAEs, AEs leading to 
study discontinuation, and AEs of interest 
(AEIs)
•
Number and proportion of subjects 
experiencing abnormalities in laboratory 
testing, ECG, physical examination, and 
vital sign parameters over time
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
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Table 7
Study Objectives and Endpoints
Objectives
Endpoints
AE = adverse event; AEI = adverse event of interest; ECG = electrocardiogram; 
 
 hsCRP = high-sensitivity C-reactive protein; 
 
IgG = immunoglobulin G; 
 
 
RB = rectal bleeding;
 
 SAE = serious adverse event;
 
SF = stool frequency; UC = ulcerative colitis; 
 
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial to assess 
the safety and efficacy of BMS-986165 6 mg BID in subjects with moderate to severe active UC. 
The primary objective is to assess the effect of BMS-986165 on clinical remission at Week 12. 
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The duration of study participation is approximately 112 weeks (784 days) in 5 periods, as follows:
•
Screening Period: up to 4 weeks (28 days; Section 5.1.1)
•
Induction Period: 12 weeks (84 days; Section 5.1.2) 
•
Maintenance Period: 40 weeks (280 days; Section 5.1.3)
•
Open-label Extension Period: 52 weeks (364 days; Section 5.1.4)
•
Post-treatment Follow-up Period: 4 weeks (28 days; Section 5.1.4.1) 
Physical examinations, vital sign measurements, 12-lead ECG, and clinical laboratory evaluations 
will be performed at selected times throughout the study, as indicated in the Schedule of Activities 
(Section 2). Subjects will be closely monitored for AEs throughout the study. 
 
 
Clinical efficacy is assessed using the modified Mayo score, which uses a combination of patient-
reported outcomes (PRO) (SF and RB captured by the subject in their electronic diary) and 
endoscopic assessments (centrally read endoscopy). Subjects should receive and be trained on an 
electronic patient diary at the screening visit. Subjects are expected to complete the electronic diary 
on a daily basis through the screening period, and then throughout their ongoing participation in 
the study.
Endoscopic (colonoscopy/sigmoidoscopy) evaluations and collection of colonic tissue biopsies 
will be performed during the screening period, at Weeks 12, 52, and 104, at unscheduled visits (if 
clinically indicated) and at early termination (ET) visits that occur at least 4 weeks after the last 
per protocol-required endoscopy. Endoscopic assessment is required for ET visits occurring 
between Week 4 and Week 12 (induction period) and optional but recommended for ET visits 
occurring between Weeks 16 and Week 52 (maintenance period), and between Weeks 56 and 104 
(open-label extension [OLE] period). Endoscopic procedures will be video recorded and scored 
for disease activity by a blinded central reader. Histologic scoring of gastrointestinal tissue 
specimens will also be performed by a blinded central reader. 
 
 
Subjects who meet the criteria for treatment failure will permanently discontinue IP and enter the 
post-treatment follow-up period (Section 5.1.4.1).
An independent DMC will be instituted to assess safety data by unblinded treatment group
(Section 5.1.7).
The study design schematics for the induction/maintenance periods and the open-label extension 
period are in Figure 1 and Figure 2, respectively.
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Figure 1
Study Design Schematic: Induction and Maintenance Periods
BID = twice daily; OL = open-label; OLE = open-label extension; R = randomization
At Week 12, clinical response is determined using the modified Mayo score (see Table 5and Section 9.1.1). Subjects 
who achieve clinical response at Week 12 and continue into the maintenance period will continue to receive their 
double-blind treatment from the induction period. Subjects who subsequently experience disease worsening (Table 5) 
can enter the Week 12 responder open-label arm at any time from Week 13 through Week 52. 
Subjects who do not achieve clinical response at Week 12 are eligible to enter the Week 12 nonresponder open-label 
arm.
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Figure 2
Study Design Schematic: Open-label Extension Period
BID = twice daily; IP = investigational product; OL = open-label
a Subjects in this arm are those who achieved clinical response at Week 12 of the induction period, but they 
subsequently lost clinical response to IP between Week 13 and Week 52 of the maintenance period and switched to 
the Week 12 responder open-label arm (Section 5.1.3.2). 
b Subjects in this arm are those who did not achieve clinical response at Week 12 of the induction period and switched 
to the Week 12 nonresponder open-label arm.
5.1.1
Screening Period
Once subjects sign the informed consent form (ICF), they are considered "enrolled" in the study, 
and they enter the screening period. During the screening period, subjects will complete the study 
procedures and baseline assessments outlined in the Schedule of Activities (Table 1) to determine 
if they continue to meet eligibility criteria (Section 6). 
To be eligible for the study, a subject must meet minimum disease activity criteria outlined in the 
inclusion criteria (Section 6.1), including a modified Mayo score of 5 to 9 points, inclusive.
Subjects are expected to complete a daily diary throughout the screening period. SF and RB data 
recorded in the daily diary contribute to disease activity assessment throughout the study. The 
minimum daily diary requirements for modified Mayo score calculations are outlined in 
APPENDIX 9. To ensure that a subject can be successfully randomized, sites should confirm prior 
to each study visit that subjects are successfully entering and uploading daily diary data (see 
APPENDIX 9 and Table 26).
A screening endoscopy (sigmoidoscopy or colonoscopy) will be performed to determine if a 
subject has active intestinal inflammation (assessed by central reading) and to obtain biopsies for 
histological 
 assessment 
. In order to avoid unnecessary endoscopies, 
best practice is to complete other screening investigations first, and to check the results of those 
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investigations for abnormalities before a subject begins bowel preparation for endoscopy. This 
ensures that a subject continues to be potentially eligible for the study before they commence 
bowel preparation. Subjects must be randomized within 14 calendar days of the screening 
endoscopy.
Note: a full colonoscopy will be required 1) if normal margins are not apparent from 
sigmoidoscopy or proximal colonic involvement is suspected; or 2) in subjects with a history of 
UC > 8 years, if endoscopy was not performed in the prior 12 months. 
When operationalizing the screening period, please consider the following:
i.
Study procedures cannot be performed before the subject signs the ICF. Once the ICF is 
signed at the screening visit, sites should consider obtaining a medical history, vital signs 
and physical examination, and other per protocol screening visit investigations such as 
blood tests, ECG, and chest x-ray (if required); giving the subject the electronic study diary 
and training on the diary; and also scheduling the screening endoscopy and Week 0 (Day 1) 
visit. Sites should consider the turnaround time for the centrally read endoscopy result 
when scheduling the endoscopy and Week 0 (Day 1) visits.
ii.
The study diary requirements for the calculation of the modified Mayo score are outlined 
in APPENDIX 9. To ensure that a modified Mayo score can be determined, sites should 
confirm prior to each study visit that subjects are successfully entering and uploading daily 
diary data and that an appropriate number of valid entry days is available for the calculation 
of the SF and RB subscores (APPENDIX 9).
iii.
Sites should check the results of screening investigations to confirm that a subject remains 
potentially eligible for inclusion before they commence bowel preparation for the screening 
endoscopy. 
iv.
Once the screening endoscopy is performed, subjects must be randomized within 14 days. 
To be eligible for randomization, subjects must have had an inadequate response, loss of response, 
or intolerance to a standard treatment course of 1 or more of the medications outlined in the 
Inclusion Criteria in Section 6.1 2) Type of Subject and Target Disease Characteristics. 
Detailed criteria defining inadequate response, loss of response, or intolerance to biologic therapy 
are described in APPENDIX 5. The prior medication failure or intolerance used to qualify a subject 
for inclusion as defined in Section 6.1 must be recorded in source documents and the UC 
medications electronic case report form (eCRF). 
The medications outlined in APPENDIX 7 must be discontinued prior to randomization on 
Week 0 (Day 1) and include immunomodulators (eg, methotrexate [MTX], 5-azathioprine [AZA], 
6-mercaptopurine [6-MP]) and biologic medications (eg, infliximab, adalimumab, golimumab, 
vedolizumab, and ustekinumab). To be eligible for randomization, subjects taking the medications 
listed in APPENDIX 7 must discontinue them prior to randomization and comply with the required 
washout periods listed in APPENDIX 7.
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Corticosteroids (prednisone ≤20 mg QD PO or equivalent [APPENDIX 6] or budesonide ≤9 mg 
QD PO Multi-Matrix System [MMX®] colonic-delivery technology; eg, Uceris® or equivalent), 
probiotics, and 5-aminosalicylic acids (5-ASAs) are allowed, subject to dose stabilization rules 
outlined in Section 6.3. 
5.1.1.1
Therapeutic Drug Monitoring
Some subjects will require adequate washout of biologics to be eligible for randomization. 
Therapeutic drug monitoring (TDM) assays that test for drug levels of these biologic medications 
can be commercially available in routine clinical practice and also available as an optional test 
during the screening period. The washout period for the following biologics can be waived in 
subjects who have an undetectable drug level on a TDM assay, performed either in routine clinical 
practice or during the screening period: (i) infliximab, (ii) adalimumab, (iii) golimumab, 
(iv) vedolizumab (> 14 weeks of vedolizumab therapy), or (v) ustekinumab (> 12 weeks of 
ustekinumab therapy). If a TDM assay is used to waive the washout period for any of the biologics 
listed above, the result of the TDM assay must be available in source documents, and the subject 
cannot receive another dose of that biologic prior to randomization. 
5.1.2
Induction Period
On Week 0 (Day 1) of the induction period, subjects who have completed the screening procedures 
and met the inclusion/exclusion criteria will be randomized in a 2:1 ratio to receive BMS-986165 
6 mg BID or placebo BID, respectively (see Section 6.3 for randomization criteria). During the 
induction period, subjects will receive study treatment over 12 weeks. Allowed concomitant 
medication for UC (eg, 5-ASAs, probiotics, oral corticosteroids) must remain at the 
prerandomization stable dose, unless reduced or discontinued due to an AE. Corticosteroid use 
during the induction period is detailed in Section 5.1.5.1.
Endoscopy for the assessment of efficacy at Week 12 will occur within a window of 7 days prior 
to the Week 12 visit. The subject study diary requirements for the calculation of the modified 
Mayo score are outlined in APPENDIX 9.
At Week 12, the centrally read endoscopy will be used for determination of efficacy within the 
study. However, clinical response calculated using the locally read endoscopy will be used to 
determine treatment assignment of a subject in the maintenance period (See Section 9.1.1).
Rescue therapy is not offered during the induction period. If, in the opinion of the investigator, a 
subject requires rescue therapy for UC during the induction period, the subject must permanently 
discontinue study treatment (Section 8.1), complete an ET visit, and enter the post-treatment 
follow-up period (see Section 5.1.6 and Section 5.1.4.1). Endoscopy is required at the ET visit for 
subjects who permanently discontinue study medication between Weeks 4 and 12. Discontinuation 
criteria are further detailed in Section 8.
Some study-related procedures may be performed on the day of endoscopy prior to the Week 12 
visit. Please refer to the Schedule of Activity table (Table 2) for timing of specific Week 12 
assessments. 
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Subjects who discontinue study treatment will remain in the study and continue to be followed for 
protocol-specified post-treatment follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information (see Section 8).
5.1.3
Maintenance Period
The maintenance period will last up to 40 weeks. 
During the maintenance period, subjects who were on a stable dose of corticosteroids must begin 
a dose taper by Week 14. See Section 5.1.5.2 and Table 8 for recommended tapering schedules. 
Subjects who require prohibited rescue treatment for UC (ie, outside of the protocol allowance; 
see Section 5.1.6 and Section 7.7.1) during the maintenance period must permanently discontinue 
study treatment, complete an ET visit, and enter post-treatment follow-up (Section 5.1.4.1). An 
exit endoscopy is recommended for all subjects who undergo an ET visit between Weeks 16 and 
52 (i.e. exit endoscopy is not required for ET visits within 4 weeks of the Week 12 endoscopy).
5.1.3.1
Week 12 (Day 85), End of Induction Period
Subjects who achieve a protocol-defined clinical response at Week 12 (assessed using the modified 
Mayo score with a locally read endoscopy) are eligible to enter the maintenance period and 
continue to receive the same blinded study regimen they received in the induction period. Blinded 
study treatment will continue until the subject completes Week 52, experiences disease worsening 
(Section 5.1.3.2) and switches to open-label treatment, or discontinues from the study. 
At Week 12, subjects who do not achieve a clinical response will be offered the opportunity to 
switch to open-label BMS-986165 treatment (6 mg BID PO), regardless of the initial treatment 
regimen received during the induction period. Subjects receiving corticosteroids during the 
induction period who enter this open-label treatment arm must initiate a corticosteroid taper by 
Week 24, or earlier. See Section 5.1.5.3 and Table 8 for recommended tapering schedules.
5.1.3.2
Week 12 Responders: Disease Worsening in the Maintenance Period
Subjects who achieve clinical response at Week 12 and continue on blinded study treatment will 
be judged to have disease worsening (as defined in Table 5) if they experience a worsening of 
clinical disease activity between Weeks 13 and 52.
These subjects are eligible to enter the Week 12 responder open-label arm, during which they will 
receive BMS-986165 6 mg BID PO through Week 52.
Subjects who switch to open-label treatment and experience disease worsening based on the 
definition in Table 5 should discontinue from the study (Section 8.1). Investigators should have a 
low threshold for evaluating whether these subject should continue based on their clinical 
judgment. 
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5.1.3.3
Week 12 Nonresponders: Disease Worsening in the Maintenance Period
Subjects who do not achieve clinical response at Week 12 are eligible to enter the open-label 
BMS-986165 6 mg BID PO arm and continue into the maintenance period through Week 52. 
Alternatively, nonresponder subjects may be discontinued from the study per investigator 
discretion. 
Nonresponder subjects who switch to open-label treatment and experience disease worsening 
between Weeks 13 and 52 (Table 5) should discontinue from the study (Section 8.1). 
See Section 5.1.5.3 regarding subjects receiving corticosteroids in this open-label treatment arm 
who experience disease worsening at Week 36 (and thereafter).
5.1.3.4
Week 52 (Day 365): End of Maintenance Period
Endoscopy for the assessment of efficacy at Week 52 will occur within a window of 7 days prior 
to the Week 52 visit. The subject study diary requirements for the calculation of the modified 
Mayo score are outlined in APPENDIX 9. 
5.1.4
Open-label Extension Period
Subjects who continue to safely derive a clinical benefit from IP at Week 52, as judged by the 
investigator, are eligible to receive BMS-986165 6 mg BID PO in the open-label extension period. 
The open-label extension period will last 52 weeks, to Week 104. Study visits in this period occur 
every 4 weeks for the first 3 months, then approximately every 3 months afterwards, to Week 104. 
Subjects in the open-label extension period who meet any of the discontinuation criteria as defined 
in Section 8.1 should discontinue from the study (Section 8.2). An exit endoscopy is recommended 
for all subjects who undergo an ET visit between Weeks 56 and 104. 
The final endoscopy for the assessment of efficacy at Week 104 will occur within a window of 
7 days prior to the Week 104 visit. The subject study diary requirements for the calculation of the 
modified Mayo score are outlined in APPENDIX 9.
5.1.4.1
Post-treatment Follow-up
Subjects who complete the Week 104 visit, or who permanently discontinue study drug at any time 
during the study (Section 8), will enter a 4-week post-treatment follow-up period.
For subjects who continue to demonstrate clinical benefit after Week 104, a separate long-term 
extension study may become available in the future, subject to regulatory and Institutional Review 
Board (IRB) approval (Section 7.8).
5.1.5
Corticosteroid Use and Tapering Schedules
5.1.5.1
Corticosteroid Use in the Induction Period 
Prednisone ≤20 mg/day or budesonide MMX ≤9 mg/day are allowed, provided the dose is stable 
for 2 weeks prior to randomization (Section 7.7.2), and thereafter stable during the induction 
period. Corticosteroid tapering is not allowed during the induction period.
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5.1.5.2
Corticosteroid Tapering in the Maintenance Period
Subjects receiving corticosteroids during the induction period who achieve a clinical response at 
Week 12 must initiate a corticosteroid taper by Week 14, according to a standardized tapering 
schedule. Corticosteroids must be discontinued by Week 24, unless the subject has evidence of 
adrenal insufficiency. 
If a subject experiences disease worsening during the corticosteroid taper, the corticosteroid dose 
may be increased back to the baseline corticosteroid dose (ie, the dose the subject received at
Week 0 [Day1]), if clinically indicated. This may only be done once. The investigator must 
recommence the corticosteroid taper as soon as possible, with the intention of tapering 
corticosteroids by Week 24. 
Failure to discontinue corticosteroids by Week 24 will be considered a treatment failure (defined 
in Section 5.1.6), unless the subject requires glucocorticoid treatment for adrenal insufficiency. 
Subjects who remain on corticosteroids at Week 24 to treat adrenal insufficiency must be discussed 
with the medical monitor to continue on the study. 
The recommended tapering schedules for prednisone (or equivalent oral corticosteroid) and 
colonic-release budesonide are in Table 8. 
Table 8
Recommended Corticosteroid Tapering Schedule
Medication
Starting Dose
Schedule 
Prednisonea
≥15 mg QD PO
Taper daily dose by 5 mg/week until 
10 mg/day; continue tapering at 
2.5 mg/week until 0 mg/day
Prednisonea
11 mg - 15 mg QD PO
Taper daily dose to 10 mg/day for 
1 week; continue tapering at 
2.5 mg/week until 0 mg/day
Prednisonea
< 10 mg QD PO
Taper daily dose by 2.5 mg/week 
until 0 mg/day
Budesonide MMXb
≤9 mg QD PO
9 mg every other day for 1-2 weeks; 
continue tapering 9 mg every third 
day for 1-2 weeks until 0 mg/day
MMX = Multi-Matrix System; PO = oral; QD = every day
a Or equivalent oral corticosteroid
b Uceris extended release or equivalent colonic-release corticosteroid 
5.1.5.3
Corticosteroid Tapering in the Open-label Treatment Arm
Subjects receiving corticosteroids during the induction period who do not have a clinical response 
at Week 12 may be eligible to enter the open-label treatment arm. Such subjects must initiate a 
corticosteroid taper at Week 24 or earlier, according to the standardized tapering schedule 
described in Table 8 (Section 5.1.5.2). Corticosteroids must be discontinued by Week 36 unless 
the subject has evidence of adrenal insufficiency. As discussed in Section 5.1.5.2, 1 corticosteroid 
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dose escalation to the baseline (Week 0/Day 1) corticosteroid dose is allowed, but the 
corticosteroid taper must be recommenced as soon as possible, with the intention of tapering 
corticosteroids by Week 36. Failure to discontinue corticosteroids by Week 36 will be considered 
a treatment failure (defined in Section 5.1.6), unless the subject requires glucocorticoid treatment 
for adrenal insufficiency. Such subjects must be discussed with the medical monitor.
Subjects receiving corticosteroids in this open-label study arm who experience disease worsening 
(as defined in Table 5) at Week 36 (and thereafter) will permanently discontinue study treatment. 
They will enter the post-treatment follow-up period (see Section 5.1.4.1) and should be referred 
for appropriate treatment.
5.1.6
Treatment Failure 
For study purposes, treatment failure will be defined as:
1) Requirement for corticosteroid rescue therapy due to increased UC activity or failure to taper 
corticosteroids:
a) For subjects who are on an allowed, stable dose of corticosteroids at randomization: A 
requirement for the dose of corticosteroids to be increased above that baseline dose to 
treat UC during the induction period (Section 5.1.5.1) or more than 1 corticosteroid dose 
increase during the maintenance period (Section 5.1.5.2)
b) For subjects who are not on corticosteroids at randomization and in subjects who have 
tapered corticosteroids to 0 mg/day during the maintenance period: A course of systemic 
corticosteroids (> 24 hours in duration) or more than 1 discrete exposure to systemic 
corticosteroids (< 24 hours in duration) required to treat UC 
c) Failure to taper corticosteroids during the maintenance period by Week 24 unless the 
subject has adrenal insufficiency (in which case, the subject must be discussed with the 
medical monitor)
d) Failure to taper corticosteroids during the maintenance period by Week 36 in the Week 12 
nonresponder open-label arm, unless the subject has adrenal insufficiency (in which case, 
the subject must be discussed with medical monitor)
2) Requirement for an alternative, efficacious therapy for UC
5.1.7
Data Monitoring Committee and Other External Committees
An external DMC will be used in this study to perform safety monitoring by unblinded treatment 
group. 
Unblinded data summaries and listings will be provided to the DMC to facilitate their safety 
assessment at the regularly scheduled times, and on an ad hoc basis if needed. The safety review 
includes all AEs and events of special interest, focusing on early signal detection. Further details 
on the frequency, content, and methods of data reports to the DMC will be outlined in the DMC 
charter along with the processes and procedures the committee will follow.
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5.2
Number of Subjects
Approximately 120 subjects will be randomized. The sample size justification is in Section 10.1. 
Subjects who have completed screening procedures and met inclusion/exclusion criteria will be 
randomized in a 2:1 ratio to receive BMS-986165 6 mg BID PO or placebo BID PO during the 
induction period of 12 weeks. Current standard of care treatments may be continued as long as the 
dosing has been stable and allowed per the concomitant medications section of the protocol 
(Section 7.7). 
Randomization will be stratified based on corticosteroid use (yes/no) and prior exposure to 
biologics indicated for the treatment of UC (ie, no prior exposure, exposure to 1 biologic, or 
exposure to > 1 biologic; see Section 7.2). JAK inhibitors are considered as a biologic for 
stratification purposes. (Note: failure or loss of response to JAK inhibitors is exclusionary, but 
prior exposure without failure or loss of response is not exclusionary.)
To ensure real-world subpopulations are well represented in this study (ie, biologic-naive subjects 
and biologic-exposed subjects), approximately 40% biologic-naive subjects and 60% biologic-
exposed subjects will be randomized.
5.3
End of Study Definition
The duration of study participation for individual subjects may be up to approximately 112 weeks 
(784 days).
The start of the study is defined as the first visit for the first subject screened. The end of the study 
is defined as the last scheduled procedure shown in the Schedule of Activities (Section 2) for the 
last subject. Study completion is defined as the final date on which data were or are expected to be 
collected (Week 108 for collection of potential AEs and SAEs). 
 
