Clinical trial NCT02671461
Conditions: Thrombosis
Sponsor: Bristol-Myers Squibb
Start date: 2016-04-25; Completion date: 2017-03-31
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether BMS-986141 is effective in reducing the recurrence of stroke in people who recently had a stroke, or a transient ischemic attack (known as a TIA or "mini stroke") and are receiving acetylsalicylic acid (also known as aspirin or ASA) to treat the stroke or TIA.

Detailed description:

Arms: arm 1: BMS-986141 0.8mg orally (tablets) and Aspirin (ASA) 75 to 162 mg orally (tablets) arm 2: BMS-986141 4.8mg orally (tablets) and ASA 75 to 162 mg orally (tablets) arm 3: Placebo orally (tablets) and ASA 75 to 162 mg orally (tablets)
Interventions: intervention 1: BMS-986141 intervention 2: Aspirin intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_001.pdf: 

Page:
1
Protocol Number:
CV006004
IND Number:
122,675
Ex-US
Non-IND
EUDRACT Number
2015-003959-22
Date:
19-Nov-2015
Revised Date:
07-Jul-2016
Clinical Protocol CV006004
A Phase 2, Placebo Controlled, Randomized, Double-Blind, Parallel-Arm Study to Evaluate 
Efficacy and Safety of BMS-986141 For the Prevention of Recurrent Brain Infarction in Subjects 
receiving acetylsalicylic acid (ASA) following Acute Ischemic Stroke or Transient Ischemic
Attack
Revised Protocol Number: 01
Incorporates: Amendment 06 and Administrative Letters 01 and 02
Bristol-Myers Squibb
Research and Development
Study Academic Leadership
Study Director
Principal Investigator
 
Medical Monitor
Fraz Ismat, M.D.
24-hr Emergency Telephone Number
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Revised Protocol No: 01
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Bristol-Myers Squibb Research and Development
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).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Revised Protocol No: 01
Date: 07-Jul-2016
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
07-Jul-2016
Incorporates Amendment 06
Amendment 06
07-Jul-2016
Changed top dose to be studied from 16 mg QD to 8 mg QD. Initiation of 
the 8 mg dose group will only begin following DMC review of safety 
and laboratory data from the Day 28 study visit for at least 10% of total 
planned subjects. Changes were made to some exclusion criteria to 
minimize subject risk. Guidance around the use of CYP3A4 inhibitors 
and inducers has been further clarified. The statistical sections and 
sample size calculations have been updated to correspond to these 
changes.
PK sampling windows were expanded; changed requirements for 
contraception to be the use of one highly effective method of 
contraception or one less effective method of contraception; added 
statement to Appendix 1 that local laws and regulations may require use 
of alternative and/or additional contraception methods; clarified 
genotyping testing; provided further clarifications to assist with study 
implementation; updated text per new BMS protocol model document 
template; corrected typographical errors. 
Administrative 
Letter 02
08-Apr-2016
Changed unit of measure on Exclusion Criteria 3c to Hemoglobin < 9 
g/dL.
Administrative 
Letter 01
25-Feb-2016
Specified that procedures performed as part of standard of care may be 
used as screening data for the study. Deleted supplies to aid in keeping 
the study medication cold. Corrected visit numbering in the Time and 
Events table for Part 2. 
Original 
Protocol
19-Nov-2015
Not applicable
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SYNOPSIS
Clinical Protocol CV006004
Protocol Title: A Phase 2, Placebo Controlled, Randomized, Double-Blind, Parallel-Arm Study to Evaluate 
Efficacy and Safety of BMS-986141 For the Prevention of Recurrent Brain Infarction in Subjects receiving 
acetylsalicylic acid (ASA) following Acute Ischemic Stroke or Transient Ischemic Attack
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational
Product(s): Each subject will be administered BMS-986141 or matching placebo once daily (QD) in a blinded 
fashion with open label acetylsalicylic acid (ASA) at a dose of 75 to 162 mg/day in the following treatment groups.
ASA is a non-investigational product in this study. 
Treatment A: Subjects will receive matching placebo (to BMS-986141) QD for up to 28 days in Part 1 of the Study 
or up to 90 days in Part 2 of the Study
Treatment B: Subjects will receive BMS-986141 0.8 mg QD for up to 28 days in Part 1 of the Study or up to 90 days 
in Part 2 of the Study
Treatment C: Subjects will receive BMS-986141 4.8 mg QD for up to 28 days in Part 1 of the Study or up to 90 days 
in Part 2 of the Study
Treatment D: Subjects will receive BMS-986141 8 mg QD for up to 28 days in Part 1 of the Study or up to 90 days 
in Part 2 of the Study
Study Phase: 2
Research Hypothesis: BMS-986141 is effective in reducing the recurrence of stroke in subjects with recent 
transient ischemic attack (TIA) or stroke.
Objectives:
Primary Objective:
To determine the dose-response relationship of BMS-986141 on the recurrence of brain infarction at 28 days as 
assessed by a composite of symptomatic ischemic stroke and unrecognized brain infarction as assessed by MRI in 
subjects with ischemic stroke or TIA treated with ASA.
Secondary Efficacy Objectives:

To assess the effect of BMS-986141 on the occurrence of major adverse cardiovascular events (MACE, 
including all stroke, myocardial infarction, and CV death) by Day 90

To assess the effect of BMS-986141 on the occurrence of the composite of ischemic stroke, myocardial 
infarction, and CV death by Day 90

To assess the effect of BMS-986141 on incidence of symptomatic recurrent stroke up to 28 days of treatment 

To assess the effect of BMS-986141 on the occurrence of the composite of unrecognized brain infarction 
assessed by MRI at Day 28 and MACE by Day 90
Safety Objectives:

To assess the effect of BMS-986141 on the composite of Major and Clinically Relevant Non-Major (CRNM) 
Bleeding 

To assess the effect of BMS-986141 on all reported bleeding

To evaluate safety and tolerability of BMS-986141
Study Design: This is a randomized, double-blind, placebo-controlled, parallel-arm, study to evaluate the efficacy 
and safety of BMS-986141 in addition to ASA in subjects following acute ischemic stroke or transient ischemic 
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attack (TIA). Eligible subjects will be randomized within 48 hours of the time they were last seen normal prior to 
acute ischemic stroke/TIA and must have a baseline study-specific MRI no later than 24 hours after randomization.
The study will be conducted in two parts. Subjects in both parts of the study will be randomly assigned to one of 
three different doses of BMS-986141 or matching placebo and will continue on the assigned dose for the duration of 
the treatment period. Initially randomization will be limited to the two lower doses of BMS-986141 or placebo. 
Randomization to the highest dose of BMS-986141 will only be initiated after DMC review of safety and laboratory 
data from the Day 28 study visit for at least 10% of the planned total subjects. In Part 1 of the study, the treatment 
period will be 28 days. Part 2 of the study will only be initiated after regulatory review of reports from 90-day 
nonclinical toxicology studies. The treatment period in Part 2 will be 90 days.
The Primary efficacy endpoint will be assessed at 28 days after the initial dose in all subjects. Additional objectives 
will be assessed at 28 or 90 days.
Study Schematic:
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Study Population: Male and female subjects, 18 years of age who meet the inclusion and exclusion criteria for 
the study as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and clinical 
laboratory evaluations will be eligible to participate in the study. 
Potentially eligible subjects:

Must have had an acute ischemic stroke (National Institutes of Health Stroke Scale (NIHSS) 7) or high risk 
TIA (ABCD2 score 4 or motor or speech symptoms; or atherosclerotic stenosis that could account for clinical 
presentation for which there is not a plan for revascularization therapy)

Must have had head Computed Tomography (CT) or MRI ruling out hemorrhage or other pathology

Randomization occurring within 48 hours after onset of symptoms; if symptoms are first present on awakening, 
onset should be considered as time last seen normal

Must not have clinical evidence or any history of atrial fibrillation (other than transient AF related to cardiac 
surgery), severe left ventricular systolic dysfunction, left ventricular thrombus, or other high-risk cardioembolic 
source deemed the likely cause of brain ischemia

Must be able to have a study-specific MRI no later than 24 hours after randomization
Study Drug: Includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for BMS-986141
Medication
Potency
IP/Non-IP
BMS-986141
0.8 mg
IP
BMS-986141
4 mg
IP
Placebo (matching to BMS-986141)
0 mg
IP
Acetylsalicylic acid
162 mg
Non-IP
Study Assessments:
Safety: The main safety outcome of the study is bleeding. Subjects with bleeding or suspected bleeding will undergo 
confirmatory laboratory or other testing (ultrasound [US], CT, MRI, etc.) and an (S)AE CRF must be completed. All 
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clinically overt bleeding events that lead to medical treatment or evaluation, or discontinuation of study medication 
must be submitted for adjudication. Bleeding will be adjudicated by a blinded Clinical Events Adjudication 
Committee (CEC) according to definitions adapted from the International Society on Thrombosis and Hemostasis 
(ISTH). Bleeding will be classified as Major Bleeding, Clinically Relevant Non-Major (CRNM) Bleeding, or Minor 
Bleeding.
An independent Data Monitoring Committee (DMC), separate from the CEC, will monitor the safety of all subjects 
during the study and give recommendations to the Study Executive Committee. At the beginning of the study, 
subjects will be randomized to placebo, 0.8 or 4.8 mg of BMS-986141, with no subjects being randomized to the 
8 mg dose. The DMC will review safety data when at least 10% of the total planned subjects for the study have 
completed their scheduled Day 28 visit and clinical laboratory results and other safety data from those subjects are 
available. Data to be included in that review will be specified in the DMC charter. As a result of this review, the 
DMC can recommend expansion of the randomization to all 4 study arms, additional experience on placebo and the 
2 lower doses, or other modifications as necessary to ensure subject safety.
Efficacy: The primary efficacy endpoint of the study is the incidence of a composite of symptomatic ischemic stroke
by Day 28 and unrecognized brain infarction assessed by MRI at Day 28. Additional Secondary Efficacy Endpoints 
include Major Adverse Cardiovascular Events, including symptomatic stroke, myocardial infarction, and 
cardiovascular death. Symptomatic efficacy events will be adjudicated by the CEC. Unrecognized brain infarction 
will be adjudicated by a blinded imaging adjudication committee (IAC) based on comparisons of MRI at baseline 
and Day 28.
Statistical Considerations:
Sample Size:
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic ischemic stroke by 
Day 28 and unrecognized brain infarction at Day 28. Initially, randomization will be limited to the two lower doses 
of BMS-986141 (0.8 mg or 4.8 mg) or placebo in a 1:1:1 ratio until after DMC review of safety and laboratory data 
from the Day 28 study visit for at least 10% of planned total subjects (approximately 132 subjects). If the DMC 
recommends proceeding to inclusion of the highest dose (8 mg), subsequent randomization will be in a 1:1:1:1 ratio. 
Based on the staggered randomization and with a total of 1240 evaluable subjects, there is at least 80% power to 
demonstrate a dose-response relationship assessed by MCP-Mod method (see below), with Emax and logistic 
models included as candidate models, and using a 1-sided type I error of 15%. This assumes a true incidence for 
placebo of 14%, a maximum relative risk reduction of 30% for BMS 986141 8mg compared to placebo, and 
reductions of 75% and 90% of the maximum reduction for the 0.8 and 4.8 mg doses, respectively. To account for 
about 5% of subjects without post-randomization data, a total of 1312 subjects will be randomized.
Endpoints:
Primary efficacy endpoint
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic ischemic stroke by 
Day 28 and unrecognized brain infarction assessed by MRI at Day 28.
Additional efficacy endpoints
Secondary endpoints:

The incidence of major adverse cardiovascular events (MACE) by Day 90, defined as a composite of all 
adjudicated stroke, myocardial infarction, or CV death

The incidence of the composite of adjudicated ischemic stroke, myocardial infarction, and CV death by Day 90

The incidence of adjudicated symptomatic stroke (including fatal and non-fatal) by Day 28

The incidence of the composite of unrecognized brain infarction assessed by MRI at Day 28 and MACE by 
Day 90
Primary safety endpoint
The primary safety endpoint will be incidence of a composite of adjudicated major bleeding and adjudicated CRNM 
bleeding during the treatment period.
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Additional safety endpoints

Additional safety endpoints include the incidence of adjudicated major bleeding events, all bleeding events, 
intracranial hemorrhage events, as well as the incidence of AEs and markedly abnormal standard clinical 
laboratory test results.
Analyses:
Adjudicated results will be the basis for the primary and secondary analyses. 
Primary Efficacy Endpoint Analysis:

To demonstrate the dose-response relationship between BMS-986141 treatment (including placebo) and 
primary endpoint, the primary analysis will be based on an MCP-Mod analysis. This analysis tests for a 
dose-response relationship, allowing for uncertainty in the dose-response relationship through inclusion of 
contrasts from pre-specified candidate models to assess dose-response. Fitted estimates for the incidence of the 
primary endpoint will be calculated in each of the treatment groups using a weighted model-averaging method

The incidence of the composite of adjudicated symptomatic recurrent ischemic stroke by Day 28 and 
unrecognized brain infarction at Day 28 will also be summarized by treatment. Point estimates and 95% CIs for 
event rates will be presented by treatment, together with point estimates and 95% CIs for the relative risk 
reduction between each BMS-986141 arm and placebo

A single categorical variable based on study change points (length of treatment [28 or 90 days] and 
randomization phase [randomized prior to or after DMC safety interim analysis decision]) will be included as a 
covariate
Secondary Efficacy Endpoint Analyses

Similar analysis methods will be used for the secondary endpoint incidence of MACE as for the primary 
endpoint

A sequential testing approach will be used for the primary and MACE endpoints. Dose-response relationship for 
the primary endpoint will be tested first using a one-sided 0.15 type I error; if the p-value for this comparison is 
< 0.15, then the dose-response relationship for the same endpoint will be tested using a one-sided 0.025 type I 
error. If the p-value for this comparison is < 0.025, then the dose-response relationship for the MACE endpoint 
will be tested using a one-sided 0.025 type I error

Other secondary endpoints will use similar analysis methods as the primary and secondary endpoint of MACE
Safety analysis:

For safety analyses, separate summaries taking into account length of treatment (28 or 90 days) and 
randomization phase (randomized prior to or after DMC safety interim analysis decision) will be provided

The incidences of the composite of major bleeding and clinically relevant non-major (CRNM) bleeding, all 
bleeding events (including major bleeding, clinically relevant non-major bleeding and minor bleeding), and 
intracranial hemorrhage during the treatment period will be summarized by treatment. Point estimates and 
95% CIs for event rates of each of above safety endpoint will be presented by treatment, together with point 
estimates and 95% CIs for the difference of event rates between each BMS-986141 arm and placebo. A single 
categorical variable based on study change points (length of treatment [28 or 90 days] and randomization phase 
[randomized prior to or after DMC safety interim analysis decision]) will be included as a stratum in the 
calculation of the CIs

All other safety endpoints will be summarized descriptively by treatment
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Safety Objectives ...................................................................................... 
1.3.4 Exploratory objectives ............................................................................. 
1.4 Product Development Background ................................................................... 
1.4.1 Clinical Pharmacology and Safety .......................................................... 
1.4.1.1 Pharmacokinetics of BMS-986141 ................................................. 
1.4.1.2 Dose Selection ................................................................................. 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 MRI Contraindications ............................................................................ 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Modifications .................................................................................. 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
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4.8 Destruction or Return of Investigational Product ............................................. 
4.9 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.3.2 Bleeding ................................................................................................... 
5.3.3 Physical Examination .............................................................................. 
5.3.4 Vital Signs ................................................................................................ 
5.3.5 Physical Measurements ........................................................................... 
5.3.6 Electrocardiograms ................................................................................. 
5.3.7 Laboratory Test Assessments ................................................................... 
5.3.7.1 Renal Impairment............................................................................ 
5.3.8 Other Supplemental (Unscheduled) Visits ............................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Symptomatic Stroke .................................................................................. 
5.4.2 Unrecognized Brain Infarction ................................................................ 
5.4.2.1 Magnetic Resonance Imaging ......................................................... 
5.4.3 Myocardial Infarction .............................................................................. 
5.4.4 Classification of Death ............................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic Sample Analyses .......................................................... 
5.6 Biomarker Assessments .................................................................................... 
5.6.1 Exploratory Biomarker Assessments ....................................................... 
5.6.1.1 Study Specific Genotyping .............................................................. 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
5.8.1 National Institutes of Health Stroke Scale (NIHSS) ................................ 
5.8.2 ABCD2 ..................................................................................................... 
5.8.3 Oxfordshire Community Stroke Project (OCSP) Subtyping .................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Data Monitoring Committee ............................................................................. 
7.2 Independent Central Adjudication Committees ................................................ 
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8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.3.4 Safety Endpoints....................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Efficacy Endpoint Analysis ............................................... 
8.4.2.2 Secondary Efficacy Endpoint Analyses ........................................... 
8.4.2.3 Other Efficacy Analyses .................................................................. 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 2 NIH STROKE SCALE (NIHSS) .......................................................... 
APPENDIX 3 ABCD2 ASSESSMENT SOURCE DOCUMENT ............................... 
APPENDIX 4 OXFORDSHIRE COMMUNITY STROKE PROJECT 
CLASSIFICATION ................................................................................................ 
APPENDIX 5 CHILD-PUGH CLASSIFICATION CRITERIA ................................. 
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1.2
Research Hypothesis 
BMS-986141 is effective in reducing the recurrence of stroke in subjects with recent TIA or 
stroke.
1.3
Objectives(s)
1.3.1
Primary Objectives
To determine the dose-response relationship of BMS-986141 on the recurrence of brain 
infarction at 28 days as assessed by a composite of symptomatic ischemic stroke and 
unrecognized brain infarction as assessed by MRI in subjects with ischemic stroke or TIA treated 
with ASA.
1.3.2
Secondary Objectives

To assess the effect of BMS-986141 on the occurrence of major adverse cardiovascular 
events (MACE, including all stroke, myocardial infarction, and CV death) by Day 90

To assess the effect of BMS-986141 on the occurrence of the composite of ischemic stroke, 
myocardial infarction, and CV death by Day 90

To assess the effect of BMS-986141 on incidence of symptomatic recurrent ischemic stroke 
up to 28 days of treatment

To assess the effect of BMS-986141 on the occurrence of the composite of unrecognized
brain infarction assessed by MRI at Day 28 and MACE by Day 90
1.3.3
Safety Objectives

To assess the effect of BMS-986141 on the composite of Major and Clinically Relevant 
Non-Major (CRNM) Bleeding

To assess the effect of BMS-986141 on all reported bleeding

To evaluate safety and tolerability of BMS-986141
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1.3.4
Exploratory objectives

 
 
 
 
 
 
 
 