5.4
Scientific Rationale for Study Design
This is a Phase 2 randomized, double-blind, placebo-controlled study to assess the safety and 
efficacy of BMS-986165 6 mg BID in subjects with moderate to severe UC. The primary objective 
is to assess the effect of BMS-986165 on clinical remission at Week 12. Subjects who have 
completed screening procedures and met eligibility criteria will be randomized in a 2:1 ratio to 
receive oral BMS-986165 6 mg BID or placebo BID during the 12-week induction period. The 
dose chosen for this study was done so with the intent to maintain exposure at or above the IC50 
of the target engagement. 
This Phase 2 study in subjects with UC will provide evidence of biologic activity of BMS-986165 
in a relevant disease population and will help determine the safety and efficacy of the BMS-986165 
dose of 6 mg BID. 
Inhibition of TYK2 is expected to provide therapeutic benefit for patients with UC for multiple 
reasons: 1) IL-12 and IL-23 have been implicated in the pathogenesis of UC8, 9, 10, 11; 2) Biologic 
agents targeting IL-23p19 and IL-12/IL-23p40 cytokines have been shown to be efficacious in UC 
and CD, and ustekinumab targeting IL-12/IL-23p40 has been approved for the treatment of CD12
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and UC; and 3) BMS-986165 has been shown to be efficacious in psoriasis, an IL-23-mediated 
disease, in a recent Phase 2 study.14
The eligibility and randomization criteria of this study are designed to ensure that subjects have 
the expected level of UC activity and to minimize the risk for serious infections that may be 
associated with immunosuppressive therapies.
The Mayo score is a combined endoscopic and clinical scale that is designed to assess UC severity. 
This score was first proposed by Schroeder et al16 and has since become widely accepted and used 
in many clinical trials and in clinical practice. 
 
 
 
 
The modified Mayo score is a composite of 
SF, RB, and ES subscores. Further details on the 
 modified Mayo score are 
in Section 9.1 and APPENDIX 9. The modified Mayo score will be used to assess disease severity 
for study eligibility and will be used to assess clinical remission and clinical response. 
 
A plan for corticosteroid tapering is included to allow subjects to discontinue corticosteroid 
throughout the maintenance period of the study (Section 5.1.5.2). Corticosteroid doses are required 
to be stable for at least 2 weeks prior to the randomization visit and must be at or below the allowed 
doses prior to the first dose of study treatment on Week 0 (Day 1) of the induction period (see 
Section 7.7.2). Subjects who take corticosteroid under the above mentioned conditions during the 
induction period and who achieve clinical response at Week 12 (Day 85) are to undergo 
recommended corticosteroid tapering during the start of the maintenance period (Section 5.1.3 and 
Table 8). This eventual corticosteroid withdrawal will make it possible to isolate the effects of 
assigned study treatments and to assess the effect of the IP in eliminating the need for corticosteroid 
use while maintaining disease control.
5.5
Justification for Dose
Subjects randomized for treatment in the induction period will receive 1 of 2 treatments: 
BMS-986165 at 6 mg BID or placebo BID during the induction period. 
The following points were considered for dose selection:
1. The preclinical studies of BMS-986165 showed an exposure-response relationship between 
BMS-986165 PK, target engagement assays, and efficacy indicators of interest in animal 
models of IBD.
2. Psoriasis is a disease highly dependent upon IL-17/IL-23 pathway;19 thus, the observed 
efficacy and dose response observed in psoriasis are assumed to be informative for dose 
selection in UC. In data from the psoriasis trial IM011011, an association was shown between 
the average concentration (Cavg) of BMS-986165 and efficacy. Based on this finding and the 
very limited information available to identify the exposure measure that best correlates with 
efficacy for TYK2 inhibition, the assumption that Cavg is correlated with efficacy is the most 
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reasonable assumption to make. Because preclinical studies of BMS-986165 indicate that 24-
hour coverage of the IC50 of the target engagement assay is correlated with a robust response, 
additional consideration was given to trough observed plasma concentration (Ctrough) to 
ensure that an adequate range of Ctrough spanning the IC50 was also captured in this trial.
3. The primary target engagement measurement used for dose selection based on the IL-12/IL-23 
pathway was the inhibition of IL-12/IL-18 induced interferon gamma (IFNγ) production 
measured in an ex-vivo assay in the FIH study. It is assumed that the inhibition of IL-12/IL-18 
assay is associated with efficacy in IBD. This assumption is supported by preclinical studies 
of BMS-986165 and the clinical improvements observed in UC and CD clinical trials 
conducted using biologic therapies directed against either the p40 subunit shared between 
IL-12 and IL-23 or p19, IL-23 only. Using the PK and target engagement data from the single 
ascending dose and multiple ascending dose portions of the FIH studies, a direct effect (Emax) 
model was developed to characterize the concentration-response relationship in the FIH study. 
Results of the analysis showed that the estimated IC50 for IL-12/IL-18-induced IFNγ 
production was approximately 6 ng/mL. With the assumption that the IC50 should be similar 
between healthy subjects and those with UC, the selected treatment level of 6 mg BID is 
expected to provide a median Cavg up to approximately 5.8 × the IC50 for this selected assay. 
The selected dose is also expected to provide a median Ctrough of approximately 2.6 × the 
IC50 for the assay.
The ideal amount of target inhibition in patients with UC using a selective inhibitor of TYK2 is 
not known because BMS-986165 is the first compound of this class. A higher dose (6 mg BID) 
was chosen as UC typically requires higher doses than in psoriasis (eg, ustekinumab) and greater 
target engagement to observe efficacy.
6
STUDY POPULATION
Eligibility criteria for this study have been carefully considered to ensure both the safety of the 
study subjects and the validity of the study results. It is imperative that subjects fully meet all 
eligibility criteria.
All screening and randomization evaluations must be completed and reviewed by the responsible 
investigator to confirm that potential subjects meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all subjects screened and to confirm eligibility or 
record reasons for screening failure, as applicable. Procedures conducted as part of the subject’s 
routine clinical management (eg, blood count) and obtained before signing of the ICF may be used 
for pre-screening purposes to allow predicting for potential eligibility during the screening period.
The duration of the screening period is up to 4 weeks. If eligibility parameters cannot be obtained 
within this time period, the screening period may be extended by up to 5 days if approved by the 
medical monitor. Rules for retesting and rescreening are provided in Section 6.5.1.
To be eligible for the study, subjects must meet all criteria in Sections 6.1 and 6.2. To be 
randomized into the study on Week 0 (Day 1), subjects must meet the criteria in Section 6.3.
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6.1
Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1) Signed Written Informed Consent
a) Willing to participate in the study and sign the ICF
b) Willing and able to complete all study specific procedures and visits
2) Type of Subject and Target Disease Characteristics
a) Not applicable (N/A) per Revised Global Protocol v3.0
b) N/A per Revised Global Protocol v3.0 
c) Active UC extending ≥15 cm from the anal verge and confirmed by a screening/baseline 
colonoscopy/sigmoidoscopy prior to the randomization visit
d) N/A per Revised Global Protocol v3.0
e) N/A per Revised Global Protocol v3.0 
f)
Documented diagnosis of UC of at least 3 months’ duration prior to screening, confirmed 
by:
1. Source: Medical records with report of an endoscopy, which shows features consistent with UC, 
as determined by the procedure performing physician, AND
2. Source: Medical record documentation of a histopathology report showing features consistent 
with UC, as determined by the local pathologist
Note: If a histopathology report is not available, histologic samples can be obtained at the 
screening endoscopy and sent to a local laboratory to confirm diagnosis of UC before 
proceeding to randomization. The screening endoscopy must show features consistent with 
UC, and medical records must still document a clinical diagnosis of UC of at least 
3 months’ duration prior to screening.
g) Must have active moderate to severe UC, as defined by a modified Mayo score of 5 to 
9 points (inclusive; see APPENDIX 9), which includes all of the following subscore 
values:
•
A stool frequency (SF) subscore of ≥2, and
•
A rectal bleeding (RB) subscore ≥1, and
•
A screening endoscopic (ES) subscore of ≥2 
h) Documentation of an inadequate response, loss of response, or intolerance to a treatment 
course of 1 or more of the following standard of care medications; specific criteria and 
dosing details are in APPENDIX 5:
•
Oral 5-aminosalicylic acids (5-ASAs) (eg, mesalamine, sulfasalazine, olsalazine, or 
balsalazide)
•
Corticosteroids (eg, prednisone [or equivalent] or budesonide [or equivalent])
•
Immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or 
methotrexate [MTX])
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•
Anti-tumor necrosis factor-alpha (TNF-α) agents (eg, infliximab, adalimumab, or 
golimumab)
•
Integrin inhibitors (eg, vedolizumab)
•
Anti-interleukin (IL)-12/IL-23p40 antibodies (eg, ustekinumab); subjects can only be 
included if they were intolerant to treatment. Inadequate response or loss of response 
is exclusionary.
i)
Subjects currently using concomitant salicylates, probiotics, or oral corticosteroid 
(≤20 mg prednisone or equivalent, ≤9 mg budesonide MMX or equivalent) at stable doses 
prior to the randomization visit are eligible provided they are on stable doses for the time 
period specified in Section 7.7.2
3) Age and Reproductive Status
a) N/A per Revised Global Protocol v3.0
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding, lactating, or planning pregnancy during the study 
period.
d) N/A per Revised Global Protocol v3.0 
e) N/A per Revised Global Protocol v3.0
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section. 
g) Males and females ages 18 (or age of majority) to 80 years, inclusive, at the time of 
screening
h) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatment(s) (BMS-986165 or placebo).
Investigators shall counsel WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective 
or less than highly effective methods of contraception (APPENDIX 4). 
6.2
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this 
study:
1) Target Disease
a) N/A per Revised Global Protocol v3.0
b) Current or recent (within 12 weeks prior to the randomization visit) evidence of fulminant 
colitis, abdominal abscess, toxic megacolon, or bowel perforation
c) History or evidence of any extensive colonic resection, subtotal or total colectomy, with or 
without presence of a stoma or ileoanal pouch. Current need for, or anticipated need for, 
surgical intervention for UC during the study
d) N/A per Revised Global Protocol v3.0
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e) N/A per Revised Global Protocol v3.0
f)
Current or recent (within 3 months before the first dose) gastrointestinal disease, including 
gastrointestinal surgery, which could impact the absorption of study treatment, or current 
or recent (within 6 months before the first dose) gastrointestinal resections
g) Previous/current documented diagnosis of CD, indeterminate colitis, ischemic colitis, or 
pseudomembranous colitis other than associated with Clostridium difficile (C. difficile). 
(See Section 6.2 5)h) Physical and Laboratory Test Findings for specific C. difficile
exclusion criterion.)
h) History of diverticulitis within 60 days prior to the randomization visit. (Previous 
diverticulitis that has been successfully treated with a local standard course of antimicrobial 
therapy is permitted; however, the course of antimicrobial therapy must be completed at 
least 60 days prior to the randomization visit.)
i)
Current colonic adenomas, dysplasia, or past confirmed colonic dysplasia that has not been 
eradicated (subjects who have had UC > 8 years should have had a colonoscopy to screen 
for dysplasia within 1 year prior to the randomization visit, or this can be performed as part 
of the screening colonoscopy). A subject with prior history of adenomatous polyps will be 
eligible if the polyps have been completely removed (documented), and the subject is free 
of polyps and without evidence of dysplasia on histology at randomization.
j)
Receiving tube feeding, defined formula diets, or total parenteral alimentation
2) Medical Conditions and History
a) Women who are pregnant or breastfeeding
b) Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, immunologic, 
psychiatric), or local active infection/infectious illness that, in the investigator’s judgment, 
will substantially increase the risk to the subject if he or she participates in the study
c) Any major surgery (requiring general anesthesia) within the last 30 days prior to the 
randomization visit, or any other major surgery planned during the course of the study
d) History of bleeding disorders or recent use of anti-platelet or anti-thrombotic agents that in 
the investigator’s judgment preclude safely performing endoscopic procedures and biopsy 
within the timeframe outlined in the study protocol
e) Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(other than adequately treated cutaneous basal cell or squamous cell carcinoma or resected 
cervix carcinoma in situ with no evidence of recurrence)
f)
Class III or IV congestive heart failure, as classified by the New York Heart Association 
(NYHA) Functional Classification or any recent onset of heart failure resulting in NYHA 
Class III/IV symptoms
g) Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or any 
history of significant cerebrovascular disease (eg, stroke, cerebral hemorrhage, transient 
ischemic attack) within 24 weeks before screening
h) Female subjects with a breast cancer screen suspicious for malignancy, and in whom the 
possibility of malignancy cannot be reasonably excluded after additional clinical, 
laboratory, or other diagnostic evaluations
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i)
Significant blood loss (> 500 mL) or blood transfusion within 4 weeks prior to the 
randomization visit
j)
Inability to tolerate oral medication
k) Inability to undergo venipuncture and/or tolerate venous access
l)
Drug or alcohol abuse, as determined by the investigator, within 6 months prior to 
Week 0 (Day 1). (Note: medical marijuana is not allowed.) 
m) Any other sound medical, psychiatric, and/or social reason as determined by the 
investigator
3) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments, as listed in Section 7.7
b) Previous exposure to BMS-986165 in any study
c) Prior exposure to treatment with TYK2 inhibitors
d) N/A per Revised Global Protocol v3.0
e) Failure or loss of response to JAK inhibitors, such as tofacitinib. Prior exposure is not 
exclusionary.
f)
N/A per Revised Global Protocol v3.0
g) N/A per Revised Global Protocol v3.0
h) Use of topical rectal treatment with 5-ASA or corticosteroid within 2 weeks prior to the 
randomization visit
i)
Current use of corticosteroid at a dose of > 20 mg/day for prednisone or equivalent or 
> 9 mg/day for budesonide MMX or equivalent
j)
N/A per Revised Global Protocol v3.0
k) N/A per Revised Global Protocol v3.0
l)
Previous stem cell transplantation
m) Receipt of either lymphocyte apheresis or selective monocyte, granulocyte apheresis (eg, 
Cellsorba™) is prohibited within 12 months prior to the randomization visit.
n) Use of therapeutic enema or suppository, other than required for ileocolonoscopy, within 
7 days prior to the randomization visit
o) N/A per Revised Global Protocol v3.0 
p) Inadequate response or loss of response to medications that target the same pathway as 
BMS-986165, such as anti-IL-12/IL-23p40 antibodies (eg, ustekinumab, briakinumab) or 
anti-IL-23p19 antibodies (eg, guselkumab, risankizumab, tildrakizumab, brazikumab 
[MEDI2070], and mirikizumab [LY3074828]). However, subjects who have been exposed 
to the medications listed above, but who have not had a treatment failure (ie, an inadequate 
response or loss of response) may be eligible for inclusion. Similarly, subjects who have 
experienced intolerance to the medications listed above (eg, an infusion reaction) without 
a treatment failure may be eligible for inclusion.
q) Use of other investigational agents within 4 weeks or 5 half-lives, whichever is longer, 
prior to randomization (APPENDIX 7) 
r)
Use of immunomodulators (AZA, 6-MP, or MTX) within 4 weeks prior to randomization 
(APPENDIX 7)
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s) Use of a biologic agent within the minimum washout period prior to randomization, as 
listed in APPENDIX 7
t)
Fecal transplant is considered an “investigational” biologic agent, and the washout period 
must be ≥4 weeks prior to the randomization visit.
4) Infections/Immune-related Exclusions
a) Evidence of active or latent tuberculosis (TB), as follows:
•
History of active TB prior to the screening visit, regardless of completion of adequate 
treatment
•
Has signs or symptoms of active TB as judged by the investigator
•
A chest x-ray obtained during the screening period or anytime within 6 months before 
screening, with documentation, with evidence of current active or old active 
pulmonary TB
•
Latent TB infection (LTBI) defined as positive IFNγ release assay (IGRA) such as 
QuantiFERON® - TB Gold, QuantiFERON® - TB Gold Plus, or T-Spot® at screening, 
or other diagnostic test in the absence of clinical manifestations
Note: such subjects may be eligible if (1) there are no current signs or symptoms 
of active TB and (2) the subject has received adequate documented treatment 
for LTBI within 5 years of screening OR has initiated prophylactic treatment 
for LTBI per local guidelines and is rescreened now after 1 month of treatment. 
The subject must agree to complete a locally recommended course of treatment 
for LTBI to continue in the study. 
•
An indeterminate IGRA result at screening with no signs or symptoms of active TB
•
Note: A subject with an indeterminate IGRA test result must be retested for 
confirmation. If the second result is again indeterminate, the subject will be excluded 
from the study. If the second result is positive, the subject should be treated as having 
LTBI. If the second result is negative, the subject may be eligible provided no other 
exclusion criterion for TB is met.
b) N/A per Revised Global Protocol v3.0
c) N/A per Revised Global Protocol v3.0
d) Positive for human immunodeficiency virus (HIV) by antibody testing (HIV-1 and 2 Ab) 
at screening. NOTE: Subjects who are newly found to be HIV-positive should be directed 
to appropriate follow-up. 
e) Currently on any therapy for chronic infection (eg, pneumocystis, cytomegalovirus, herpes 
simplex, herpes zoster, invasive bacterial or fungal infections, or atypical mycobacteria)
f)
History of congenital or acquired immunodeficiency
g) N/A per Revised Global Protocol v3.0
h) Previous history of herpes zoster, herpes simplex, or influenza infection within 12 weeks 
before the first dose of study treatment or a history of disseminated/complicated herpes 
zoster infection (multidermatomal involvement, ophthalmic zoster, central nervous system 
involvement, or post-herpetic neuralgia)
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i)
Administration of a live vaccine within 90 days or an inactivated vaccine within 30 days 
before the first dose of study treatment administration. Heat-killed, or otherwise inactivated 
or protein vaccines (eg, influenza and pneumococcal vaccines) may be received at any time 
on study. Furthermore, live vaccines should not be used during the study and within the 
2 months following last dose, and any other inactivated vaccines (eg, tetanus, etc.) should 
be used according to local guidelines during the treatment period. 
j)
Evidence of, or positive test for, hepatitis B virus (HBV) at screening as defined per 
APPENDIX 8.
k) Evidence of, or positive test for, hepatitis C virus (HCV) at screening. A positive test for 
HCV is defined as:
(1) Positive for HCV antibody (anti-HCV) and
(2) Positive via a confirmatory test for HCV (eg, detectable HCV RNA, HCV 
polymerase chain reaction) (see APPENDIX 8).
l)
Known serious infection, defined as any infection requiring hospitalization or treatment 
with parenteral (intramuscular [IM] or IV) antimicrobial agents (eg, antibiotics, antiviral, 
antifungal, or antiparasitic agents) within 30 days of the first dose of study treatment, or 
completion of oral antimicrobial agents within 2 weeks of the first dose of study treatment. 
Antibiotics used to cover a procedure such as endoscopy would not exclude the subject.
(1) In the case of prior SARS-CoV-2 infection, symptoms must have completely 
resolved 4 weeks prior to screening and based on investigator assessment in 
consultation with the medical monitor, there must be no sequelae that would place 
the participant at a higher risk of receiving BMS-986165. See Section 9.8 for 
additional information regarding retesting subjects who have prior SARS-CoV-2 
infection.
5) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG, chest x-ray, or clinical laboratory determinations 
beyond what is consistent with the target population
b) Clinically significant abnormalities on chest x-ray or ECG
c) N/A per Revised Global Protocol v3.0
d) N/A per Revised Global Protocol v3.0
e) Any other significant laboratory abnormalities that, in the opinion of the investigator, might 
place the subject at unacceptable risk for participation in this study 
f)
Clinically significant abnormalities in laboratory testing including:
•
Serum alanine aminotransferase (ALT) > 2× upper limit of normal (ULN) 
•
Serum aspartate aminotransferase (AST) > 2× ULN 
•
Serum total bilirubin > 2× ULN (Exception: subjects can be included if they have a 
confirmed diagnosis of Gilbert Syndrome that is documented, and when other causes 
of isolated bilirubin elevation have been excluded.)
•
Alkaline phosphatase > 2.5× ULN
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•
Serum creatinine > 2× ULN and/or renal impairment based on an estimated glomerular 
filtration rate (eGFR) <45 mL/min (calculated using the Modification of Diet in Renal 
Disease [MDRD] equation)
•
Hemoglobin level < 9.0 g/dL 
•
Absolute white blood cell count < 3000/mm3 
•
Absolute lymphocyte count < 750/mm3
•
Neutrophil count < 1000/mm3
•
Platelet count < 100,000/mm3 
g) Positive stool culture for enteric pathogens (not including flora that are considered 
commensal within a study region) at screening visit; subjects may rescreen 30 days after 
completion of a standard treatment course with antimicrobial agents without recurrence of 
clinical symptoms.
h) Stool positive for C. difficile toxin at screening visit; subjects may be rescreened 30 days 
after completion of an institutional standard of care course with antibiotics, and subsequent 
negative testing for C. difficile stool toxin and a C. difficile nucleic acid amplification test. 
Test results should be discussed with the medical monitor prior to rescreening.
6) Allergies and Adverse Drug Reaction
a) N/A per Revised Global Protocol v3.0
b) History of any significant drug allergy (eg, anaphylaxis) or significant adverse drug 
reaction (eg, hepatotoxicity)
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply, and Bristol-Myers Squibb approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
6.3
Randomization Criteria
Eligible subjects must meet the following criteria on Week 0 (Day 1) before randomization and 
the first dose of study treatment: 
1) The subject continues to satisfy all eligibility criteria 
2) Previous therapy must follow the rules outlined below:
a) Dose stabilization: 
•
5-ASAs must be at stable doses for at least 2 weeks prior to randomization.
•
Probiotics must be at stable doses for at least 2 weeks prior to randomization.
•
Prednisone ≤20 mg QD PO (or equivalent) or budesonide MMX ≤9 mg QD PO (eg, 
Uceris extended release or equivalent) must be stable for at least 2 weeks prior to 
randomization.  
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b) Washout periods for immunomodulator and biologic treatments: Subjects must comply 
with the washout periods outlined in APPENDIX 7.
6.4
Lifestyle Restrictions
No restrictions are required.
Smoking can have an influence on the severity of UC disease symptoms. Consequently, use of 
tobacco products will be assessed at each study visit. Use of a nicotine patch should be recorded 
as a concomitant medication.
Study treatment may be taken without regard to meals. However, subjects are required to fast for 
a minimum of 10 hours before visits on which fasting lipid and fasting glucose samples will be 
drawn; at 2 of these visits (Week 0 [Day 1] and Week 12 [Day 85])
 