1.4
Product Development Background
The Investigator Brochure (IB) for BMS-986141 provides detailed information on the preclinical 
pharmacology, toxicology, metabolism, pharmacokinetics, and potential for drug-drug 
interactions of BMS-986141.The clinical experience to date is summarized below, and additional 
detail can be found in the IB.
1.4.1
Clinical Pharmacology and Safety
Preliminary data have been reviewed on a total of 116 subjects who have received single doses 
of BMS-986141 of up to 150 mg and multiple doses of up to 30 mg QD for up to 14 days in 
study CV006003. This includes subjects receiving multiple doses of 20 mg QD or placebo 
co-administered with ASA 325 mg QD for up to 14 days and subjects who received single doses 
of BMS-986141 in the presence of itraconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor.
Preliminary results show dose proportional PK and a consistent concentration-dependent PD
effect. In addition, exposures in subjects who also received itraconazole increased up to 8-fold
and the half-life of BMS-986141 increased ~3-fold.
Review of preliminary safety data showed no clinically significant AEs or laboratory 
abnormalities, including coagulation profiles, template bleeding times, BUN, creatinine,
bilirubin, or hepatic enzymes. This includes all subjects who received BMS-986141 co-
administered with ASA and BMS-986141 co-administered with itraconazole.
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1.4.1.1
Pharmacokinetics of BMS-986141 
BMS-986141 was rapidly absorbed following oral administration to fasted healthy subjects, with 
maximum concentrations achieved between 1.75-3 hours. The mean terminal half-life of 
BMS-986141 was between 35.2-45.5 hours. The accumulation index was < 2 (ranging from 
1.3 to 1.9). Both maximum concentration (Cmax) and total drug exposures of BMS-986141 
increased in a dose-proportional manner.
There are 3 major circulating metabolites of BMS-986141; BMT-162856 (700 – fold less active), 
BMT-181551, and BMT-162853. Exposures of BMT-162856 were 6.8-36.4-fold higher than 
BMS-986141, with the exposures of the other metabolites much lower than BMS-986141. The 
exposures of BMS-986141 and its major circulating metabolites are expected to be below 
no-observed-adverse-effect level (NOAEL) exposures at all doses. All metabolites are expected 
to have minimal contribution to the overall PD effect.
1.4.1.2
Dose Selection
A combination of preclinical efficacy and safety data, inhibition of human ex vivo platelet 
aggregation, and Phase 1 PK, PD and safety have been taken into consideration in selecting 
doses for this study. Doses have been selected to optimize the ability to address the primary 
objective, which is to determine the dose-response relationship of BMS-986141 on the 
recurrence of brain infarction at 28 days as assessed by a composite of symptomatic ischemic 
stroke by Day 28 and unrecognized brain infarction as assessed by MRI.
1.5
Overall Risk/Benefit Assessment
The current study is a Phase 2 study of BMS-986141 in patients with ischemic stroke or TIA 
who are also receiving ASA. Prior to this study BMS-986141 has only been dosed in healthy 
subjects.
Preclinical studies in non-human primates suggest that BMS 986141 may be more effective at 
preventing the growth of an arterial thrombus than treatment with ASA alone. Furthermore, 
substantial antithrombotic efficacy has been observed at doses which increase provoked bleeding 
to an extent that is comparable to or less than that of ASA. Thus BMS-986141 may have the 
potential to provide an improved benefit-risk profile compared to existing therapies for the 
prevention and/or treatment of atherothrombotic diseases such as stroke.
The study and dosing scheme described herein has been designed to minimize risks to study 
subjects and is based on the previous clinical experience in healthy subjects and preclinical 
toxicity studies as described in the Investigator Brochure. There were no adverse findings in 
28-day preclinical toxicology studies. In 3-month studies, the major preclinical findings of note 
were microscopic changes in kidneys of some of the monkeys that received the highest dose of 
BMS-986141, 75 mg/kg/day. These changes have been characterized as moderate degeneration 
and regeneration of tubular epithelium, and the effect was not observed one month after 
cessation of dosing. Monitoring of kidney function, urinalysis, and exploratory renal biomarkers 
will occur throughout the treatment period to facilitate early identification of renal abnormalities
in subjects in the study.
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The doses selected for this study are projected to span the anticipated pharmacologically active 
dose range and are considered within the safety margin indicated by the preclinical toxicology 
and the clinical experience in healthy volunteers. Of note, co-administration of moderate 
inhibitors of CYP3A4 (eg, diltiazem, verapamil) have the potential of increasing exposures of 
BMS-986141 beyond those observed with ASA co-administration. However, it is not anticipated 
that exposures will exceed those observed in Phase 1 study (CV006003).
While bleeding was not observed to any significant degree either pre-clinically or in healthy 
volunteers, there is a potential risk of bleeding with any antithrombotic agent. There will 
therefore be close monitoring of subjects for bleeding and oversight of the study by an 
independent Data Monitoring Committee (DMC). 
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
2.2
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, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates.
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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2.3
Informed Consent
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.
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate.
BMS 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.
Investigators must:

Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood

Allow time necessary for subject or subject’s legally acceptable representative to inquire 
about the details of the study

Obtain an informed consent signed and personally dated by the subject or the subject’s 
legally acceptable representative and by the person who conducted the informed consent 
discussion

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
Revise the informed consent 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 or the subject’s legally acceptable representative or legal 
guardian, 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 United States, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
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Subjects unable to give their written consent (eg, stroke or subjects with severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject 
must also be informed about the nature of the study to the extent compatible with his or her
understanding, and should this subject become capable, he or she should personally sign and date 
the consent form as soon as possible. The explicit wish of a subject who is unable to give his or 
her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a randomized, double-blind, placebo-controlled, parallel-arm, study to evaluate the 
efficacy and safety of BMS-986141 in addition to ASA in subjects following acute ischemic 
stroke or TIA. Eligible subjects will be screened for possible inclusion in the study as soon as 
possible after arrival at the hospital, and randomized within 48 hours of the time they were last 
seen normal prior to acute ischemic stroke/TIA. In order to study subjects during their period of 
highest risk for recurrent stroke, randomization and treatment as early as possible after admission 
to the hospital is preferred. A baseline study-specific MRI evaluation must be performed no later 
than 24 hours after randomization.
The study will be conducted in two parts. Subjects in both parts of the study will be randomly 
assigned to one of three different doses of BMS-986141 or matching placebo, and will continue 
on the assigned dose for the duration of the treatment period. Approximately 1312 subjects will 
be randomized into the study in total. Initially randomization will be limited to the two lower 
doses of BMS-986141 or placebo. Randomization to the highest dose of BMS-986141 will only 
be initiated after DMC review of safety and laboratory data from the Day 28 study visit for at 
least 10% of the planned total subjects.
In Part 1 of the study, the treatment period will be 28 days. Part 2 of the study will only be 
initiated after regulatory review of reports from 90-day nonclinical toxicology studies that were 
recently completed. The treatment period in Part 2 will be 90 days. Subjects that are entered into 
Part 1 of the study will not be allowed to enter into Part 2.
The primary efficacy endpoint will be assessed at 28 days after the initial dose in all subjects. 
Additional objectives will be assessed at 28 or 90 days.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
Screening Period
Subjects with acute ischemic stroke or TIA will be evaluated for study eligibility. Subjects 
should be evaluated and treated according to the local standard of care. Subjects who meet the 
inclusion/exclusion criteria are eligible. In order to prevent overrepresentation of lacunar 
infarction in the study population, subjects with lacunar infarction will not be able to be
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randomized after a limit of approximately 20% of the total study population have been 
randomized with lacunar infarction. This limit will be imposed by the study IVRS. Informed 
consent must be obtained before any study-specific procedures are performed. Local laboratory 
values will be used for assessment of eligibility. A head MRI that meets criteria established for 
the study will be required in all subjects within 24 hours of randomization. It is preferred that 
imaging be performed as early as possible after enrollment. Imaging may be performed before 
randomization but should not be a cause of delayed randomization. Images obtained prior to 
screening will only be acceptable if performed under the same criteria that will be established for
the Day 28 MRI. Similarly, any other study related procedures including but not limited to 
physical examination (PE), vital signs, or laboratory work performed as part of standard of care 
may be used as screening data if they meet the requirements of the study protocol.
Randomization (Day 1)
Subjects must be randomized within 48 hours of onset of symptoms of stroke or TIA. If 
symptoms are present on awakening, the time for onset of symptoms should be considered as the 
time at which they were last seen normal. Subjects will be randomized via IVRS to one of three 
doses of BMS-986141 or placebo. All subjects will receive open-label ASA at a dose from 75 to
162 mg per day beginning at a time consistent with local standard of care for patients with acute 
ischemic stroke or TIA. 
Treatment Period
Subjects should receive the first dose of study medication as soon as possible after randomization
and continue with once daily dosing for the duration of the treatment period. Dosing after Day 1
should be in the morning, and must be done while fasting. Subjects who receive their first dose 
of study medication in the afternoon or evening should be given their second dose on the 
morning of the second day. Subjects should be made aware of the signs or symptoms of recurrent 
stroke, and instructed to report any adverse events.
A study visit will be performed on the day of hospital discharge. Subjects will be instructed to 
report any adverse events occurring after hospital discharge, including any occurrence of 
bleeding or signs or symptoms of recurrent stroke.
The study site will contact the subject by telephone on Day 10 3 days to assess study 
medication compliance and assess the subject’s health status.
A study visit will be performed 28 3 days after the first dose of study medication. Head MRI 
will be performed for assessment of unrecognized brain infarctions. For subjects enrolled in 
Part 1 of the study, Day 28 will be the end of the treatment period and it is preferred that the 
study visit be performed on Day 28 or earlier.
Part 2 of the study will only be initiated after regulatory review of 90-day preclinical toxicology 
study reports and the updated Investigator Brochure. For subjects enrolled in Part 2 of the study, 
the treatment period will be 90 days. There will be no change in study visits through Day 28. 
Additional treatment period study visits for these subjects will occur 56 and 90 days after the 
beginning of the treatment period.
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Pharmacokinetic (PK) sampling will be performed in all subjects. See Section 5.5.
A sub-study conducted at select sites will enroll approximately 50 subjects per arm for which 
additional blood will be collected for analysis of platelet aggregation as a pharmacodynamic 
biomarker. See Section 5.6.
Follow-Up Period
The follow-up period will last until the later of 90 days after the first dose of study drug or 
30 days after treatment discontinuation. Subjects will be instructed to report any adverse events 
that occur during the follow-up period. No additional study assessments are planned at the 
follow-up visit, which may be an in-person study visit or if necessary conducted by telephone.
Duration of Study
The expected duration of the study, from first subject, first visit through the last subject, last 
follow-up visit (eg, the End of the study), is approximately 28 months.
3.2
Post Study Access to Therapy
At the end of the study treatment period, BMS will not continue to provide BMS supplied study 
drug to subjects/investigators unless BMS chooses to extend the study. The investigator should 
ensure that the subject receives appropriate standard of care to treat the condition under study.
Treatment codes will be provided to the investigators following the final database lock and after 
unblinding by BMS.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects or Legally Acceptable Representatives (LAR), must be willing and able to give 
signed and dated written informed consent. (Note: Consent by a LAR will only be 
allowed if permitted by local regulations.)
2. Target Population
a)
Either acute ischemic stroke or high-risk TIA as defined here 
i)
Acute ischemic stroke, defined as:
(1) Neurological deficit attributed to the focal brain ischemia, and either of the 
following:

Persistent signs or symptoms of the ischemic event at the time of 
randomization

Acute, ischemic brain lesion documented by computed tomography
(CT) scan or MRI
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AND
(2) National Institutes of Health Stroke Score (NIHSS) 7
ii) High-risk TIA, defined as:
(1) Neurological deficit of acute onset attributed to focal ischemia of the brain by 
history or examination with complete resolution of the deficit, and at least one of 
the following:

ABCD2 score 4 OR motor or speech symptoms

Symptomatic intracranial arterial occlusive disease documented by 
transcranial Doppler, ultrasound or vascular imaging, defined as at 
least 50% narrowing in diameter of a vessel that could account for the 
clinical presentation

Documented internal carotid arterial occlusive disease, defined as at 
least 50% narrowing in diameter of a vessel that is presumed to be 
atherosclerotic and could account for the clinical presentation

Documented stenosis in the vertebral circulation that is presumed to be 
atherosclerotic and could account for the clinical presentation
b) CT or MRI ruling out hemorrhage or other pathology, such as vascular malformation, 
tumor, or abscess that could explain symptoms or contraindicate therapy
c) Randomization occurring within 48 hours after onset of symptoms; if the time of onset of 
symptoms is unknown, such as when symptoms are first present on awakening, onset 
should be considered as time last seen normal
d) Subject is able to be evaluated by study-specific MRI no later than 24 hours after 
randomization, does not have contraindications to the performance of the MRI, and has
suitable weight and circumference. See Section 3.4.3 for further details.
e) Ability to tolerate ASA at a dose from 75 to 162 mg/day
f)
Subject Re-enrollment: This study does not permit the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure
3. Age and Reproductive Status
a) Males and females, minimum age 18 years old or age of majority (if local age of 
majority is > 18 years of age) at the time of the screening visit
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (s) BMS-986141 plus 5 half-lives of study drug
BMS-986141 (6 days) plus 30 days (duration of ovulatory cycle) for a total of 36 days 
post-treatment completion
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e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) BMS-986141
plus 5 half-lives of the study drug (6 days) plus 90 days (duration of sperm turnover) for 
a total of 96 days post-treatment completion. In addition, male subjects must be willing to 
refrain from sperm donation during this time.
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) Women of child-bearing potential who use hormonal contraception must agree to use an 
additional method of birth control (highly effective or less effective) as detailed in 
Appendix 1. Female partners of male subjects participating in the study may use hormone 
based contraceptives as an acceptable method of contraception since they will not be 
receiving study drug.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception - (Appendix 1). Highly effective methods of 
contraception have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to use one highly effective method of contraception OR one 
less effective method as detailed in Appendix 1.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Any history of atrial fibrillation (AF) other than transient AF related to cardiac surgery
b) Severe left ventricular systolic dysfunction, left ventricular thrombus, or other high-risk 
cardioembolic source deemed the likely cause of brain ischemia
c) TIA symptoms limited to isolated numbness, isolated visual changes, or isolated 
dizziness/vertigo
d) Carotid or vertebral stenosis for which there is a plan for revascularization therapy
e) Any condition requiring ongoing treatment with an anticoagulant after discharge. For 
prophylactic measures to prevent deep vein thrombosis (DVT), pneumatic pressure 
devices are preferred
2. Medical History and Concurrent Diseases
a) Subjects with known bleeding diathesis or coagulation disorder (eg, thrombotic 
thrombocytopenic purpura)
b) History of previous non-traumatic or traumatic intracranial hemorrhage at any time
c) Acute gastrointestinal ulcer or history of gastrointestinal (GI) bleed which required 
medical treatment within the past 3 months 
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d) Planned or anticipated invasive surgery or procedure during study duration
e) Persistent, uncontrolled hypertension (systolic BP > 180 mm Hg, or diastolic 
BP > 100 mm Hg) that does not respond to acute treatment
f)
Moderate or severe hepatic impairment, defined as Child-Pugh Class B or C; (see 
Appendix 5)
g) Moderate to severe renal impairment, defined as estimated glomerular filtration rate 
(eGFR) < 45 mL/min; (see Section 5.3.7.1)
h) Any other reason, in the opinion of the investigator that the subject may be at undue risk 
from study participation
i)
Qualifying ischemic event induced by angiography or surgery
j)
Any gastrointestinal surgery that could impact upon the absorption of study drug
k) Inability to tolerate oral medication or swallow tablets whole
l)
Inability to undergo venipuncture and/or tolerate venous access
m) Subjects in whom MRI procedures cannot be performed. Section 3.4.3 provides a list of 
some common conditions that may preclude the subjects from having MRI. However, 
this should not be used as a substitute for local clinical standards of care. The ultimate 
decision to perform any of these procedures in an individual subject in this study rests 
with the site radiologist, the investigator and the standard set by the local ethics 
committee/institutional review board
n) Any other medical, psychiatric and/or social reason including drug or alcohol abuse 
which in the opinion of the investigator may impact the subject’s ability to comply with 
study procedures
o) Subjects who have received intravenous or intra-arterial thrombolysis or mechanical 
thrombectomy within the past 48 hours or who are currently eligible and able to receive 
these treatments for their current stroke
3. Physical and Laboratory Test Findings
a) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug 
administration, confirmed by repeat
i)
Atrial fibrillation or atrial flutter
ii) Complete heart block or Mobitz 2 second degree heart block
iii) QRS 180 msec
iv) QT 500 msec
v) QTcF 450 msec (Not applicable per Protocol Amendment 06)
b) Platelet count < 100 x 103/µL (100 x 109/L)
c) Hemoglobin (Hb) < 9 g/dL
4. Allergies and Adverse Drug Reaction
a) History of allergy to BMS-986141, acetylsalicylic acid, or related compounds
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b) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
c) History of drug-induced hematologic or hepatic abnormalities
5. 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
6. Prohibited Medications
a) Any investigational drug or placebo exposure within 4 weeks of study drug 
administration is prohibited
b) Any prior exposure to BMS-986141
c) Planned use of anticoagulants including warfarin or other vitamin K antagonists, oral 
thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and 
low molecular weight heparins, with the exception of heparin or low molecular weight 
heparin (LMWH) used to maintain patency of indwelling catheters or for prophylaxis of 
venous thromboembolism (VTE)
d) Planned use of antiplatelet therapy other than study medication or ASA at a dose from 
75 to 162 mg. including ASA at a dose < 75 mg/day or > 162mg/day, GPIIb/IIIa 
inhibitors, clopidogrel, ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol, and 
ticagrelor. Treatment with ASA at a dose >162 mg/day before randomization is allowed.
e) Receipt of any intravenous or intra-arterial thrombolysis within 48 hours of 
randomization (This criterion is Not Applicable per Protocol Amendment 06; refer to 
Exclusion Criteria 2o)
f)
Anticipated requirement for ongoing treatment with non-steroidal anti-inflammatory 
drugs (NSAIDs). COX-2 inhibitors are allowed. NSAID use prior to randomization is 
allowed
g) Use of strong CYP3A4 inhibitors or strong CYP3A4 inducers in the 7 days prior to 
randomization or the need for ongoing treatment with concomitant oral or intravenous 
therapy with strong CYP3A4 inhibitors or strong CYP3A4 inducers during the study.
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.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
Any investigational drug or placebo exposure during and 60 days post study drug administration 
is prohibited.
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Use of the following treatments is prohibited during the treatment period: 

Anticoagulants including warfarin or other vitamin K antagonists, oral thrombin and factor 
Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and LMWH, with the 
exception of heparin or LMWH used to maintain patency of indwelling catheters or for 
prophylaxis of VTE

Antiplatelet therapy other than study medication or ASA at a dose from 75 to 162 mg/day
including ASA at a dose < 75 mg/day or > 162 mg/day, GPIIb/IIIa inhibitors, clopidogrel, 
ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol, and ticagrelor

Requirement for treatment with concomitant oral or intravenous therapy with strong CYP3A 
inhibitors or CYP3A4 inducers

Ongoing treatment with non-steroidal anti-inflammatory drugs (NSAIDs); COX-2 inhibitors
are allowed
For WOCBP the use of hormonal contraceptives should not be the primary method of 
contraception; women may continue on these medications but must commit to using another 
method of highly effective birth control while on study. See Section 3.3.1.
The following medical procedures are prohibited while the subject is receiving study medication: 
carotid revascularization such as endarterectomies and stenting.
If treatment with the therapies noted above, except for strong CYP3A4 inhibitors or strong 
CYP3A4 inducers, becomes necessary, the study medication should be stopped temporarily up to 
a maximum of 14 days while subjects are treated with the prohibited medications. Study 
medication should be restarted upon completion of treatment with the prohibited therapy. 
Subjects who will require treatment with strong CYP3A4 inhibitors or strong CYP3A4 inducers
must be discontinued from study treatment.  It is recommended the strong CYP3A4 inhibitor or 
inducer is not started until at least 24 hours after the last dose of study medication. For guidance 
related to dosing of study medication, please refer to Section 4.5.
3.4.2
Other Restrictions and Precautions
The potential for drug interactions between BMS-986141 and statins (eg, atorvastatin, 
rosuvastatin, simvastatin) has not been evaluated in a clinical study and may occur when they are 
taken at the same time. Statins should be dosed at least 4-6 hours after administration of 
BMS-986141.
It is strongly recommended that subjects refrain from drinking grapefruit juice throughout the 
duration of the treatment period of the study.
3.4.3
MRI Contraindications
1)
Subjects who have a history of claustrophobia.
2) Subjects who have a physical limitation related to fitting in the bore of the magnet (ie, weight 
greater than that allowable by the MRI table).
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3) Subjects with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac valve 
prostheses, and MRI-incompatible vascular clips less than two-months old, or
MRI-incompatible aneurysm clips of any age.
4) Subjects with MRI-incompatible cochlear implants.
5) Subjects with spinal nerve stimulators.
6) Subjects with an infusion pump.
7) Subjects with tattoos near the eye.
8) Subjects with metallic fragments in the eyes/orbits or in the vicinity of the brain or major 
neurovascular structures of the body.
9) Subjects with an employment history, which involves exposure to welding; unless absence of 
metallic fragments is documented by X-ray examination as per institutional practice.
10) Subjects who have shrapnel at any place in their body.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
During treatment period circumstances may arise which require temporary or permanent 
discontinuation of investigational product. For guidance related to the temporary discontinuation 
please refer to Section 3.4.1.
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Any clinical condition requiring treatment with a prohibited medication for more than 14 
days

Termination of the study by Bristol-Myers Squibb (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

Severe non-compliance to protocol, as judged by the investigator and/or Sponsor (BMS)

Incorrect enrollment (ie, the subject does not meet the required inclusion/exclusion criteria) 
for the study, as determined after consultation with the sponsor

Pregnancy

Moderate or severe renal impairment defined as eGFR < 45 mL/min (see section 5.3.7.1) for 
more than 7 days.