.
6.5
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but who are 
not subsequently randomized in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects, to meet the Consolidated Standards of
Reporting Trials (CONSORT) publishing requirements, as applicable, and to respond to queries 
from regulatory authorities. Minimal information includes date of consent, demography, screen 
failure details, eligibility criteria, and any SAEs. 
6.5.1
Retesting During the Screening Period and Rescreening 
This study permits the rescreening of a subject who has been deemed as ineligible (screen failure) 
during the screening period (ie, the subject has not been randomized/has not been treated). The 
subject must be re-consented.
For laboratory parameters and/or assessments (Table 1) that initially do not meet eligibility 
requirements, a single retest within the 28-day screening period is permitted in an effort to find all 
possible well-qualified subjects, unless otherwise noted. Consultation with the medical monitor 
may be needed to identify whether repeat testing of any particular parameter is clinically relevant. 
A subject can only be rescreened 1 time (ie, if the subject fails 1 rescreening attempt, no additional 
rescreening is allowed). If a subject is rescreened, the endoscopy previously performed at the 
initial screening may be used for rescreening purposes. This is permitted if the 
randomization following rescreening occurs within 14 days of the initial screening 
endoscopy. 
NOTE: Use of the initial screening endoscopy for rescreening purposes should be discussed 
with the medical monitor before randomization occurs. 
Duration of existing treatments and required discontinuation periods shall be considered relative 
to the successful screening visit and/or randomization. 
If a subject is positive for C. difficile toxin, they can be rescreened 30 days after completing a full 
course of standard treatment for C. difficile colitis and subsequently testing negative for C. difficile
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stool toxin and a C. difficile nucleic acid amplification test. The subject must be re-consented and 
will be assigned a new identification number, and a full screening visit must be performed again. 
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the subject’s most current clinical state. 
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 subject according to the study randomization 
or treatment allocation. 
An investigational product (IP), also known as an investigational medicinal product (IMP) in some 
regions, is defined as 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.
IM011024 consists of IP study treatments BMS-986165 and placebo (see Table 9). Information 
about the pharmacology and previous experience with BMS-986165 is provided in Section 3.2.1
and Section 3.2.2.
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-IPs.
Table 9
Study Treatments for IM011024
Product 
Description/
Class and 
Dosage Form
Potency
IP/
Non-IP
Blinded or 
Open-label
Packaging/Appearance
Storage 
Conditions
(per label)
BMS-986165 
oral tablet
6 mg 
(as the 
free base)
IP
Blinded
Bottle containing 68 (6 mg) 
active tablets required for 
daily dosing
Store 15° to 25°C; 
Store in a tightly 
closed container; 
Protected from 
light
Placebo 
matching 
BMS-986165 
oral tablet
Not 
applicable
IP
Blinded
Bottle containing 68 (6 mg) 
placebo tablets required for 
daily dosing
Store 15° to 25°C; 
Store in a tightly 
closed container; 
Protected from
light
BMS-986165 
oral tablet
6 mg 
(as the 
free base)
IP
Open-label 
Bottle containing 68 (6 mg) 
active tablets required for 
daily dosing
Store 15° to 25°C; 
Store in a tightly 
closed container; 
Protected from 
light
IP = investigational product
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7.1
Treatments Administered
During the induction period, subjects will take BMS-986165 6 mg BID or placebo BID over 
12 weeks (Section 5.1.2), once in the morning and once in the evening. Dose information for each 
treatment group in the induction period is provided in Table 10. 
 
Study treatment will be supplied in bottles, each containing 68 film-coated active or placebo 
tablets. Bottles are to be stored at 15 C to 25°C and protected from light.
If a subject forgets a dose, but remembers within 4 hours of the expected dose, the dose should be 
taken. If it is past 4 hours, that dose should be missed, and the next expected dose should be taken 
at the usual time.
Study treatment will be administered in the maintenance period, as described in Section 5.1.3 and 
illustrated in Figure 1.
Clinical Responders at Week 12: Subjects who achieve a clinical response at Week 12 (Table 5) 
who enter the double-blind, placebo-controlled maintenance period, will take the same blinded 
study treatment (BMS-986165 6 mg BID or placebo BID) that was assigned during the induction 
period. 
Clinical Nonresponders at Week 12: Subjects who do not achieve a clinical response at Week 12 
(Table 5) may be eligible to receive BMS-986165 6 mg BID in the open-label study arm, 
regardless of the initial treatment regimen received during the 12-week induction period.
Study treatment will be administered in the OLE period as described in Section 5.1.4 and 
illustrated in Figure 2.
Table 10
Selection and Timing of Dose
Study Treatment
Unit dose 
strength
Dosage formulation
Frequency of Administration
Route of 
Administration
6 mg BID 
BMS-986165
6 mg
1 active tablet; BID
Oral
Placebo BID
Not applicable
1 placebo tablet; BID
Oral
BID = twice daily
7.2
Method of Treatment Assignment
At the time of the screening visit, immediately after informed consent is obtained and before any 
study-related procedures are performed, the investigative site will access the interactive response 
technology (IRT) system for assignment of the subject number. This number will be unique across 
all sites. All subjects who sign informed consent will be assigned sequential subject numbers. The 
subject number may not be used for any other subject. If a potential subject is rescreened, they will 
be given a new subject number. 
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Eligible subjects will be centrally randomized using IRT at a 2:1 randomization ratio to receive 
oral treatment during the induction period with either BMS-986165 6 mg BID or placebo BID, 
according to a computer-generated block randomization scheme and in accordance with 
stratification criteria. Randomization numbers will be assigned prior to dosing. Randomization 
will be stratified by corticosteroid use (yes/no) and prior exposure to biologics indicated for 
treatment of UC; biologics includes JAK inhibitors for stratification purposes. Stratification 
groups: no prior biologic exposure (0), exposure to 1 biologic (1), or exposure to more than 1 (> 1) 
biologic.
Before the study is initiated, each user (at investigative sites) will receive log-in information and 
directions on how to access the IRT. Study treatment will be dispensed at study visits as shown in 
Section 2 (Schedule of Activities). 
Subjects who have completed the 12-week induction period will be eligible to enter the 
maintenance period. Their assigned maintenance treatment will be based on whether or not they 
achieved clinical response at Week 12 (Section 9.1.1). Responders will continue on their assigned 
double-blind treatment while nonresponders will be given the option to switch to open-label 
BMS-86165 6 mg BID through Week 52 or may choose to discontinue the study.
For subjects who are entered into the open-label portion of the study, BMS-986165 will be supplied 
in bottles of 6 mg tablets and subjects will take the requisite number of tablets for their daily 
dosing. These bottles will be assigned through the IRT to each subject during their dosing visits. 
Subjects who have completed the 52-week maintenance period will be eligible to enter the 52-week 
open-label extension period. Eligibility will be based on the investigator's assessment of clinical 
benefit at Week 52 (Section 5.1.4). 
7.3
Blinding
7.3.1
Maintaining the Blind
Blinded treatment assignments will be managed using IRT. 
All tablets (BMS-986165 6 mg and placebo) are identical in appearance and will be supplied in 
bottles (see Section 7.1). Investigative site staff, Sponsor and designee personnel, and subjects and 
their families will remain blinded to treatment assignments. 
7.3.2
Circumstances for Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the IP
is critical to the subject’s management, the blind for that subject may be broken by the investigator. 
The subject’s safety takes priority over any other considerations in determining if a treatment 
assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the IP, the 
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problem may be properly managed by assuming that the subject is receiving active product. It is 
highly desirable that the decision to unblind treatment assignment be discussed with the medical 
monitor, but the investigator always has ultimate authority for the decision to unblind. The 
Principal Investigator should only call in for emergency unblinding AFTER the decision to 
discontinue the subject has been made.
In case of an emergency, the investigator has unrestricted access to randomization information via 
IRT and is capable of breaking the blind through the IRT system without prior approval from the 
Sponsor. After the unblinding, the investigator shall notify the medical monitor and/or study 
director. The method of unblinding for emergency purposes is described in the IRT manual. 
Subject and unblinded treatment information and the reason for the blind being broken, must be 
recorded on the appropriate study status page of the electronic case report form (eCRF). After 
unblinding via IRT, the investigator shall notify the medical monitor.
In cases of accidental unblinding, contact the medical monitor, and ensure every attempt is made 
to preserve the blind. Any request to unblind a subject for nonemergency purposes must be 
discussed with the medical monitor.
7.4
Dosage Modification and/or Interruption
There is no provision for dose modification of study treatment. Titration of corticosteroid and its 
use as rescue therapy are discussed in Section 5.1.5.2 and Section 5.1.5.3. Modification of other 
background UC therapies or dose regimens is not permitted during study participation. Subjects 
should continue to take their assigned treatment even if they experience flares and/or are unable to 
taper their corticosteroid dose, unless any of the criteria in Section 8.1 are met. If a subject’s 
clinical condition worsens (eg, flares) during the induction period to the extent that rescue therapy 
is required based on the investigator’s judgment, the subject must discontinue study treatment (IP 
or placebo) for appropriate alternative available treatment. 
If treatment is interrupted for a subject due to an AE, study treatment can be restarted in 
consultation with the medical monitor.
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study subjects. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
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concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and BMS should be contacted immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
APPENDIX 2 and the Study Reference Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence
Not applicable.
7.6
Treatment Compliance
Study treatment compliance will be monitored as indicated in the Schedule of Activities 
(Section 2) using standard drug accountability procedures (comparing the number of tablets 
returned to number dispensed, considering the expected regimen and any reported missed doses). 
Drug accountability will be reviewed by the investigative site staff at each visit to confirm 
treatment compliance. Site staff will discuss any discrepancies with the subject and remind the 
subject of the importance of compliance with the assigned regimen. A real-time monitoring 
platform may be used.
7.7
Concomitant Therapy
All medications taken from within 4 weeks before the first dose of study treatment until 30 days 
after the last dose of IP or last visit (whichever comes later) must be recorded on the eCRF.
Other than existing treatment for UC (with restrictions as described in the eligibility criteria 
[Section 6]), concomitant medications (prescription, over-the-counter [OTC], or herbal) should be 
administered during the study only if they are prescribed for treatment of specific medical reasons 
separate from UC.
7.7.1
Prohibited and/or Restricted Treatments
Restrictions and prohibitions on prior and concomitant medications are summarized in Table 11.
Table 11
Prohibited and/or Restricted Treatments
Prohibited Treatments 
Medication/Formulation 
Notes 
BMS-986165 or other TYK2 inhibitors
Prior exposure is prohibited
Corticosteroids: oral > 20 mg/day prednisone (or 
equivalent) or > 9 mg/day budesonide MMX (or 
equivalent)
Prohibited during the study; subjects are allowed to reduce 
their oral corticosteroid dose to ≤20 mg/day (Section 7.7.2) 
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Table 11
Prohibited and/or Restricted Treatments
Prohibited Treatments 
Medication/Formulation 
Notes 
and be rescreened for study entry. Only 1 rescreening is 
allowed (Section 6.5.1)
Corticosteroids: IV, IM, intra-articular, intrabursal
Prohibited during the study; use of IV corticosteroid is also 
prohibited within 2 weeks prior to the screening period
Corticosteroid or 5-ASA/topical rectal treatment
Prohibited within 2 weeks of the randomization visit and 
during study
Immunomodulatory drugs
Prohibited within required washout periods (APPENDIX 7)
Biologic drugs 
Prohibited within required washout periods (APPENDIX 7)
Live vaccines
Prohibited 90 days prior to the randomization visit; during 
the induction period, maintenance period, or OLE; or within 
the 2 months after the last dosea
Apheresis
Receipt of either lymphocyte apheresis or selective 
monocyte, granulocyte apheresis (eg, Cellsorba™) is 
prohibited within 12 months prior to the randomization visit
Investigational agents
Prohibited within 4 weeks or 5 half-lives (whichever is 
longer) before the randomization visit
Over-the-counter medications or
herbal preparations 
Prohibited within 1 week prior to the randomization visit; 
any exceptions to this must be cleared by the medical 
monitor
Restricted Treatments
Medication
Notes 
Corticosteroids/topical or inhaled to treat non-UC 
medical conditions
Allowed but must be discussed with the medical monitor
Systemic corticosteroids (< 7 days in duration) to 
treat non-UC medical conditions 
Allowed but must be discussed with the medical monitor to 
determine if the intercurrent illness affects the safety of the 
subject, or if the corticosteroid treatment is likely to 
confound efficacy assessment
Nonsteroidal anti-inflammatory drugs (NSAIDs) for 
indications other than UC-related pain (eg, 
headache)
May be used on an as-needed basis during the study, but 
use is not recommended. If a subject enters the study on a 
stable dose of NSAIDs, they may continue this dose 
throughout the study after discussing with the medical 
monitor. NSAID dosing may be decreased or discontinued 
if due to NSAID toxicity
5-ASA = 5-aminosalicyclic acid; COVID-19 = coronavirus disease 2019; IM = intramuscular; IV = intravenous;
MMX = Multi-Matrix System; NSAID = nonsteroidal anti-inflammatory drug; OLE = open-label extension; TYK2 = 
tyrosine kinase 2; UC = ulcerative colitis
a Heat-killed (or otherwise inactivated) or protein or subunit vaccines such as influenza and pneumococcal vaccines, 
nucleic acid vaccines that do not encode potentially infectious virus, and replication-incompetent recombinant 
vector vaccines may be received at any time during the study. The efficacy of vaccination in subjects who are 
receiving BMS-986165 is unknown. For COVID-19 vaccine information refer to APPENDIX 19.
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7.7.2
Existing Therapies for Ulcerative Colitis
Use of concomitant 5-ASAs, probiotics, and oral corticosteroids (prednisone ≤20 mg/day or 
equivalent, or budesonide MMX [≤9 mg/day or equivalent]) is permitted. All subjects will 
continue their existing UC treatment(s) during the study (provided the treatment complies with the 
eligibility criteria; Section 6), unless dose modification or discontinuation is required for subject 
safety reasons, as follows:
•
5-ASAs: Must be at stable doses for at least 2 weeks prior to the randomization visit; stable 
doses must be maintained during the induction period. During the maintenance period, a dose 
decrease is permitted if due to moderate to severe drug-related toxicity.
•
Probiotics: Must be at stable doses for at least 2 weeks prior to the randomization visit; stable 
doses must be maintained during the induction period. During the maintenance period, a dose 
decrease is permitted if due to moderate to severe probiotics related toxicity.
•
Oral corticosteroids: Prednisone ≤20 mg QD PO (or equivalent) or budesonide
MMX ≤9 mg QD PO (eg, Uceris extended release or equivalent) must be stable for at least 
2 weeks prior to the randomization visit; stable doses must be maintained during the induction 
period (Section 5.1.5.1). Corticosteroid tapering must occur in the maintenance period, as 
described in Section 5.1.5.2.
•
If a subject has recently stopped taking any of the above medications (5-ASAs, probiotics, oral 
corticosteroids), he/she must have been stopped for ≥4 weeks prior to the randomization visit.
•
Prior exposure to immunomodulator and biologic treatments: Subjects must comply with the 
washout periods outlined in Section 5.1.1 and APPENDIX 7. 
7.8
Treatment After the End of the Study
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS-supplied study treatment. Study treatment will be provided via an 
extension of the study, a rollover study requiring approval by responsible health authority and 
ethics committee or through another mechanism at the discretion of BMS.
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 BMS-986165 is 
terminated for any reason, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the subject 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
Subjects MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons: 
•
Subject’s request to stop study treatment. Subjects who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol-specified post-treatment 
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follow-up procedures (Section 5.1.4.1). The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information.
•
Subject meets 1 of the following criteria for laboratory abnormalities in 2 sequential laboratory 
measurements taken 3 to 5 days apart: 
•
White blood cell count < 1.5 × 109/L (< 1,500/mm3)
•
Absolute neutrophil count < 0.75 × 109/L (< 750/mm3)
•
Absolute lymphocyte count < 0.5 × 109/L (< 500/mm3)
•
Hemoglobin < 8.0 g/dL or a decrease of > 30% from baseline
•
Platelet count < 75 × 109/L (< 75,000/mm3)
•
An increase in serum creatinine > 50% over the average of screening and baseline 
(Week 0/Day1) values and
an absolute increase in serum creatinine > 0.5 mg/dL 
(> 44.2 μmol/L)
•
Creatine kinase elevations > 10 × ULN, unless the causality is known not to be medically 
serious (eg, exercise induced)
•
Subject who develops a serious infection during the study defined as any infection (viral, 
bacterial, and fungal) requiring parenteral antimicrobial therapy, hospitalization for treatment, 
or meeting other criteria that require the infection to be classified as an SAE
•
Any drug-related rash or hypersensitivity reaction (eg, anaphylaxis, angioedema, urticaria, 
Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms [DRESS], 
Toxic Epidermal Necrolysis [TEN]) deemed by the investigator to be severe or life threatening
•
Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Unblinding of a subject’s treatment assignment for any reason (emergency or nonemergency)
•
Inability or failure to comply with protocol requirements
•
Pregnancy, positive pregnancy test, or subject expresses an interest in becoming pregnant 
(Refer to Section 9.2.5 Pregnancy)
•
Requirement for any rescue therapy during the induction period
•
Requirement for additional rescue therapy during the maintenance period, other than as 
specified in Section 5.1.5.2
•
Requirement for any rescue therapy during the open-label extension period
•
Subject meets any of the criteria for treatment failure defined in Section 5.1.6
•
Abnormal liver tests suggestive of drug-induced liver injury (DILI), as defined Section 9.2.7, 
or if the investigator believes that it is in the best interest of the subject
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Refer to the Schedule of Activities (Section 2, Table 4) for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that would be completed.
All subjects who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in the Schedule of Activities (Section 2). The only exception to this 
requirement is when a subject withdraws consent for all study procedures including post-treatment 
study follow-up or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated 
for the treatment of either a psychiatric or physical illness). Replacement of subjects is not 
permitted (Section 8.4). 
If study treatment is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate eCRF page.
8.1.1
Post-Study Treatment Study Follow-Up
Subjects who discontinue study treatment will continue to be followed for 28 days post last dose 
of study medication, or longer, as required, and in line with Section 9.2.3 (Follow-up of AEs and 
SAEs).
8.2
Discontinuation from the Study
Subjects who request to discontinue study treatment (Section 8.1) will remain in the study and 
continue to be followed for protocol-specified post-treatment follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact with 
him/her or persons previously authorized by subject to provide this information. 
•
Subjects 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 and entered on the appropriate eCRF page.
•
In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
•
If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
8.2.1
Temporary Discontinuation
The following criteria for temporary interruption of study treatment apply:
•
For those subjects who present with signs and/or symptoms of COVID-19 during the study, 
the study treatment should be temporarily interrupted while the subject undergoes diagnostic 
testing for SARS-CoV-2 (see Section 9.8).
•
Study treatment must be temporarily interrupted for subjects who test positive for 
SARS-CoV-2 until complete recovery (if symptomatic), and a negative molecular test result is 
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obtained. Study treatment may be restarted at investigator discretion following consultation 
with the BMS medical monitor/designee provided that the subject meets the criteria outlined 
in Section 9.8.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject.
•
Lost to follow-up is defined by the inability to reach the subject after a minimum of 
3 documented phone calls, faxes, or emails as well as lack of response by subject to 1 registered 
mail letter. All attempts should be documented in the subject’s medical records.
•
If it is determined that the subject 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 subject’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, to obtain updated contact information.
•
If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical 
records.
8.4
Replacement of Subjects
Subject replacement is not permitted.
8.5
Discontinuation of Study Conduct/Study Stopping Rules
There will be a DMC to provide oversight of the safety in this trial as outlined in Section 5.1.7 of 
the protocol. The DMC is responsible for assessing the ongoing acceptability of the benefit/risk 
profile for the study drug in an unblinded manner. Subjects, investigators, site staff, and Sponsor 
all remain blinded to study treatment throughout the conduct of the trial. 
The DMC will review unblinded study treatment information and safety data to adjudicate study 
treatment relatedness and to make a recommendation regarding the appropriateness of continuing 
the study, with or without study modifications, or stopping the study under the following 
circumstances, which are not clearly related to the underlying UC:
•
Two or more subjects experience an SAE of the same preferred term and that is considered 
related to the study treatment by the investigator (for example, not explained by intercurrent 
medical condition or concomitant medication)
•
Two or more subjects are discontinued due to the same laboratory abnormality as defined by 
criteria in Section 8.1
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Full details of the DMC data review can be found in the DMC Charter.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (Section 2). Waivers or 
exemptions from protocol-required evaluations are not allowed.
All immediate safety concerns must be discussed with the medical monitor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue treatment.
Adherence to the study design requirements, including those specified in the Schedule of Activities 
(Section 2), is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects meet 
all eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the subject’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 (Section 2).
The study data includes all the information that is collected as a result of the study, including 
subject demographics, disease characteristics (eg, Montreal classification), clinical information, 
blood tests, 
 endoscopic videos, intestinal biopsies obtained during endoscopy, and 
other tests listed in Section 2. Study data collected during this study will be used to help understand 
how BMS-986165 works in people with UC and related health conditions. The study data may 
also be used to help understand the biology of UC and related health conditions, study test 
performance in people with UC, and for other relevant health research relating to BMS-986165 or 
these health conditions.
9.1
Efficacy Assessments
Every effort must be made to ensure that the same evaluator(s) complete the assessment for each 
subject. If the evaluator(s) is unable to complete the evaluation, then a qualified individual with 
overlapping experience may perform the evaluation. Documentation of who performed the 
evaluation is to be recorded in source documents. Assessments are to be performed at 
approximately the same time of day throughout the duration of the study. 
Baseline assessments must be performed per protocol (standard of care assessments may not be 
used for baseline). Procedures not specified in the protocol that are part of standard care may be 
performed if they do not interfere with study procedures; any data arising from such procedures 
are not to be reported in the eCRF. 
The following procedures or tools will be used to assess subjects’ UC activity during the study 
(see Schedule of Activities in Section 2): 
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•
Mayo Scores: Details regarding the calculation of the modified 
 Mayo score  and the 
recording of the individual Mayo score components (SF, RB, ES
) 
are provided in APPENDIX 9. Electronic diaries will be provided to each subject for daily 
recording of SF and RB. Each day, a subject will enter his/her number of stools and RB 
assessment into the electronic subject diaries, according to instruction in APPENDIX 9. Should 
the subject miss daily entries prior to a visit, the investigator will assess if the visit should be 
rescheduled to ensure an adequate number of daily entries are recorded. 
−
Modified Mayo Score18: The modified Mayo score is an adapted total Mayo score that is 
a composite of the following components (each scored on a scale of 0 to 3 points): 
♦SF subscore 
♦RB subscore 
♦ES subscore
The modified Mayo score is a 9-point scale in which a score of 5 to 9 points denotes moderate to 
severe disease. 
Timings of SF and RB assessments, endoscopy, and the modified Mayo score calculations are 
provided in the Schedule of Activities (Section 2).
•
Geboes Score21: Biopsies for histological assessment will be taken on the days indicated in the 
Schedule of Activities (Section 2). This assessment will be carried out by the 
 