Subjects with an ALT and/or AST > 3ULN will be scheduled for a follow up visit within 
3 days following the receipt of the result. Subjects should be discontinued from study if the 
initial and repeat laboratory tests meet any of the following criteria:
ALT and/or AST are > 3ULN and total bilirubin (TB) > 2ULN
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ALT and/or AST are > 5ULN for 14 consecutive days, at any time after initial 
confirmatory results
ALT and/or AST are 10ULN

Subjects requiring treatment with strong CYP3A4 inhibitors or strong CYP3A4 inducers 

Subjects treated with any intravenous or intra-arterial thrombolysis or with mechanical 
thrombectomy
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Sponsor or designee must occur.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. 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).
If study drug 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 case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, major adverse cardiovascular events (MACE) and the Day 28 MRI is a key 
endpoint of the study. Post treatment follow-up is of critical importance and is essential to 
preserving subject safety and the integrity of the study. Subjects who discontinue study drug
must continue to be followed for collection of outcome and/or survival follow-up data as 
required and in line with Section 5 until death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by 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, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF 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.
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3.6.2
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 as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one 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 the 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, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug
includes
both Investigational [Medicinal] Product
(IP/IMP)
and
Non-investigational [Medicinal] Product
(Non-IP/Non-IMP) and can consist of the following:
Table 4-1:
Study Drugs for CV006004: Parts 1 and 2
Product Description / 
Class and Dosage Form
Potency
IP /
Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-986141-01 Tablet
0.8mg
IP
Blinded
Plain, white to 
pale-yellow, oval tablet
Store at 2-8ᵒC; In a tightly 
closed container; light and 
moisture protected
BMS-986141-01 Tablet
4mg
IP
Blinded
Plain, white to 
pale-yellow, oval tablet
Store at 2-8ᵒC; In a tightly 
closed container; light and 
moisture protected
BMS-986141-01 Tablet
Placebo for 0.8 mg 
and 4 mg
IP
Blinded
Plain, white to 
pale-yellow, oval tablet
Store at 2-8ᵒC; In a tightly 
closed container; light and 
moisture protected
Acetylsalicylic acid
(ASA)
As available 
locally such that 
dose is 75-162 mg
Non-IP
Open
Commercially Sourced
(Not Provided by BMS)
Per manufacturer’s
instructions.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
In this protocol, non-investigational product(s) are: Acetylsalicylic acid (ASA).
The Sponsor will not be providing the ASA. It should be sourced locally by the investigator in 
commercial packaging.
4.3
Storage of Study Drug 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2 for guidance on IP records and documentation.
The blinded study medication requires refrigeration and protection from light and moisture. 
While at the study site the blinded study medication must be maintained at a temperature 
between 2-8ᵒC.
Subjects will be instructed to ensure study medication is kept refrigerated between 2-8ᵒC and 
protected from light and moisture while in their possession. Refer to Table 4-1 for the specific 
storage requirements for the blinded study medication.
4.4
Method of Assigning Subject Identification
At the screening visit each subject will be assigned a unique sequential subject number by the 
Interactive Voice Response System (IVRS). The subject number will consist of 5 digits which 
are assigned sequentially (00001, 00002, 00003, etc.) by the IVRS. This number will be used for 
identification throughout the study and will not be used for any other participant. Screening of 
subjects with lacunar infarcts will be capped at approximately 20%.
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Randomization schedules will be generated by BMS and kept by the IVRS vendor. Subjects will 
be randomly assigned to 1 of the 4 blinded treatment groups (BMS-986141 0.8 mg, 
BMS-986141 4.8 mg, BMS-986141 8 mg, or placebo) by the IVRS. Randomization will be
limited to the two lower doses of BMS-986141 or placebo in a 1:1:1 ratio until after DMC 
review of safety and laboratory data from the Day 28 study visit for at least 10% of the planned 
total subjects. If the DMC recommends proceeding to inclusion of the highest dose, subsequent 
randomization will be in a 1:1:1:1 ratio.
At all study visits when study drug is dispensed, each subject will be assigned a container 
number by the IVRS. Container numbers will be assigned non-sequentially and will correspond 
to the numbers printed on the packages and bottles containing study drug, and will be recorded 
on the appropriate eCRF. The IVRS will be available 24 hours per day, 7 days a week.
4.5
Selection and Timing of Dose for Each Subject
Study drug may be administered in the clinical facility or self-administered by the subject or 
their caregiver at home. Caregivers will need to be properly instructed about study medication 
dosing requirements by the study staff. The same caregiver should assist the subject with their 
daily dosing. 
Double blind study medication (BMS-986141 or matching placebo) will be taken once daily. The 
first dose of study medication should be taken as soon as possible after randomization. 
Subsequent doses including on Day 2 of the study should be taken in the morning and before 
breakfast. The subject must be in a fasted state for at least two (2) hours when taking study 
medication. Subjects should wait at least one (1) hour before consuming food.
Initially, each daily dose of double blind study medication will consist of 4 tablets. The double 
blind treatment period will be 28 days for Part 1 of the study and 90 days for Part 2 of the study.
Drug supplies that may become available in early 2017 may allow for dosing with 2 tablets per 
day. Sites will be provided with instructions and guidance on how to implement this change if it 
is to occur.
Subjects treated in Part 1 of the study MUST be instructed to stop study medication dosing on 
Day 28, even if visit will not occur on exactly Day 28.
Sparse PK sampling will occur at the Day 28 visit. Subjects will be instructed not to take their 
study medication dosage on Day 28 prior to coming to the study site. 
Additional drug, dosage and mode of administration
All subjects will be dispensed open label ASA at a dose prescribed by the investigator (not less 
than 75 mg and not to exceed 162 mg per day). It is recommended subjects remain on the same 
dose of ASA throughout the treatment period.
4.5.1
Dose Modifications
The dosage of double blind study medication may not be increased or decreased during the 
treatment period. Double blind study medication may be interrupted if treatment with prohibited 
or restricted concomitant therapies is needed. Refer to Section 3.4.1.
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4.6
Blinding/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 
investigational product 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 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is IVRS.
For further instructions on how to unblind in the event of an emergency please consult the IVRS 
manual provided for this study. Following the unblinding of a subject’s treatment 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 non-emergency purposes should be discussed with the 
Medical Monitor.
Except as noted, BMS Research and Development personnel and all vendors responsible for the 
conduct of the trial (protocol team) will remain blinded for the duration of the trial. Staff of BMS 
Research and Development that are independent from the protocol team will be unblinded to 
pharmacokinetic data during the course of the trial and may make recommendations to enroll 
additional participants to specific dosage tiers in order to obtain sufficient exposures. Any such 
recommendations will be considered by the Steering Committee and DMC.
The DMC will assess safety on an ongoing basis, and will have access to unblinded treatment 
codes. An analysis team, including a reporting statistician and programming support, who are not 
involved with the conduct of the study, will provide analyses to the DMC. The 
pharmacokineticist or designate in Clinical Pharmacology and Pharmacometrics; and 
programmers in Data Sciences may be unblinded in order to prepare preliminary summaries of 
pharmacokinetic and safety data as needed before data is more generally unblinded. This 
unblinded analysis team will not provide any information from unblinded analyses to the 
protocol team until after the trial completes.
The Bioanalytical Sciences section or its designate will be unblinded to the randomized 
treatment assignments in order to minimize unnecessary analysis of samples from control group 
subjects. Likewise, the Biotransformation section or its designate may be unblinded, if 
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metabolite profiling work is conducted. This unblinded analysis team will not provide any 
information from unblinded analyses to the protocol team until after the trial completes.
Platelet aggregation will be collected and reviewed for QC purposes by hospital and vendor
personnel not associated with the clinical conduct of the study. During the double-blind 
treatment period, platelet aggregation will be masked to the Investigator and protocol team. One 
biomarker representative and/or designate, may be unmasked to review the platelet aggregation 
data, and will not provide any information that can potentially be unblinding to the protocol team 
until after the trial completes. The unmasked platelet aggregation data will be provided to the 
study team after the study has been completed.
4.7
Treatment Compliance
Each time study medication (BMS-986141/placebo and ASA) is dispensed, compliance will be 
reinforced, and subjects will be given a dosing diary to complete. When study medication is 
returned, compliance will be assessed based upon the subject’s interview, review of the diary and 
a count of the tablets returned. Compliance should be between 80 and 120%. 
The investigator (or designee) will record the amounts of study medication dispensed and 
returned at each visit, as well as document reasons for non-compliance in the source document. 
The dates of all study medication dosing, including interruptions, missed doses or overdose, must 
be recorded on the eCRF. Non-compliant subjects should be re-educated regarding treatment 
compliance and/or the recording of dosing in the dosing diary.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site. 
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed 
after being inspected and reconciled by the responsible 
Study Monitor unless IP containers must be 
immediately destroyed as required for safety, or to 
meet local regulations (eg, cytotoxics or biologics).
If IP will be returned, the return will be arranged by the 
responsible Study Monitor.
IP sourced by site, not supplied by BMS (or its 
vendors) (examples include IP 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
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
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 IP provided by BMS (or its vendors). Destruction of non-IP sourced 
by the site, not supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
Not Applicable. 
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CV006004)
Procedure
Screening
(Visit 1)
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
NIH Stroke Scale (NIHSS)
X
For anyone presenting with acute neurological deficit
ABCD2
X
For TIAs only
Ischemic Stroke Sub-typing
(Oxfordshire (OCSP) classification)
X
For strokes only
Medical History
X
Safety Assessments
Physical Examination
X
Physical Measurements
X
Height, Weight
Vital Signs
X
To be done prior to blood draws and ECG.
Electrocardiogram (ECG)
X
12 lead
Concomitant Medications
X
Assessment for Serious Adverse 
Events
X
All SAEs must be collected from the date of subject’s written consent until 30 days post 
discontinuation of dosing or subject’s participation in the study, if the last scheduled visit occurs at a 
later time.
Local Laboratory Tests
Screening laboratory tests to be analyzed at a local lab. 
Retesting should be done locally during screening. 
Plasma aPTT, INR and PT
X
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Table 5.1-1:
Screening Procedural Outline (CV006004)
Procedure
Screening
(Visit 1)
Notes
Pregnancy test (serum or urine) 
WOCBP only
X
Pregnancy test to be done locally at screening.
All WOCBP must have a negative pregnancy test within 24 hours prior to dosing.
Follicle stimulating hormone (FSH) 
Test
X
Post-menopausal women under age 55 only. See Appendix 1.
Clinical Chemistry
X
Hematology
X
Urinalysis
X
MRI
X
At Screening or No later than 24 hours after randomization
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Table 5.1-2:
Part 1 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of 
Hospital 
Dischargea
(Visit 3)
Day 10
Telephone 
Contactb
(Visit 4)
Day 28 
(EOT) / 
Early 
D/Ca,b
(Visit 5)
Follow-up 
Day 90a,b
(Visit 6)
Notes
Safety Assessments
Physical Examination
X
X
Physical Measurements
X
X
Weight
Vital Signs
X
X
To be done prior to blood draws and ECG.
Electrocardiogram (ECG)
X
12-lead
Concomitant Medications
X
X
X
X
X
Assessment of Non-Serious 
Adverse Events
X
X
X
X
X
Assessment for Serious Adverse 
Events
X
X
X
X
X
All SAEs must be collected from the date of 
subject’s written consent until 30 days after 
discontinuation of dosing or subject’s 
participation in the study, if the last scheduled 
visit occurs at a later time.
Central Laboratory
Chemistry and hematology samples for Day 1 
pre-dose labs and those drawn throughout the 
study to be analyzed by the central laboratory.
Urinalysis testing (refer to Table 5.3.7-1) will be 
done locally for all time points.
Pregnancy test (serum or urine) 
WOCBP only
X
X
To be done locally. All WOCBP must have a 
negative pregnancy test within 24 hours prior to 
dosing.
Clinical Chemistry
X
Xc
X
Hematology
X
Xc
X
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Table 5.1-2:
Part 1 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of 
Hospital 
Dischargea
(Visit 3)
Day 10
Telephone 
Contactb
(Visit 4)
Day 28 
(EOT) / 
Early 
D/Ca,b
(Visit 5)
Follow-up 
Day 90a,b
(Visit 6)
Notes
Urinalysis
X
X
X
To be analyzed locally at all time points
MRI
X*
X**
*No later than 24 hours after randomization if 
not done prior to randomization
** +/- 3 days from Day 28
For subjects that stop treatment early the MRI 
should be done on Day 28
Pharmacokinetic (PK)
Serial/Sparse Blood PK Sampling
X
X
On Day 1, the last PK sample is collected 24 hrs 
(+/- 11 hrs) after first dose of study medication 
and before Day 2 dose
Biomarker Assessments
Platelet Aggregation
X
X
To be performed at select sites.
Samples should be collected at the same time as 
the time-matched PK samples.
Day 1-24 hr sample to be collected 24 hrs (+/-
11 hrs) after first dose of study medication and 
before Day 2 dose.
Exploratory Biomarker Assessments
 
 
 
 
 
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Table 5.1-2:
Part 1 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of 
Hospital 
Dischargea
(Visit 3)
Day 10
Telephone 
Contactb
(Visit 4)
Day 28 
(EOT) / 
Early 
D/Ca,b
(Visit 5)
Follow-up 
Day 90a,b
(Visit 6)
Notes
 
 
 
 
 
Clinical Drug Supplies
Randomize
X
Review study drug administration 
compliance (BMS- 986141 or 
matching placebo with ASA)
X
X
X
Subjects MUST be instructed to stop study 
medication dosing on Day 28, even if visit will 
not occur on Day 28.
Telephone contact with subject to review 
medication compliance and assess subject’s 
health status
Dispense Study Drug
X
a Subjects should participate in all study visits even if study medication dosing has been discontinued.
b Visit window is +/- 3 days.
c Laboratory tests may be done on the day prior to discharge.
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Table 5.1-3:
Part 2 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of Hospital 
Dischargea
(Visit 3)
Day 10
Telephone Contactb
(Visit 4)
Day 28a,b
(Visit 5)
Day 56a,b
(Visit 6)
Day 90 (EOT) / 
Early D/Ca,b
(Visit 7)
Follow-up 
Day 120a,b
(Visit 8)
Notes
Safety Assessments
Physical Examination
X
X
Physical Measurements
X
X
X
X
Weight
Vital Signs
X
X
X
X
To be done prior to blood draws and 
ECG.
Electrocardiogram (ECG)
X
X
12-lead
Concomitant Medications
X
X
X
X
X
X
X
Assessment of Non-Serious 
Adverse Events
X
X
X
X
X
X
X
Assessment of Serious Adverse 
Events
X
X
X
X
X
X
X
All SAEs must be collected from the date 
of subject’s written consent until 30 days 
post discontinuation of dosing or 
subject’s participation in the study, if the 
last scheduled visit occurs at a later time.
Central Laboratory
Chemistry and hematology samples for 
Day 1 pre-dose labs and those drawn 
throughout the study to be analyzed by 
the central laboratory.
Urinalysis testing (refer to Table 5.3.7-1) 
will be done locally for all time points.
Pregnancy test (serum or urine) 
WOCBP only
X
X
X
Xǂ
X
To be performed locally. All WOCBP 
must have a negative pregnancy test 
within 24 hours prior to dosing.
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Table 5.1-3:
Part 2 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of Hospital 
Dischargea
(Visit 3)
Day 10
Telephone Contactb
(Visit 4)
Day 28a,b
(Visit 5)
Day 56a,b
(Visit 6)
Day 90 (EOT) / 
Early D/Ca,b
(Visit 7)
Follow-up 
Day 120a,b
(Visit 8)
Notes
ǂHome pregnancy test kit to be sent home 
with WOCBP subjects to perform 
pregnancy test on Day 84. Test result to 
be recorded in patient diary.
Pregnancy test must also be performed at 
the Day 90 visit.
Clinical Chemistry 
X
Xc
X
X
X
Hematology
X
Xc
X
X
X
Urinalysis
x
X
X
X
X
To be analyzed locally at all time points 
MRI
X*
X**
*No later than 24 hours after 
randomization if not done prior to 
randomization
** +/- 3 days from Day 28
For subjects that stop treatment early the 
MRI should be done on Day 28
Pharmacokinetic (PK)
Serial/Sparse Blood PK Sampling
X
X
On Day 1, the last PK sample is collected 
24 hrs (+/- 11 hrs) after first dose of 
study medication and before Day 2 dose.
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Table 5.1-3:
Part 2 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of Hospital 
Dischargea
(Visit 3)
Day 10
Telephone Contactb
(Visit 4)
Day 28a,b
(Visit 5)
Day 56a,b
(Visit 6)
Day 90 (EOT) / 
Early D/Ca,b
(Visit 7)
Follow-up 
Day 120a,b
(Visit 8)
Notes
Biomarker Assessments:
Platelet Aggregation
X
X
To be performed at select sites.
Samples should be collected at the same 
time as the time-matched PK samples.
Day 1-24 hr sample to be collected 
24 hrs (+/- 11 hrs) after first dose of 
study medication and before Day 2 dose.
Exploratory Biomarker 
Assessments
 
 
 
 
 
 
 
.
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Table 5.1-3:
Part 2 Procedural Outline (CV006004)
Procedure
Day 1
(Visit 2)
Day of Hospital 
Dischargea
(Visit 3)
Day 10
Telephone Contactb
(Visit 4)
Day 28a,b
(Visit 5)
Day 56a,b
(Visit 6)
Day 90 (EOT) / 
Early D/Ca,b
(Visit 7)
Follow-up 
Day 120a,b
(Visit 8)
Notes
 
 
 
 
 
 
Clinical Drug Supplies
Randomize
X
Review study drug administration 
compliance (BMS- 986141 or 
matching placebo with ASA)
X
X
X
X
X
Telephone contact with subject to review 
medication compliance and assess 
subject’s health status
Dispense Study Drug
X
X
X
a Subject should participate in all study visits even if study medication has been discontinued.
b Visit window is +/- 3 days.
c Laboratory tests may be done on the day prior to discharge.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value).
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified subjects. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
5.2
Study Materials
BMS will supply the study sites with the following:

Patient Dosing Diaries to be completed daily after hospital discharge to record study 
medication taken. Diaries should be completed by all randomized subjects and reviewed for 
accuracy and completeness by the study staff at each study visit (refer to Section 4.7). 
WOCBP to record Day 84 urine pregnancy test result in diary.

Patient Emergency Card

Protocol specified rating scales

Electronic case report forms
The Imaging Core Lab will supply the following:

Image acquisition guidelines and submission processes will be outlined in the CV006004 
Imaging Manual, to be provided by the imaging core lab.
5.3
Safety Assessments
Only data for the procedures and assessments specified in the protocol should be submitted to 
BMS on a case report form. Additional procedures and assessments may be performed as part of 
the subject’s standard of care; however, data for these assessments should remain in the subject’s 
medical record and should not be provided to BMS, unless needed to support an AE, SAE report,
adjudication dossier or specifically requested by the sponsor.
5.3.1
Imaging Assessment for the Study
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.
Imaging is an important component of the study. All subjects will undergo standardized MRI at 
baseline and at the Day 28 visit. Images may be evaluated locally, but must also be submitted for 
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analysis by the Imaging Adjudication Committee. Results of centralized analysis will not be 
returned to the sites. 
In addition, various types of imaging may be used for the clinical evaluation of suspected
efficacy or safety endpoints. For these events, investigators should perform and analyze imaging 
and other assessments according to their normal clinical practice and the local standard of care, 
and base any treatment decisions on the local interpretation. Results of these assessments will 
also be submitted for adjudication by the CEC. Results of the adjudication by the CEC will not 
be returned to the sites.
5.3.2
Bleeding
The main safety outcome of the study is bleeding. Subjects with bleeding or suspected bleeding 
will undergo confirmatory laboratory or other testing (ultrasound [US], CT, MRI, etc.) and an 
(S)AE CRF must be completed. All clinically overt bleeding events that lead to medical 
treatment or evaluation, or discontinuation of study medication must be submitted for 
adjudication. Major and clinically relevant non-major bleeding will be adjudicated by CEC 
according to definitions specified in the CEC charter.
Acute clinically overt bleeding is defined as new onset, visible bleeding or signs or symptoms 
suggestive of bleeding with confirmatory imaging techniques which can detect the presence of 
blood (eg, US, CT, MRI).
The definition of major bleeding described below is adapted from the International Society on 
Thrombosis and Hemostasis (ISTH) definition.
Major bleeding event is defined as a bleeding event that is:

Acute clinically overt bleeding accompanied by one or more of the following:

A decrease in hemoglobin (Hb) of 2 g/dL or more

A transfusion of 2 or more units of packed red blood cells

Bleeding that occurs in at least one of the following critical sites:
Intracranial
Intra-spinal
Intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an 
intraocular bleed)
Pericardial
An operated joint and requires re-operation or intervention
Intramuscular with compartment syndrome
Retroperitoneal

Bleeding that is fatal
Clinically relevant non-major bleeding event is defined as a bleeding event that is:

Acute clinically overt bleeding
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
Does not satisfy additional criteria required for the bleeding event to be defined as a major 
bleeding event 

Requires medical treatment or evaluation, or leads to discontinuation of study medication.
Minor bleeding event is defined as any adjudicated bleeding event that does not meet the criteria 
for Major Bleeding or Clinically Relevant Non-Major Bleeding.
Fatal Bleeding Event is defined as a bleeding event that the CEC determines is the primary 
cause of death or contributes directly to death.
5.3.3
Physical Examination

A complete physical examination should include general appearance, head, eyes, ears, nose, 
throat, neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, 
and musculoskeletal

The individual performing the physical examinations must be licensed by state law 
(or applicable local law) to perform this procedure
5.3.4
Vital Signs
Vital signs (blood pressure and heart rate) will be recorded during the Screening visit and at each 
study visit during the treatment period. Vital signs scheduled at the same visit as blood samples 
or ECG should be completed before blood is drawn, ECG is collected or any medication is 
administered.
5.3.5
Physical Measurements
Physical measurements, including height (Screening only) and weight will be measured at the 
Screening visit and at each study visit during the treatment period.
5.3.6
Electrocardiograms
A 12-lead ECG will be recorded at Screening and at the end of treatment period visits.
5.3.7
Laboratory Test Assessments
A local/central laboratory will perform the analyses and will provide reference ranges for these 
tests. All screening laboratory tests will be performed locally. Day 1 pre-dose labs and those 
drawn throughout the study should be analyzed by the central laboratory. Results of clinical 
laboratory tests performed at Screening must be available prior to dosing. 
Unexpected abnormal results on urinalysis should be confirmed by retesting of a new, carefully 
obtained sample.
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The following clinical laboratory tests will be performed:
Table 5.3.7-1:
Laboratory Assessments
Screening
Performed by Local 
Laboratory
(Outlined in Table 5.1-1)
Study Visits
Performed at Central
Laboratory except Urinalysis
(Outlined in Table 5.1-2 and 
Table 5.1-3)
Hematology
Hemoglobin
X
X
Hematocrit
X
X
Red blood cell count (RBC)
X
X
Total leukocyte count with differential
X
X
Absolute platelet count
X
X
Chemistry
Aspartate aminotransferase (AST)
X
X
Alanine aminotransferase (ALT)
X
X
Total bilirubin
X
X
Direct bilirubin
(done as reflex if total bilirubin is 
> 2 ULN)
If needed
If needed
Alkaline phosphatase
X
X
Bicarbonate
X
Lactate dehydrogenase (LDH)
X
X
Creatinine
X
X
Blood urea nitrogen (BUN)
X
X
Uric acid
X
X
Glucose 
(random; fasting or non-fasting)
X
X
Total protein
X
X
Albumin
X
X
Sodium
X
X
Potassium
X
X
Chloride
X
X
Calcium
X
X
Phosphorus
X
X
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Table 5.3.7-1:
Laboratory Assessments
Screening
Performed by Local 
Laboratory
(Outlined in Table 5.1-1)
Study Visits
Performed at Central
Laboratory except Urinalysis
(Outlined in Table 5.1-2 and 
Table 5.1-3)
Other
Follicle stimulating hormone (FSH) -
post-menopausal women under age 55 
only (Refer to Appendix 1)
X
Urine Pregnancy Test - WOCBP only
(if positive reflex to serum)
X
X
Coagulation - Screening Only
International normalized ratio (INR)
X
Will be done by Central Lab 
only if part of DILI Reflex
Activated partial thromboplastin time 
(aPTT)
X
Prothrombin time (PT)
X
Will be done by Central Lab 
only if part of DILI Reflex
Urinalysis - Urinalysis Testing 
specified below is to be done locally 
for all time points
Protein
X
X (done locally)
Glucose
X
X (done locally)
Blood
X
X (done locally)
Leukocyte esterase
X
X (done locally)
Specific gravity
X
X (done locally)
pH
X
X (done locally)
Microscopic Examination -
A full microscopic examination 
X
X (done locally)
Serology - Central Lab Only
Done as part of DILI reflex
HepA antibody
Will be done by Central Lab 
only if part of DILI Reflex
HepB surface antigen
Will be done by Central Lab 
only if part of DILI Reflex
HepC antibody
Will be done by Central Lab 
only if part of DILI Reflex
Results of all laboratory tests required by this protocol must be provided to BMS, either recorded 
on the laboratory pages of the CRF or by another mechanism as agreed upon between the 
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investigator and BMS (eg, provided electronically). If the units of a test result differ from those 
printed on the CRF, the recorded laboratory values must specify the correct units. Any abnormal 
laboratory test result considered clinically significant by the investigator must be recorded on the 
appropriate AE page of the CRF (see Section 6.3) and evaluated as clinically indicated.
5.3.7.1
Renal Impairment 
The exclusion and discontinuation criteria for severe renal impairment should be evaluated based 
on eGFR calculated by the local laboratory. In the event that eGFR is not reported by the local 
laboratory, it should be calculated by the Modification of Diet in Renal Disease (MDRD) Study 
Equation. 
eGFR = 186*serum creatinine mg/dL-1.154*Age-0.203[*0.742 if female][*1.212 if African 
American]).6,7
5.3.8
Other Supplemental (Unscheduled) Visits
At any time during the trial, the investigator may at his/her discretion arrange for a subject to 
have an unscheduled (supplemental) assessment(s), especially in the case of AEs that require 
follow-up. If a subject is seen for an unscheduled assessment, the appropriate Supplemental 
Pages of the eCRF must be completed.
5.4
Efficacy Assessments
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic 
ischemic stroke by Day 28 and unrecognized brain infarction assessed by MRI at Day 28.
Symptomatic stroke is defined in Section 5.4.1. Unrecognized brain infarction is defined in 
Section 5.4.2.
Additional secondary efficacy endpoints include Major Adverse Cardiovascular Events (MACE), 
including symptomatic stroke, myocardial infarction, and cardiovascular death. Myocardial 
infarction is defined in Section 5.4.3. Classification of deaths is described in Section 5.4.4.
5.4.1
Symptomatic Stroke
All cases of suspected recurrent stroke will be adjudicated by a blinded Clinical Events 
Adjudication Committee (CEC). Further information regarding the CEC and its processes are 
detailed in the CEC Charter.
Diagnosis of stroke will require the abrupt onset of focal neurological symptoms lasting at least 
24 hours or identification of an acute, new infarct by CT or MRI in subjects with symptoms 
lasting less than 24 hours. Evaluation and treatment of strokes will be according to the local 
standard of care. It is strongly recommended (but not required) that an imaging procedure such 
as a CT scan or MRI be performed to evaluate events of suspected stroke or TIA. Adjudicated 
strokes will be categorized by the CEC as definite ischemic, definite hemorrhagic, hemorrhagic 
transformation or type uncertain. Additional classification of stroke subtypes will be specified in 
the CEC charter.
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Evaluation of suspected TIA events should be performed according to the local standard of care. 
If a TIA is considered to be a suspected stroke event by the investigator, the procedure for 
reporting a suspected stroke event should be followed and the event will be adjudicated.
5.4.2
Unrecognized Brain Infarction
MRI of the brain will be obtained in all subjects no later than within 24 hours of randomization
and at the Day 28 visit as described in the Imaging Procedures Manual. The baseline and Day 28 
MRIs for each subject will be reviewed independently by the blinded neuroradiologists of the 
Imaging Adjudication Committee to determine if any new areas of infarction have developed 
since the baseline MRI. These independent assessments will undergo adjudication according to 
the processes described in the Imaging Charter with a single, adjudicated determination recorded 
for each subject.
Details regarding MRI acquisition, including required sequences, slice thickness, and quality 
control are presented in the Imaging Procedures Manual.
5.4.2.1
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) has now become the primary noninvasive modality for 
stroke imaging. Diffusion weighted imaging (DWI) is highly sensitive in identifying hyperacute 
and acute cerebral infarction, showing ischemia within minutes of vascular occlusion.8 The 
stroke lesion appears bright on DWI scans in the acute and subacute stages, while chronic 
infarcts are characterized by dark signal on DWI8. Fluid-attenuated inversion recovery (FLAIR) 
MRI has had important applications in the imaging of stroke patients9. FLAIR depicts areas of 
tissue T2 prolongation while suppressing CSF signal, offering a sensitive method to detect 
lesions.8 Hyperintensity of the ischemic brain in acute strokes is seen on FLAIR as early as 4 to 
6 hours after infarction at a time when T1-weighted images (T1WI) and T2-weighted images 
(T2WI) are usually normal. After the first 24 hours, T1W1, T2W1, and FLAIR are most useful in 
subacute and chronic stroke. FLAIR and DWI sequences will be used to identify any new 
ischemic infarction lesions as compared to the baseline MRI. Details of study-required MRI 
parameters will be described in the study imaging manual.
5.4.3
Myocardial Infarction
All cases of suspected myocardial infarction will be adjudicated by the CEC based on evidence 
in the clinical dossier prepared for all reported suspected MI events. 
An acute MI requires the presence of at least two out of the three following conditions:

an appropriate clinical situation suggestive of an MI (eg, abnormal history, physical 
examination or new ECG changes)

elevation of CK-MB or Troponin T or I 2 x ULN; if no CK-MB or troponin values are 
available, a total CK 2x ULN; 