 group. Further details on the biopsy collection and processing for this histological 
assessment are provided in the Histopathology Image Review Charter.
 
 
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•
Serum hsCRP levels
The 
 group is the central vendor responsible for reading and scoring all 
endoscopies and biopsies 
. These procedures are 
described in the Endoscopy Image Review Charter and Histopathology Image Review Charter.
9.1.1
Clinical Response Assessment
Clinical response for efficacy analysis will be determined with the modified Mayo score (defined 
in Section 9.1 and APPENDIX 9) calculated with an ES subscore derived from the central read of 
endoscopies. The central read of the endoscopy will be used for efficacy analysis at all time points.
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At Week 12, clinical response for the determination of maintenance period treatment assignment 
will be determined with the modified Mayo score calculated with an ES subscore derived from a 
local read of endoscopies. 
9.2
Adverse Events
The definitions of an AE or SAE can be found in APPENDIX 3.
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject’s 
legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the subject to 
interrupt or discontinue study treatment before completing the study. 
Contacts for SAE reporting are specified in APPENDIX 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until the 
follow-up visit at Week 108 or the last visit, at the time points specified in the Schedule of 
Activities (Section 2). Nonserious AE information should also be collected from the start of the 
treatment period at Day 1. The Reference Safety Information in Sections 5.6.1 and 5.6.2 of the IB 
should be used to determine the expectedness of SAEs for expedited reporting.15
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. 
All AEs and SAEs related to SARS-CoV-2 infection must be collected from the time of signing 
the consent to the end of the safety follow-up period (30 days after treatment discontinuation) or 
roll-over into an extension study.
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 eCRF module.
•
All SAEs will be recorded and reported immediately to Sponsor or designee but no later than 
24 hours after awareness of the event, as indicated in APPENDIX 3. 
•
The investigator will submit any updated SAE data to the Sponsor or designee immediately
but no later than 24 hours of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study treatment 
or study participation, the investigator must promptly notify the Sponsor or designee.
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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 subject. (To prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
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 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 case report form (CRF). 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 subject at 
subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as defined in 
Section 9.2.8) will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the subject is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in APPENDIX 3.
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 toward the safety of subjects 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 IB and will notify the Institutional Review Board (IRB)/Independent Ethics Committee 
(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 suspected, unexpected serious adverse reaction 
(SUSAR) 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 
5 half-lives after study product administration, the investigator must immediately notify 
Drug 
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Safety of this event and complete and forward a Pregnancy Surveillance Form to 
Drug Safety 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in APPENDIX 3.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form (see APPENDIX 3).
Any pregnancy that occurs in a female partner of a male study subject should be reported to 
 
Drug Safety. In order for the Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form 
in APPENDIX 3.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the AE eCRF page:
•
Any laboratory test result that is clinically significant or meets the definition of an AE or SAE 
•
Any laboratory test result abnormality that required the subject to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
If a laboratory test result meets the definition of an AE or SAE, the laboratory test result should be 
reported as an AE or SAE and submitted to 
Drug Safety, as specified in APPENDIX 3. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
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 9.2 and APPENDIX 3 for reporting 
details).
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN,
3) AND
4. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
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AND
5. No other immediately apparent possible causes of ALT or AST 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
Adverse Events of Interest (Clinical Safety Program)
All AEs and SAEs that arise in the study will be reported and investigated. However, because of 
the characteristics of the disease under study and BMS-986165 in particular, some AEs are 
considered AEIs. Adverse events of interest may be serious or nonserious. Such events may require 
further investigation to better characterize and understand them. In the BMS-986165 clinical 
development program, certain skin-related AEs (eg, acne) and 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 BMS-986165. 
In addition, given that immunosuppression is consistent with the mechanism of action of 
BMS-986165, malignancies are considered to be an important potential risk of therapy with 
BMS-986165 and should be monitored as AEIs. Malignancies were not identified as adverse 
findings in nonclinical studies and no serious adverse reactions of malignancy have been reported 
to date in clinical studies of BMS-986165.
For purposes of reporting these AEIs, specialized eCRF pages will be required to collect additional 
information related to characterization, social/family history, risk factors, signs/symptoms, 
diagnostics, and treatments. 
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a nonserious AE or SAE, as appropriate, and reported accordingly.
9.3
Overdose
For this study, any dose of BMS-986165 that is more than 2-days’ worth of study treatment within 
a 24-hour time period will be considered an overdose.
In the event of an overdose the investigator should do the following:
1. Contact the medical monitor immediately
2. Closely monitor the subject for AEs/SAEs and laboratory abnormalities until BMS-986165 
can no longer be detected systemically (at least 3 days)
3. 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 subject.
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9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2). 
All urgent safety concerns must be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue treatment.
Safety evaluations that will be performed in addition to AE monitoring are physical examination 
(Section 9.4.1), TB screening (Section 9.4.2), vital signs (Section 9.4.5), ECGs (Section 9.4.6), 
concomitant medication use (Section 7.7), laboratory tests (Section 9.4.3).
9.4.1
Physical Examinations
Schedules for physical examinations are provided in the Schedule of Activities (Section 2). 
Complete physical examinations may be performed by a Doctor of Medicine (MD), or someone 
who is authorized to perform the examinations by training and has been delegated this task by the 
Principal Investigator. Key aspects of the examination should evaluate important body systems as 
clinically indicated. Every effort should be made to ensure the same evaluator will complete the 
examination for each subject at all visits throughout the study. Documentation of who performed 
the examination is to be recorded in source notes.
9.4.2
Tuberculosis Screening and Chest X-ray
A chest x-ray and physical examination are part of the process to assess a subject’s eligibility, as 
outlined in Section 2, and as defined in the Exclusion Criteria, Section 5.2). A chest x-ray at the 
screening visit is required if not already performed and documented within 6 months of obtaining 
written informed consent. A subject must not have active signs or symptoms of TB, as judged by 
the investigator, to be eligible for the study.
In addition to a complete physical examination and medical history to evaluate exposure to TB, all 
subjects will have a screening test, an IGRA (eg, T-spot® or QuantiFERON®-TB Gold, or 
QuantiFERON®-TB Gold Plus) performed centrally. If unable to obtain central laboratory results,
an IGRA test could be obtained locally, after consultation with the medical monitor. A subject 
with an indeterminate IGRA test result must be retested for confirmation. If the second result is 
again indeterminate, the subject will be excluded from the study. If the second result is positive, 
the subject should be treated as having LTBI provided there are no signs or symptoms of active 
TB. If the second result is negative, the subject may be eligible provided no other exclusion 
criterion for TB is met.
9.4.3
Clinical Safety Laboratory Assessments
•
A central laboratory will perform safety laboratory assessments (except pregnancy tests) and 
provide reference ranges and laboratory reports.
•
Investigators must document their review of each laboratory safety report.
•
Any laboratory test result that the investigator considers clinically relevant for safety is to be 
recorded on the appropriate AE page of the eCRF (Section 9.2.6). 
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•
Results of clinical laboratory tests performed during the screening period must be available 
prior to randomization.
The laboratory parameters to be assessed are as follows: 
•
Hematology: hemoglobin, hematocrit, total leukocyte count (including absolute neutrophil 
count and absolute lymphocyte count), platelet count, RBC count, and manual differential 
(separate smear) 
•
Chemistry: AST, ALT, gamma glutamyltransferase, total bilirubin, direct bilirubin, alkaline 
phosphatase, lactate dehydrogenase, creatinine, blood urea nitrogen, uric acid, total protein, 
albumin, sodium, potassium, chloride, calcium, phosphorus, magnesium, creatine kinase, 
creatinine clearance (screening only) with eGFR calculated using the MDRD equation, and
thyroid-stimulating hormone (TSH) blood test (with reflex T3/T4 testing for abnormal TSH 
results at screening) 
•
Coagulation: prothrombin time, international normalized ratio, and either partial 
thromboplastin time or activated partial thromboplastin time
•
Tests performed after a ≥10-hour fast: lipid panel (total cholesterol, high-density lipoprotein 
cholesterol, low-density lipoprotein cholesterol, and triglycerides) and glucose 
•
Urinalysis: protein, glucose, blood, leukocyte esterase, specific gravity, pH; microscopic 
examination of the sediment if blood, protein, or leukocyte esterase are positive on dipstick; 
spot urine will be assessed for urine protein and urine creatinine 
•
Serology to be performed at screening: hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb) (only in Japan and selected countries), hepatitis B core antibody 
(HBcAb), reflex to HBV deoxyribonucleic acid (DNA); anti-HCV, HCV ribonucleic acid 
(RNA) if anti-HCV is positive or indeterminate; HIV-1 and HIV- 2 antibody; and IGRA 
testing
•
Quantitative serum immunoglobulins (Igs): IgG, IgM, IgA, and IgE
•
T cells, B cells, and natural killer cells (TBNK)
•
Serum high-sensitivity C-reactive protein (hsCRP)
Urine and/or serum pregnancy testing will be performed for WOCBP, and FSH will be measured 
to confirm postmenopausal status (as applicable; at screening only). 
9.4.4
Imaging Safety Assessment
Not applicable.
9.4.5
Vital Signs
Refer to Schedule of Activities in Section 2.
9.4.6
Electrocardiograms
Refer to Schedule of Activities in Section 2.
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9.8
SARS-CoV-2 Testing
Diagnostic testing for SARS-CoV-2 infection refers to a molecular test (PCR or nucleic acid 
amplification test [NAAT]) or an antigen test for SARS-CoV-2 infection, performed according to 
local standard of care. PCR testing is preferred. Antibody testing is not acceptable as a diagnostic 
test for SARS-CoV-2 infection.
Diagnostic testing for SARS-CoV-2 infection should be performed as close as possible to 
randomization and must be confirmed as “negative” prior to randomization.
Subjects will be screened for AEs (including signs and symptoms of COVID-19) at each study 
visit. Subjects will be instructed to contact the investigator at any time if they develop an 
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intercurrent illness, including a diagnosis, or signs and symptoms of COVID-19, which will enable 
close monitoring and additional screening for the infection between study visits.
The investigator should obtain a diagnostic test for SARS-CoV-2 infection if COVID-19 is 
clinically suspected. If a subject reports having recent direct contact with someone known to have 
COVID-19, the subject should undergo diagnostic testing for SARS-CoV-2. 
Investigational product should be temporarily interrupted in subjects who present with signs and/or 
symptoms suggestive of COVID-19 while the subject undergoes diagnostic testing for 
SARS-CoV-2 infection. This testing should be performed as soon as feasible.
Investigational product must be temporarily interrupted in subjects who test positive for 
SARS-CoV-2 infection. Such subjects should continue to be followed by the investigator. Such 
subjects must meet all the criteria outlined below prior to restarting IP. The final decision to restart 
IP must be made in consultation with the BMS medical monitor/designee.
Subjects with a positive diagnostic test for SARS-CoV-2 infection during the screening period 
may be considered eligible for the study once they meet all eligibility criteria related to active 
infection, and after meeting the criteria outlined below.
Criteria to rescreen or recommence IP after a positive SARS-CoV-2 test:
•
At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result, and
•
At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
•
Acute symptoms (eg, cough, shortness of breath) have resolved, and
•
In the opinion of the investigator, there are no COVID-19 sequelae that may place the subject 
at a higher risk from receiving investigational treatment, and
•
There are no COVID-19 sequelae that may confound the assessment of safety or efficacy 
within the study, and
•
Negative follow-up molecular test for COVID-19 based on institutional, local, or regional 
guidelines, and
•
The above must be discussed with the BMS medical monitor prior to rescreening or 
recommencing IP (as applicable)
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
Sample size was determined based on providing exposure to a sufficient number of subjects to be 
able to observe a true difference in the rate of clinical remission (modified Mayo score) after 
12 weeks of treatment. With the assumption that the observed placebo population will have similar 
clinical remission rate as seen in current UC investigative trials (mirikizumab),9 it is expected that 
the placebo response rate will be 5%. Assuming that BMS-986165 will provide similar efficacy as 
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observed in current UC trials (mirikizumab and upadacitinib),9, 28 the expected treatment difference 
of BMS-986165 6 mg BID vs placebo is assumed to be 15%.
Approximately 120 subjects will be randomized in a 2:1 ratio to BMS-986165 6 mg BID or 
placebo, respectively (80 subjects on BMS-986165 and 40 on placebo). In this proof of concept 
study, if the observed response rates are the same as the assumed rates given above, the total 
number of 120 subjects (80 subjects on BMS-986165 and 40 on placebo) will provide 
approximately 82% power to detect a 15% treatment difference in clinical remission at Week 12 
with a 1-sided 0.1 level of significance.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 23
Table 23:
Analysis Populations 
Population
Description
Enrolled Set
All subjects who sign informed consent.
Full Analysis Set (FAS)
All subjects who are randomized to study treatment; subjects will be 
grouped according to the treatment to which they are randomized 
within the IRT. The FAS population is the primary efficacy analysis 
population.
Safety Analysis Set
All randomized subjects who receive at least 1 dose of double-blind 
study treatment. Subjects will be analyzed according to treatment 
received.
FAS = full analysis set; IRT = interactive response technology
10.3
Endpoints
Study endpoints are defined in Section 4.
10.4
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the selection of 
subjects to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. 
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Categorical data will be summarized as frequency counts and percentages. Continuous data will 
be summarized using n, mean, standard deviation, median, minimum, and maximum unless 
otherwise specified.
During the induction period, data will be presented for the following treatments:
•
BMS-986165 6 mg BID
•
Placebo
After Week 12, subjects continuing into the maintenance period of the study (see Section 5.1.3 for 
details) will have their data presented as follows:
•
Responders at Week 12 continuing blinded treatment:
•
BMS-986165 6 mg BID → BMS-986165 6 mg BID
•
Placebo → Placebo
•
Nonresponders at Week 12 continuing open-label treatment:
•
BMS-986165 6 mg BID → BMS-986165 6 mg BID
•
Placebo → BMS-986165 6 mg BID
After Week 52, subjects with clinical benefit continuing open-label treatment during the open-
label extension period of the study (see Section 5.1.4 for details) will have their data presented as 
follows:
•
Responders at Week 12, clinical benefit at Week 52 continuing open-label treatment:
•
BMS-986165 6 mg BID → BMS-986165 6 mg BID→ BMS-986165 6 mg BID
•
Placebo → Placebo→ BMS-986165 6 mg BID
•
Nonresponders at Week 12, clinical benefit at Week 52 continuing open-label treatment:
•
BMS-986165 6 mg BID → BMS-986165 6 mg BID→ BMS-986165 6 mg BID
•
Placebo → BMS-986165 6 mg BID → BMS-986165 6 mg BID
10.4.1
Efficacy Analyses
Efficacy data will be summarized using the FAS population unless otherwise stated. Variables will 
be summarized for all visits in which the variable is assessed. Efficacy data will be listed by study 
period and treatment group. 
A summary of planned statistical analyses of the primary and secondary endpoints is in Table 24. 
Baseline values are defined as the last non-missing value prior to the first dose of study drug unless 
otherwise indicated. 
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Table 24
Planned Statistical Analyses of the Primary and Secondary 
Endpoints
Endpoint
Statistical Analysis Methods
Primary
General Analysis Methodology
The proportion of subjects who achieve the primary endpoint, clinical 
remission (modified Mayo score), will be analyzed using a stratified Cochran-
Mantel-Haenszel test. Clinical remission (modified Mayo score) responder 
rates at Week 12 between the BMS-986165 6 mg BID group and placebo group 
will be compared adjusting for the randomization stratification factors 
(corticosteroid use [yes/no] and prior exposure to biologics [0, 1, > 1]); 
JAK inhibitors are considered as a biologic for stratification purposes. If 
expected cell counts are not sufficient for each strata level, then strata levels 
will be combined for analysis. The assessment of statistical significance will be 
based upon a 1-sided, 0.1 alpha, which is in alignment with the sample size 
calculation. The odds ratio and corresponding 2-sided 95% CI will be provided 
for descriptive purposes.
Supportive analyses using logistic regression may be performed to incorporate 
additional covariates of interest and to confirm primary analysis results. The 
model will include treatment, geographic region, corticosteroid use (yes/no), 
prior exposure to biologics (0, 1, > 1) as well as other covariates as applicable. 
The odds ratio and the corresponding 2-sided 95% CI will be provided.
Imputation Method
Occurrence of intercurrent events may have an impact on the estimand of 
interest. For the following types of subjects:
•
Subjects who discontinue treatment or study early (ie, prior to Week 12)
•
Subjects who start a protocol prohibited medication/therapy prior to the 
evaluation of the primary endpoint (clinical remission [modified Mayo 
score]) at Week 12
•
Subjects who are lost to follow-up or have otherwise missing endpoint data 
at or prior to the Week 12 assessment
The primary endpoint (clinical remission [modified Mayo score]) will be 
determined using the “Composite Strategy” as defined in International Council 
for Harmonisation (ICH) E9R1 addendum29. Subjects with the identified 
intercurrent events will have their clinical remission endpoint imputed as being 
a “nonresponder.” This is commonly known as nonresponder imputation
(NRI).
Sensitivity analyses using different imputation methods may be performed and 
will be defined in the SAP.
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Table 24
Planned Statistical Analyses of the Primary and Secondary 
Endpoints
Endpoint
Statistical Analysis Methods
Secondary
General Analysis Methodology
The secondary endpoints will use the same analysis approach as the primary 
endpoint analysis with missing data, due to the incurrent events as defined 
above, being imputed as nonresponders.
Testing Strategy for Secondary Endpoints
Statistical analysis of secondary endpoints will be performed in a hierarchical 
fashion to control for Type I error rate inflation. The statistical testing of the 
primary endpoint will be the serial gatekeeper for proceeding to the testing of 
the secondary endpoints. Each secondary endpoint will be tested sequentially 
in a fixed-sequence order, as outlined below, using a 1-sided alpha = 0.1 for 
significance testing. No further testing will be performed once a test fails to 
show significance at the alpha level stated above.
Secondary endpoints will be tested in the following order:
1. Clinical response
2. Endoscopic response
3. Histologic improvement
BID = twice daily; CI = confidence interval; ICH = International Council for Harmonisation; JAK = Janus kinase; 
SAP = statistical analysis plan
10.4.1.1
Subgroup Analyses
Subgroup analyses will be conducted for the primary and secondary efficacy endpoints on the FAS 
population. Subgroups will not be further stratified based on the factors used for randomization. 
Subgroups to be evaluated include the following:
1. Sex
2. Age categories (< 65, ≥65)
3. Race
4. Prior exposure to biologics (0, 1, > 1); JAK inhibitors are considered as a biologic for 
stratification purposes
5. Prior corticosteroid use (yes/no)
6. Subjects taking corticosteroid at baseline who discontinue use after induction period
7. Baseline modified Mayo score (≤7, > 7)
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A complete list of subgroups will be detailed in the SAP.
10.4.2
Safety Analyses
Safety data for each period will be summarized separately and combined. All safety data will be 
listed by study period and treatment group.
10.4.2.1
Adverse Events
Treatment-emergent AEs (TEAEs) are defined as AEs that occur after the subject received first 
dose of study treatment or if a pre-existing condition worsens in severity or becomes serious after 
receiving the first dose of study treatment up to 30 days after the last dose of study treatment. All 
reported TEAEs, SAEs and deaths, AEs leading to study treatment discontinuation, and target 
AEIs will be summarized by the Medical Dictionary for Regulatory Activities system organ class 
and preferred term.
10.4.2.2
Vital Signs and ECGs
Vital signs and ECGs will be summarized as raw, change from baseline, including the maximum 
postbaseline value. Baseline values are defined as the last non-missing value prior to the first dose 
of study drug. The number and proportion of subjects with vital signs and ECG abnormalities will 
be summarized at each scheduled visit.
10.4.2.3
Clinical Laboratory Tests
Laboratory analytes will be summarized as raw, change from baseline, including the maximum 
post-baseline value. Incidence of abnormal, high, or low values will be summarized. Shift tables 
will also be provided. Baseline values are defined as the last non-missing value prior to the first 
dose of study drug. The number and proportion of subjects with clinical laboratory abnormalities 
will be summarized at each scheduled visit.
10.4.4
Interim Analyses 
In addition to the primary efficacy analysis conducted when subjects have either completed 
Week 12 efficacy assessments or have discontinued prior to Week 12 (as outlined above), an 
interim analysis may be performed after 50% of subjects, approximately 60 subjects, have reached 
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this milestone. The purpose of this interim analysis will be to help in early planning for further 
clinical development of the compound.
To maintain the overall probability of Type I error at the specified 0.1 level, a modified 
Haybittle-Peto method30 will be used as the alpha-spending function, which assigns alpha = 0.001 
to each interim analysis, and the remaining alpha to the final (Week 12) analysis of the primary 
efficacy endpoint.
The SAP for the study will be finalized prior to any interim analysis. The details (including the 
timing) of the interim analyses will be provided in an interim analysis plan prior to the database 
lock for any interim analysis. The study will not be stopped on the basis of overwhelming efficacy 
findings at the interim analysis. The results of the interim analysis will be reviewed by an 
unblinded internal BMS team that is independent of the study team responsible for the conduct of 
the study. The study team members, including the medical monitors and other study personnel, 
will remain blinded and will not have access to any unblinded interim analysis results or data until 
the final database lock for the Week 52 data has occurred.
10.4.5
Analysis and Reporting
A database lock (12-week database lock) will occur once all randomized subjects have completed 
the Week 12 efficacy assessments or have discontinued prior to Week 12. Analyses of the collected 
efficacy and safety results during the 12-week induction period will be performed to aid in 
planning for subsequent clinical development. Details of these analyses will be described in the 
SAP. The study team responsible for managing the study, including medical monitors, will remain 
blinded to treatment assignment and the results of this analysis throughout the study.
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1.
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Min X, Ungureanu D, Maxwell S, et al. Structural and functional characterization of the 
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Shaw MH, Boyartchuk V, Wong S, et al. A natural mutation in the Tyk2 pseudokinase 
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Tokarski JS, Zupa-Fernandez A, Tredup JA, et al. Tyrosine kinase 2-mediated signal 
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Watford WT, Hissong BD, Bream JH, et al. Signaling by IL-12 and IL-23 and the 
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Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What 
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erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis 
2018;77(2):175-87.
7.
Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are
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8.
Sandborn WJ. Mirikizumab shows efficacy in moderate-to-severe UC [abstract]. Presented 
at Digestive Disease Week; 02-05 June 2018; Washington, D.C. Abstract 882.
9.
Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of anti-interleukin-23 
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Gastroenterology 2018;154(6 Suppl 1):Abstract 882, S1360-S1.
10.
Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78.
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Ramos GP, Papadakis KA. Mechanisms of disease: Inflammatory bowel diseases. Mayo 
Clin Proc 2019;94(1):155-65.
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Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance 
therapy for Crohn's disease. N Engl J Med 2016;375(20):1946-60.
13.
Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance 
therapy for ulcerative colitis. N Engl J Med 2019;381(13):1201-14.
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14.
Papp K, Gordon K, Thaci D, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in 
psoriasis. N Engl J Med 2018;379(14):1313-21.
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BMS-986165 Investigator's Brochure, Version 05. Bristol-Myers Squibb Company, 2019. 
16.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
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Kim J, Krueger JG. Highly effective new treatments for psoriasis target the IL-23/type 17 
T cell autoimmune axis. Annu Rev Med 2017;68:255-69.
, et al. Development and validation of a histological index 
for UC. Gut 2017;66(1):50-8.
21.
Geboes K, Riddell R, Ost A, et al. A reproducible grading scale for histological assessment 
of inflammation in ulcerative colitis. Gut 2000;47(3):404-9.
 
 
 
 
 
 
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Bodger K, Ormerod C, Shackcloth D, et al. Development and validation of a rapid, generic 
measure of disease control from the patient's perspective: the IBD-control questionnaire. 
Gut 2014;63(7):1092-102.
 
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28.
Sandborn WJ, Ghosh S, Panés J, et al. Efficacy and safety of upadacitinib as an induction 
therapy for patients with moderately-to-severly active ulcerative colitis: data from the 
phase 2B study U-ACHIEVE. Presented at the 26th UEG Week; IBD clinical trials I; 20-
24 October 2018; Vienna, Austria. Abstract OP195.
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Committee for Human Medicinal Products. Step 2b, Published 30 August 2017. 
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Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. 
Lancet 2005;365(9471):1657-61.
31.
Scherl EJ, Pruitt R, Gordon GL, et al. Safety and efficacy of a new 3.3 g b.i.d. tablet 
formulation in patients with mild-to-moderately-active ulcerative colitis: a multicenter, 
randomized, 
double-blind, 
placebo-controlled 
study. 
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2009;104(6):1452-9.
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(CHMP). Adopted 28 June 2018. Publication CHMP/EWP/18463/2006 Rev. 1.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
5-ASA
5-aminosalicylic acid/aminosalicylate
6-MP
6-mercaptopurine
AE
adverse event
AEI
adverse event of interest
ALT
alanine aminotransferase
Anti-HCV
hepatitis C virus antibody
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AZA
azathioprine
BCRP
breast cancer resistance protein
BID
twice daily
BMS
Bristol-Myers Squibb
C. difficile 
Clostridium difficile
Cavg
average concentration
CD
Crohn’s disease
CFR
Code of Federal Regulations
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials 
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
Ctrough
trough observed plasma concentration 
CYP450
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
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Term
Definition
DRESS
Drug Rash with Eosinophilia and Systemic Symptoms
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ES
endoscopic (Mayo score component)
ET
early termination 
FAS
full analysis set
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle stimulating hormone
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus 
HCV
hepatitis C virus
HIV
human immunodeficiency virus
h
hour
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IFNγ
interferon gamma
Ig
immunoglobulin
IgA
immunoglobulin A
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Term
Definition
IgE
immunoglobulin E
IgG
immunoglobulin G
IgM
immunoglobulin M
IGRA
interferon gamma release assay
IL
interleukin
IM
intramuscular
IMP
investigational medicinal product
IP
investigational product 
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
JAK
Janus kinase
KLH
keyhole limpet hemocyanin
LTBI
latent tuberculosis infection
MDRD
Modification of Diet in Renal Disease
Min
minute(s)
MMX
Multi-Matrix System
MTX
methotrexate
N/A
not applicable
NAAT
nucleic acid amplification test
NOAEL
no-observed-adverse-effect-level
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
OLE
open-label extension
OTC
over-the-counter
PASI
Psoriasis Activity and Severity Index
PCR
polymerase chain reaction
PD
pharmacodynamics
PGA
Physician’s Global Assessment
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Term
Definition
PK
pharmacokinetic(s) 
PO
oral
PRO
patient-reported outcome
QD 
every day
RB
rectal bleeding (Mayo score component)
RBC
red blood cell
RNA
ribonucleic acid 
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SF
stool frequency (Mayo score component)
SLE
systemic lupus erythematosus
STAT
signal transducer and activator of transcription
SUSAR
Suspected, unexpected serious adverse reaction
TB
tuberculosis
TBNK
T cells, B cells, and natural killer cells 
TDAR 
T-cell-dependent antibody response 
TDM
therapeutic drug monitoring
TEAE
treatment-emergent AE
TEN
Toxic Epidermal Necrolysis
TNF
tumor necrosis factor 
TNFi
tumor necrosis factor inhibitor(s)
TSH
thyroid-stimulating hormone
TYK2
tyrosine kinase 2
UC
ulcerative colitis
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Term
Definition
ULN
upper limit of normal
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
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 for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines
•
Applicable laws, regulations, and requirements
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive approval/favorable opinion by Institutional Review 
Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A potential
serious breach is defined as a Quality Issue (eg, protocol deviation) 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, 
subject recruitment materials (eg, advertisements), and any other written information to be 
provided to subjects. 
The investigator, Sponsor, or designee should also 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, 
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
European Union Directive 2001/20/EC; or
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•
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 local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC for 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
The sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP, and
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
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The investigator or his/her representative must:
•
Obtain IRB/IEC written approval/favorable opinion of the written ICF and any other 
information to be provided to the participant prior to the beginning of the study and after any 
revisions are completed for new information.
•
Provide a copy of the ICF and written information about the study in the language in which 
the participant is proficient prior to clinical study participation. The language must be 
nontechnical 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 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 
subject’s consent. The investigator, or a person designated by the investigator, should fully inform 
the subject of all pertinent aspects of the study and of any new information relevant to the subject’s 
willingness to continue participation in the study. This communication should be documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF and, in 
the US, the subjects’ signed HIPAA Authorization.
The ICF must also include a statement that BMS and local and foreign regulatory authorities have 
direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
SOURCE DOCUMENTS
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. 
•
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available.
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The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical 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/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol-required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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 
subject, including unique subject 
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, if 
applicable 
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If
Then
•
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 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and paper Pregnancy Surveillance Form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
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 subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
electronic data capture tool. The investigator must retain a copy of the CRFs including records of 
the changes and corrections.
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Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the electronic data capture tool using the unique user account 
provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On-site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. 
Certain CRF pages and/or electronic files may serve as the source documents.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials, and syringes may be destroyed on site. 
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If...
Then
Study treatments supplied by BMS (including 
its vendors)
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
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, 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.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs 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, ie, 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.
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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
•
Subject 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)
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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
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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.
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 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis. 
•
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/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 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 (eg, 
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 (eg, 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 or permanent damage
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. Potential drug-induced liver injury (DILI) is also considered an important 
medical event (see Section 8.2.7 for the definition of potential DILI). 
Pregnancy and potential DILI must follow the same transmission timing and processes to BMS as 
used for SAEs (see Section 8.2.5 for reporting pregnancies).
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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, evidences, 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 (IB) 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 Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
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.
•
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. 
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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization. 
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study drug, and pregnancies must be reported 
immediately to 
Drug Safety but no later than 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
o
The required method for SAE reporting is through the electronic case report form 
(eCRF). 
o
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 a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission to:
SAE Email Address: 
SAE Fax Number: 
Americas: 
Europe/East Asia Pacific: 
 
SAE Telephone Contact - For questions on SAE/pregnancy reporting, please call:
Americas: 
Europe/East Asia Pacific: 
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to Woman 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 5.1 of the protocol. Only the contraception methods as described in 
Section 5.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the subject’s medical records, 
medical examination, or medical history interview.
•
Postmenopausal female
o
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 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.
CONTRACEPTION GUIDANCE FOR FEMALE SUBJECTS OF CHILD BEARING 
POTENTIAL
One of the highly effective or less than highly effective methods of contraception listed below 
should be continued until the end of study treatment. 
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 b
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS)c
•
Bilateral tubal occlusion
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•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the 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 subject.
•
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 subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 1.3. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP subjects 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 those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects participating 
in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce 
the efficacy of the contraceptive method. Hormonal contraception is permissible only when there is 
sufficient evidence that the IMP and other study medications will not alter hormonal exposures such 
that contraception would be ineffective or result in increased exposures that could be potentially 
hazardous. In this case, alternative methods of contraception should be utilized. 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.
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
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•
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, post-ovulation methods)
•
Withdrawal (coitus interruptus)
•
Spermicide only
•
Lactation amenorrhea method (LAM)
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 8.2.5 and APPENDIX 3.
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APPENDIX 5
CRITERIA TO DEFINE INADEQUATE RESPONSE (PRIMARY), 
LOSS OF RESPONSE (SECONDARY), AND INTOLERANCE TO 
PREVIOUS STANDARD-OF-CARE MEDICATION(S)
Subject has demonstrated an inadequate response, loss of response, or intolerance to 1 or more of 
the following standard of care medications (including, but not limited to):
•
Oral 5-aminosalicylic acids (5-ASAs) (eg, mesalamine, sulfasalazine, olsalazine, or 
balsalazide):
•
Signs and symptoms of persistently active disease despite a history of at least one 4-
week regimen at highest dose (institutional practice)
•
Documented history of intolerance
•
Corticosteroids (eg, prednisone [or equivalent] or budesonide [or equivalent]):
o
Signs and symptoms of persistently active disease despite a history of at least one 4-week 
induction regimen that included a dose equivalent to oral prednisone ≥30 mg/day (or 
equivalent) for 2 weeks, or intravenously (IV) for 1 week, or oral budesonide
MMX 9 mg/day (or equivalent) for 2 weeks; OR
o
At least 2 failed attempts to taper corticosteroids below a dose that is equivalent to oral
prednisone 10 mg/day (or equivalent) or budesonide 3 mg/day (or equivalent) on 2 separate 
occasions; OR
o
Documented history of intolerance of corticosteroids where subject developed adverse 
reactions including, but not limited to, Cushing's syndrome, osteopenia/osteoporosis, 
hyperglycemia, insomnia, cataracts, refractory steroid acne, or infection.
•
Immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate 
[MTX]):
•
Signs and symptoms of persistently active disease despite a history of at least one 8-
week regimen of oral AZA, oral 6-MP, or oral or injectable MTX (per country's 
approved label); OR
•
History of intolerance of at least 1 immunomodulator (eg, nausea/vomiting, abdominal 
pain, pancreatitis, liver function test abnormalities, lymphopenia).
•
Anti-tumor necrosis factor-alpha (TNF-α) agents (eg, infliximab, adalimumab, or golimumab):
•
Signs and symptoms of persistently active disease despite an adequate trial of induction 
treatment with an anti-TNF-α agent (per country's approved label); OR
•
Recurrence of symptoms during maintenance dosing following prior clinical benefit;
OR
•
History of intolerance (including, but not limited to, infusion-related reaction, 
demyelination, congestive heart failure, development of TNF inhibitor (TNFi) 
antibodies, or infection).
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•
Integrin inhibitors (eg, vedolizumab):
•
Signs and symptoms of persistently active disease despite an adequate trial of induction 
treatment with an integrin inhibitor (per country's approved label); OR
•
Recurrence of symptoms during maintenance dosing following prior clinical benefit;
OR
•
History of intolerance (including, but not limited to, infusion-related reaction, 
arthralgia, liver test abnormalities, or infection).
•
Anti-interleukin (IL)-12/IL-23p40 antibodies (eg, ustekinumab):
•
History of intolerance (including, but not limited to, infusion-related reaction, 
arthralgia, or liver test abnormalities).
Subjects who stop biologic treatment due to loss of funding will also be eligible for inclusion into 
the study.
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APPENDIX 6
COMMONLY USED CORTICOSTEROID EQUIVALENTS
Medication
Dose Equivalence
Prednisone
20 mg
Cortisone
100 mg
Hydrocortisone
80 mg
Prednisolone
20 mg
Methylprednisolone
16 mg
Triamcinolone
16 mg
Dexamethasone
3 mg
Betamethasone
2 to 4 mg
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APPENDIX 7
EXAMPLES OF WASHOUT TIMES REQUIRED PRIOR TO 
RANDOMIZATION
Medication/treatments
Discontinuation Prior to 
Randomization 
Notes
5-azathioprine (AZA)
≥ 4 weeks 
6-mercaptopurine (6-MP)
≥ 4 weeks 
Abatacept (CTLA4Ig)
≥ 12 weeks
Adalimumaba
≥ 8 weeks
Washout period waived if undetectable 
levels on TDM assay
Alefacept
≥ 8 weeks
Alemtuzumab
≥ 12 months
AMG 623
≥ 12 weeks
Apheresis: lymphocyte apheresis or 
selective monocyte or granulocyte 
apheresis  (eg, Cellsorba™)
≥ 12 months
Atacicept (TACI-Ig)
≥ 48 weeks
Belimumab
≥ 14 weeks
Certolizumab pegola
≥ 8 weeks
Washout period waived if undetectable 
levels on TDM assay
Cyclophosphamide
≥ 4 weeks
Cyclosporine
≥ 4 weeks
Danazol
≥ 4 weeks
Dapsone
≥ 4 weeks
Darvadstrocel
≥ 24 weeks
Eculizumab
≥ 12 weeks
Efalizumab
≥ 8 weeks
Epratuzumabb
≥ 18 weeks
Fecal transplant
≥4 weeks 
This treatment is considered an 
investigational biologic agent for the 
purposes of this study.
Golimumaba
≥ 8 weeks
Washout period waived if undetectable 
levels on TDM assay
Infliximaba
≥ 8 weeks
Washout period waived if undetectable 
levels on TDM assay
Interferon
≥ 12 weeks (or more than 
5 half-lives, whichever is 
longer)
Intravenous globulin
≥ 4 weeks
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Medication/treatments
Discontinuation Prior to 
Randomization 
Notes
Investigational therapies
≥ 4 weeks (or 5 half-lives, 
whichever is longer) 
Subjects treated with investigational 
agents 4-12 weeks prior to first dose of 
study treatment must be discussed with 
the medical monitor.
IPP-201101
≥ 12 weeks
Janus kinase (JAK) inhibitorsc
≥ 8 weeks 
Subjects treated with a JAK inhibitor 
8-12 weeks prior to first dose of study 
treatment must be discussed with the 
medical monitor.
Leflunomide
≥ 12 weeks (or more than 
5 half-lives, whichever is 
longer)
Lenalidomide with cholestyramine
≥ 24 weeks
Memantine
≥ 4 weeks
Methotrexate
≥ 4 weeks
Mycophenolate mofetil
≥4 weeks 
Washout period may be waived after 
discussion with medical monitor if 
undetectable mycophenolic acid 
(MMA) level on a relevant assay; test 
not provided within the study.
Natalizumab
≥ 8 weeks
Ocrelizumaba
≥ 24 weeks
Pimecrolimus
≥ 4 weeks
Plasmapheresis
24 weeks
Retinoids
≥ 4 weeks
Rituximab
≥ 12 months
Sirolimus (rapamycin)
≥ 4 weeks
Washout period may be waived after 
discussion with medical monitor if 
undetectable sirolimus level on a 
relevant assay; test not provided within 
the study.
Tabalumab
≥ 14 weeks
Tacrolimus
≥ 4 weeks 
Washout period may be waived after 
discussion with medical monitor if 
undetectable tacrolimus level on a 
relevant assay; test not provided within 
the study.
Thalidomide
≥ 4 weeks
Other TNF inhibitors 
≥ 8 weeks
Washout period waived if undetectable 
levels on TDM assay
Tocilizumab
≥ 12 weeks
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Medication/treatments
Discontinuation Prior to 
Randomization 
Notes
Ustekinumaba, d
≥ 8 weeks 
For subjects who have received 
> 12 weeks of ustekinumab treatment: 
washout period waived if undetectable 
levels on a TDM assay
Vedolizumaba
≥4 weeks
Subjects who have received > 14 weeks 
vedolizumab treatment; or washout 
period waived if undetectable levels on 
a TDM assay
≥ 8 weeks
Subjects who have received ≤14 weeks 
of vedolizumab treatment
TDM = therapeutic drug monitoring; TNF = tumor necrosis factor
a The washout period for this biologic can be waived for subjects who have an undetectable drug level on a TDM 
assay, performed either in routine clinical practice or during the screening period. If a TDM assay is used to waive the 
washout period for this biologic, the result of the TDM assay must be available in source documents, and the subject 
cannot receive another dose of that biologic after the TDM assay is obtained (Section 4.1.1.1).
b For epratuzumab, ocrelizumab, and any other B-cell-depleting agent, follow the required washout or document 
recovery of B cells (CD19+) after discontinuation of these therapies before a subject can be randomized.
c Failure or loss of response to previous treatment with JAK inhibitors, such as tofacitinib, is exclusionary.
d Failure or loss of response to previous treatment with ustekinumab (as well as other anti-IL-12/IL-23p40 antibodies 
or anti-IL-23p19 antibodies) is exclusionary.
Note: Investigators should consult with the 
medical monitor for information about compounds not included in 
this list.
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APPENDIX 8
HBV AND HCV TEST RESULT INTERPRETATION
I. HBV
As BMS-986165 is predicted to have immunomodulatory effects in this study, subjects with 
potentially active hepatitis B (HBV) infection and subjects at risk of reactivation of HBV infection 
will be excluded (see Section 5.2).
Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis B surface 
antibody (HBsAb) are evaluated at screening, with reflex to HBV DNA testing in subjects with 
HBsAg negative, HBcAb positive serology (as listed in the “Interpretation unclear” scenario, 
below). Notes on interpretation of HBV serology within this study are given below:
Susceptible – does not meet exclusion criteria on HBV:
•
HBsAg negative
•
HBcAb negative
•
HBsAb negative
Immune due to natural infection - does not meet exclusion criteria on HBV:
•
HBsAg negative
•
HBcAb positive
•
HBsAb positive
Immune due to hepatitis B vaccination - does not meet exclusion criteria on HBV:
•
HBsAg negative
•
HBcAb negative
•
HBsAb positive
Acutely infected – meets exclusion criteria on HBV:
•
HBsAg positive
•
HBcAb positive
•
IgM HBcAb positive
•
HBsAb negative
Chronically infected - meets exclusion criteria on HBV:
•
HBsAg positive
•
HBcAb positive
•
IgM HBcAb negative
•
HBsAb negative
Interpretation unclear:
•
HBsAg negative
•
HBcAb positive
•
HBsAb negative
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HBV DNA testing will be performed in subjects with a negative HBsAg, but a positive HBcAb at 
screening. Subjects with detectable HBV DNA at screening are excluded. Subjects in this subgroup 
may be eligible for inclusion if HBV DNA is undetectable on this assay during screening.
Subjects with HBsAg negative, HBcAb positive serology and undetectable HBV DNA at 
screening will have follow-up HBV DNA testing throughout their participation in the study, as 
detailed in the Schedule of Activities (Section 1.3). 
•
During the study, subjects in this subgroup will have HBV DNA tested at Weeks 4, 8, 12, and
approximately every 3 months thereafter.
•
Subjects in this subgroup who have a clinical response at Week 12, who then enter the 
maintenance period and subsequently lose response and enter the open-label Week 12 
responder arm will have additional HBV DNA testing at the first 3 study visits after entry to 
this treatment arm.
•
Subjects in this subgroup who do not have a clinical response at Week 12 and who enter the 
open-label BMS-986165 6 mg BID PO study arm, will have HBV DNA testing at Weeks 16, 
20 and 24, and approximately every 3 months thereafter.
•
Subjects who enter the open-label extension period at Week 52 will have HBV DNA tested at 
Weeks 56, 60 and 64, and approximately every 3 months thereafter.
•
If subjects in this subgroup have detectable HBV DNA at any time, they must permanently 
discontinue study treatment, enter the post-treatment follow-up period and the investigator 
should consider referring them for appropriate specialty care and follow-up.
II. HCV
Testing for HCV is a two-step process: (i) anti-HCV antibody, and (ii) HCV RNA.
Subjects with a negative anti-HCV antibody may be eligible for the study.
Subjects with a positive or indeterminate anti-HCV antibody require additional HCV RNA testing 
to determine eligibility. Subjects with negative or undetectable HCV RNA may be eligible for the 
study. Subjects with positive or detectable HCV RNA have HCV infection, are excluded from the 
study and should be referred for appropriate assessment and consideration for treatment. 
Subjects who were previously treated with an approved, treatment regimen for HCV infection may 
be eligible to participate in the study provided they achieve a Week 24 Sustained Virologic 
Response; that is negative or undetectable HCV RNA 24 weeks after completion of a full course 
of an approved treatment regimen for HCV infection. Such subjects must be discussed with the 
medical monitor prior to screening. 
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APPENDIX 9
MAYO SCORE: COMPONENT SUBSCORES AND ELECTRONIC 
SUBJECT DIARY ENTRY INSTRUCTIONS 
The Mayo score is a composite instrument designed to assess ulcerative colitis (UC) disease 
activity. It includes patient-reported outcomes (PROs), an objective assessment of disease activity 
by endoscopy and a Physician’s Global Assessment (PGA). The Mayo score was first proposed 
by Schroeder et al.16 Scherl et al.31 proposed that the Mayo score should be modified by removing 
“mild friability” from the definition of an endoscopic (ES) subscore = 1. This was supported by 
draft guidance from the US Food and Drug Administration (FDA) that states the presence of 
friability is not consistent with the concept of “clinical remission” (Lines 249-251).18 As the PGA 
is neither a PRO nor an objective assessment of disease activity, and the concept that it purports 
to measure is not distinct from the other components of the modified Mayo score, use of the PGA 
as a component of the modified Mayo score is no longer recommended by US18 or European 
regulatory authorities.32
Consequently, disease activity assessments for inclusion and efficacy assessment will use the 
9-point modified Mayo score 
. 
 
 
Table 1 outlines the components and scoring used to calculate the modified 
Mayo score .
Table 1
Components of the Modified 
 Mayo Score  
Stool Frequency (SF)a
0 
Normal number of stools for this patient
1
1 to 2 stools/day more than normal
2
3 to 4 stools/day more than normal
3
> 4 stools/day more than normal
Rectal Bleeding (RB)b
0
None
1
Streaks of blood with stool less than half the time
2
Obvious blood with stool most of the time
3
Blood alone passed
Findings of flexible proctosigmoidoscopy (endoscopy used to determine endoscopic [ES] subscore)
0
Normal or inactive disease
1
Mild disease (erythema, decreased vascular pattern)c
2
Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
3
Severe disease (spontaneous bleeding ulceration)
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MAYO SCORES: DEFINITIONS
Two different versions of the Mayo score will be used as efficacy endpoints:
Modified Mayo Score: The modified Mayo score is a 9-point scale; a score of 5 to 9 points 
(inclusive), which is required for randomization, denotes moderate to severe disease (by protocol 
definition). The modified Mayo score is an adaptation of the total Mayo score (defined below) that 
excludes the PGA subscore.
The modified Mayo score incorporates the following 3 components:
•
Stool frequency (SF) subscore (0 to 3)
•
Rectal bleeding (RB) subscore (0 to 3)
•
Endoscopic (ES) subscore (0 to 3)
 
 
The modified 
 Mayo score  will be calculated using component subscores entered into the
electronic case report form (eCRF).
MAYO SCORES: SF AND RB COMPONENT SUBSCORES
SF and RB data will be recorded and calculated using an electronic subject diary. 
Stool Frequency and Rectal Bleeding Subscores
Subjects will enter SF and RB data into the electronic subject diaries on a daily basis throughout 
their participation in the study. Instructions for recording the number of stools and worst rectal 
bleeding and definitions of SF and RB are provided in Table 2. 
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NOTE: The subject daily diary information should be reviewed prior to each scheduled visit at 
which Mayo scores are to be calculated and during each study visit to ensure that subjects are 
successfully entering and uploading diary data. If adequate entries have not been made, the subject 
should be counseled about proper study procedures.
For eligibility and efficacy analysis purposes, the 3 most recent, valid (not necessarily 
consecutive), electronic subject diary entries recorded from the 7 days prior to a study visit
will be used to calculate the SF and RB subscores. 
The following will be considered invalid data and excluded from SF and RB subscore calculations:
•
A day that medication(s) for constipation, diarrhea, or bowel irregularity are taken
•
The 24 hours prior to the date of the endoscopy (to account for any preparation [eg, enema(s), 
laxative(s), clear liquid diet] that can affect bowel frequency or blood content of the stool)
NOTE: Formal calculation of SF and RB subscores will be done using the electronic subject 
diaries. The averages of the 3 most recent, valid (not necessarily consecutive) diary entries for SF 
and RB (recorded from the 7 days prior to a study visit) will be calculated and used to represent 
SF and RB subscores in Mayo score determination; averages will be rounded up and down at the 
0.5 cutoff. 
For the pre-endoscopy screening visit (ie, prior to the availability of electronic subject diary data): 
The baseline SF will be determined based on the number of stools a subject has in a 24-hour period 
when in remission from UC symptoms; or if a subject has not been in remission, they should be 
asked to identify the number of stools they had in a 24-hour period before initial onset of signs and 
symptoms of UC (Table 2). 
This baseline SF is used as the reference for subsequent SF subscores. 
For the endoscopy screening visit:
Best practice is to complete the other screening investigations first and check results to ensure that 
a subject continues to be potentially eligible for the study prior to commencing bowel preparation 
for the endoscopy. When the endoscopy is scheduled, SF and RB data in the electronic subject 
diary from the 7 days prior to the bowel preparation day for the endoscopy will be evaluated to 
ensure eligibility is maintained. 
Following endoscopy, the ES subscore will be received via email from the central reader 
 
. This centrally read screening ES subscore will be entered into the eCRF, in 
addition to the SF and RB subscores, and the modified Mayo score calculated to determine subject 
eligibility.
For subsequent study visits at which Mayo Scores are calculated:
For the Week 12, Week 52, and Week 104 visits, endoscopy timing should be reviewed prior to 
the visit to ensure adequate diary entries are available for SF and RB subscore determination. The 
averages of the 3 most recent, valid (not necessarily consecutive), electronic diary entries for SF 
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and RB data from the 7 days prior to the bowel preparation day for the endoscopy will be used. 
If adequate entries have not been made, the site should contact the subject to reschedule the visit, 
and the subject should be counseled about proper study procedures. Following endoscopy, ES 
subscores will be emailed from the central vendor as noted above and entered into the eCRF 
together with the SF and RB subscores to calculate the modified Mayo score for a given visit.
Missing Data: 
Assessments with fewer than 3 valid, daily diary entries for SF and RB from the 7 days prior to 
the bowel preparation day for endoscopy are considered missing data and will not count toward
assessment of disease activity during the screening period or for endpoint assessment at Week 12, 
Week 52, and Week 104. 
MAYO SCORES: ELECTRONIC SUBJECT DIARY ENTRY INSTRUCTIONS 
Standardized instructions for recording SF and RB data (based on draft FDA Guidance for UC 
clinical endpoints)18 are in Table 2.
Table 2
Standardized Instructions for Recording Number of Stools and 
Worst Rectal Bleeding (for the Mayo Scores) (Each Over a 24-hour 
Period)
Completion of electronic subject diary
Subjects will be trained on the completion of the electronic 
subject diary.
Stool Frequency (SF)
Definition of Stool
A stool is defined as a trip to the toilet when the subject has 
either a bowel movement or passes blood alone, blood and 
mucus, or mucus only.
Determine Baseline SF 
(over 24 hours)
At the screening visit, the number of stools the subject has in a 
24-hour period when in remission from UC symptoms should be 
entered in the electronic patient diary. 
If the subject has not been in remission, then the subject should 
be asked to identify the number of stools he/she had in a 24-hour 
period before initial onset of signs and symptoms of UC.
Record whether the baseline SF is based on the reported SF when 
the subject was in remission OR the reported SF before initial 
onset of signs and symptoms of UC.
Recording of SF assessments
Subjects are to record the total number of stools for the previous 
24-hour period in the electronic subject diary on a daily basis. 
Subjects should make diary entries at the same time each day.
NOTE: For eligibility and efficacy analysis purposes, the 
established baseline SF (defined above) will be used to calculate 
the number of stools above normal and subsequently assign a 
Mayo SF component score. This will be done automatically by 
the electronic diary and will not need to be calculated by the 
subject or study team. 
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Table 2
Standardized Instructions for Recording Number of Stools and 
Worst Rectal Bleeding (for the Mayo Scores) (Each Over a 24-hour 
Period)
Rectal Bleeding (RB)
Most Severe Category of RB 
(in a given 24-hour period)
Subjects should enter into the electronic subject diary the most 
severe category that describes the amount of blood they had in 
their stools for that given day.
Categories (subscore) of rectal bleeding are defined as follows:
•
No blood seen (0)
•
Streaks of blood with stool less than half the time (1)
•
Obvious blood (more than just streaks) or streaks of blood 
with stool most of the time (2)
•
Blood alone passed (3)
Subjects should enter “No Blood Seen” in the rectal bleeding 
section if they do not have stool during a given day. 
Recording of RB assessments
Subjects are to record their RB assessments in the electronic 
subject diary on a daily basis. Subjects should make diary entries 
at the same time each day.
RB = rectal bleeding; SF = stool frequency; UC = ulcerative colitis
Adapted from: Draft Guidance for Industry, Ulcerative Colitis: Clinical Trial Endpoints US Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Draft August 2016. 
Publication UCM515143.
Endoscopic (ES) Subscore 
ES subscores will be provided via email by the independent central endoscopy vendor
 
 for all eligibility and efficacy assessments, at all time points. The endoscopy 
procedure from screening (central read) will be used to determine the baseline (Week 0 [Day 1]) 
ES subscore component of the Mayo score. The ES subscores of the Mayo score will be modified 
so that the value 1 does not include friability.
At Week 12 only: Local assessment of the endoscopy will be utilized to derive the ES component 
of the Mayo Score; this is used for determination of treatment assignment during the maintenance 
period (see Section 8.1.1 for details). The central read of the endoscopy will be used for efficacy 
analysis at all time points.
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APPENDIX 19
COVID-19 VACCINES
If a subject has received a specific COVID-19 vaccination, the type of vaccine received should be 
recorded on the concomitant medication page, if given during the study, or the past history page, 
if given prior to enrollment.
•
Administration of a live vaccine is prohibited 90 days prior to the randomization visit; during 
the induction period, maintenance period, or OLE; or within 2 months after the last dose of IP.
•
Administration of a non-live vaccine is allowed during the study. However, the efficacy and 
safety of non-live vaccines (including non-live COVID-19 vaccines) in subjects receiving 
BMS-986165 is unknown.
•
The following are NOT live vaccines: inactivated vaccines (eg, heat-killed and formalin-killed 
vaccines), subunit vaccines (eg, influenza and pneumococcal vaccines), toxoid vaccines, 
nucleic acid vaccines that do not encode potentially infectious virus (eg, Pfizer/BioNTech and 
Moderna COVID-19 vaccines) and replication-incompetent recombinant vector vaccines (eg, 
AstraZeneca/University of Oxford COVID-19 vaccine).
•
For COVID-19 vaccines requiring more than one dose, the full series (eg, both doses of a 
2-dose series) should be completed prior to enrollment when feasible, and when a delay in 
enrollment would not put the study participant at risk. Ideally, adverse events attributable to a 
vaccine should have resolved prior to enrollment.
Please contact the medical monitor with any questions related to COVID-19 vaccines.
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