new, significant (0.04 seconds) Q waves in 2 contiguous leads.
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5.4.4
Classification of Death
Deaths will be categorized by the CEC as either cardiovascular or non-cardiovascular death. All 
deaths will be assumed to be cardiovascular unless a non-cardiovascular cause can be clearly 
provided.
1) Cardiovascular
This category includes cardiac deaths (eg, cardiogenic shock, arrhythmia/sudden death, 
cardiac rupture) and other cardiovascular deaths (stroke, pulmonary embolism, ruptured 
aortic aneurysm or dissection).
2) Non-cardiovascular
This category includes all deaths due to a clearly documented non-cardiovascular cause, such 
as respiratory failure (excluding cardiogenic pulmonary edema), hemorrhage (other than 
intracranial), infections/sepsis, neoplasm, and trauma (including suicide and homicide).
5.5
Pharmacokinetic Assessments
Blood will be drawn at the times indicated in Table 5.5-1 for pharmacokinetic assessments.
Table 5.5-1:
Pharmacokinetic Sampling Schedule
Study Day
Time
Relative to 
Dosing)
Hour
Time
(Relative to 
Dosing)
Hour:Min
PK Blood 
Sample
Comments
1
Pre-dose
00:00
X
1
01:00
X
Can be collected 30 minutes
1
02:30
X
Can be collected 30 minutes
1
08:00
X
Can be collected 4 hours
1
Pre-Day 2 Dose
24:00
X
Can be collected 11 hours, but 
must be collected before the next 
dose (on Day 2)
If the first dose is late in the day 
and the Day 2 pre-dose sample 
does not fall within the 
24 +/- 11 hr window, the sample 
should still be collected and the 
sampling time should be recorded
28
EOT, Pre-Dose
00:00
X
Must be collected prior to dose 
on Day 28
28
03:00
X
Can be collected 1 hour
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5.5.1
Pharmacokinetic Sample Analyses
The PK plasma samples will be analyzed for BMS-986141 using a validated LC-MS/MS assay 
and a qualified LC-MS/MS assay for BMT-162856. Pharmacokinetic samples collected from a 
subject who received placebo will not be analyzed.
In addition, after the scheduled pharmacokinetic analyses are completed, residual plasma may be 
used for metabolite profiling or assessment of other metabolites, if the need arises and to the 
extent possible. If these analyses are conducted, they will be reported separately from the CSR.
Further details of sample collection and processing will be provided to the site in the laboratory 
procedure manual.
5.6
Biomarker Assessments
5.6.1
Exploratory Biomarker Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 5.6.1-1:
Biomarker Sampling Schedule
Study 
Day
Time 
(Event)
Hour
Time 
(Relative 
To Dosing)
Hour: Min
Platelet 
Aggregationa
 
 
 
 
 
 
 
 
Comments
1
Pre-dose
00:00
X
X
X
1
01:00
X
Samples can be collected 30 minutes.
1
02:30
X
Samples can be collected 30 minutes.
1
08:00
X
Samples can be collected 4 hours
1
Pre-Day 2 
Dose
24:00
X
X
Samples can be collected 11 hours, 
but must be collected before the next 
dose (on Day 2)
If the first dose is late in the day and the 
day 2 pre-dose sample does not fall 
within the 24 +/- 11 hr window, the 
sample should still be collected and the 
sampling time should be recorded
28
Pre-Dose
00:00
X
X
X
Samples must be collected prior to dose 
on Day 28
Exploratory renal biomarkers do not
have to be collected prior to dose
28
03:00
X
Samples can be collected 1 hour
56
Part 2 only
X
90
EOT
(part 2
only)/Early 
D/C
X
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a Platelet aggregation sampling only applies to subjects participating in the PK/PD sub-study. These samples should be collected at the same time as time-
matched PK samples
b
 
Platelet aggregation samples should be collected at the same time as time-matched PK samples.
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5.6.1.1
 
 
 
 
 
 
 
5.7
Outcomes Research Assessments
Not Applicable.
5.8
Other Assessments 
The following assessments are required to be done at Screening to confirm patient eligibility.
5.8.1
National Institutes of Health Stroke Scale (NIHSS)
The National Institutes of Health Stroke Scale (NIHSS) is a well-validated, reliable graded 
neurological examination that rates speech and language, cognition, visual field deficits, motor 
and sensory impairments, and ataxia.10 The NIHSS has become a standard part of clinical 
assessments used in many stroke trials because of its utility to measure the neurologic deficits 
most often seen with acute stroke patients. It consists of 11 elements that reflect the wakefulness, 
vision, and motor, sensory, and language function of stroke patients. Possible scores range from 
0-42 with higher scores indicating more severe deficits. Performing the NIHSS has been timed to 
take 5-8 minutes. Sites should only use the version of the rating scale provided by BMS for this 
study. 
5.8.2
ABCD2
The ABCD2 (age, blood pressure, clinical features, duration, diabetes) score is a risk assessment 
tool designed to improve the prediction of short-term stroke risk after a TIA.11 The ABCD2 
score is calculated by summing up points for five independent factors, specifically age, blood 
pressure, clinical features of the TIA, duration of the TIA, and the presence of diabetes. Multiple 
studies have shown that as the ABCD2 score increases the risk of subsequent stroke also 
increases. Sites should only use the source document of this risk assessment tool provided by 
BMS for this study.
5.8.3
Oxfordshire Community Stroke Project (OCSP) Subtyping
The investigators of Oxfordshire Community Stroke Project (OCSP) described a method of 
subtyping cerebral infarctions into four clinically identifiable subgroups12. Using the OCSP 
approach, the clinical stroke is categorized based on presenting symptoms and signs. The authors 
pointed out that the subtyping is based on the clinical pattern at the time of maximum deficit 
from stroke onset. Their approach utilized the patient history and neurological examination but 
not the results of investigations such as imaging or cardiac rhythm monitoring. Cerebral infarcts 
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are subtyped as Lacunar Infarcts (LACI), Total Anterior Circulation Infarcts (TACI), Partial 
Anterior Circulation Infarcts (PACI), or Posterior Circulation Infarcts (POCI) based on clinical 
features. Descriptions of the clinical features of the subtypes can be found in their publication12.
In recent years, the OSCP approach has been extended by utilizing the results of cerebral 
imaging for the classifications13. For this study, the last letter for each classification will indicate 
whether or not the index infarct is identified on imaging. The last character of the OCSP 
classification will be either I (infarction) for cases when the index infarct is identified on imaging 
or S (syndrome) for cases in which imaging has not shown the index infarct at time of 
classification. Strokes will be subtyped using the extended OSCP categories by the investigator 
during Screening for index strokes.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:

Related: There is a reasonable causal relationship between study drug administration and the 
AE.

Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
Sponsor or designee will be reporting adverse events 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.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)
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
requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at 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 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs.
(See Section 6.1.1 for reporting pregnancies).
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)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
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protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing or subject’s participation in the study, if the last 
scheduled visit occurs at a later time. If applicable, SAEs must be collected that relate to any 
later protocol specified procedure.
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. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the eCRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to Sponsor
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
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6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the Sponsor or
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please call the Sponsor or designee within 
24 hours of awareness of the pregnancy.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours of awareness of 
the event and in accordance with SAE reporting procedures described in Section 6.1.1.
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from 
the female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
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 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 
1. Aminotransaminases (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND
3. No other immediately apparent possible causes of aminotransaminases (AT) elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic
6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
When required, adjudicated events will be submitted to the Data Monitoring Committee (DMC)
and Health Authorities for review on a specified timeframe in accordance with the adjudication 
documentation.
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7.1
Data Monitoring Committee
For the protection of subjects participating in the study, an independent Data Monitoring 
Committee (DMC) will review safety data including reports of bleeding. The full role of the 
DMC will be defined in the DMC charter. The committee will review partially unblinded 
accumulating data on a regular basis and will make recommendations regarding the continuing 
safety of subjects currently enrolled and yet to be enrolled in the trial. The DMC may 
recommend suspension of accrual into a BMS-986141 treatment group or early termination of 
the trial, for safety reasons. At all times during the course of the study, the DMC may request 
access to fully unblinded data if needed.
At the beginning of the study, subjects will be randomized to placebo, 0.8 or 4.8 mg of 
BMS-986141, with no subjects being randomized to the 8 mg dose. The DMC will review safety 
data when at least 10% of the total planned subjects for the study have completed their scheduled 
Day 28 visit and clinical laboratory results and other safety data from those subjects are 
available. Data to be included in that review will be specified in the DMC charter. As a result of 
this review, the DMC can recommend expansion of the randomization to all 4 study arms, 
additional experience on placebo and the 2 lower doses, or other modifications as necessary to 
ensure subject safety.
7.2
Independent Central Adjudication Committees
The clinical events adjudication committee (CEC) will be a blinded, independent group of 
clinicians experienced in the diagnosis of stroke and other cardiovascular diseases who are not 
otherwise involved with the study. The CEC will evaluate clinical events related to study 
endpoints, including adjudication of suspected symptomatic stroke, suspected myocardial 
infarction, bleeding, and death. The full role of the CEC and criteria for evaluation of clinical 
events will be defined in the CEC charter.
The imaging adjudication committee (IAC) will be an independent group of neuroradiologists 
experienced in the interpretation of brain MRI images. The IAC will evaluate blinded MRI 
images obtained no later than 24 hours after randomization and at the Day 28 study visit for
detection of unrecognized brain infarctions. The full role of the IAC and criteria for evaluation of 
unrecognized brain infarction will be defined in the IAC charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic 
ischemic stroke by Day 28 and unrecognized brain infarction at Day 28. Sample size calculations 
were performed for detecting a dose-response effect with the MCP-MOD methodology using 
simulations with the DoseFinding package in R14. Simulations of 1000 clinical trials were 
performed, assuming a true incidence for placebo of 14%, a maximum relative risk reduction of 
30% for BMS-986141 8 mg relative to placebo, and relative reductions of 75% and 90% of the 
maximum for the 0.8 and 4.8 mg doses, respectively. Candidate models included an Emax model 
and a logistic model.
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Initially, randomization will be limited to the two lower doses of BMS-986141 (0.8 mg or 
4.8 mg) or placebo in a 1:1:1 ratio until after DMC review of safety and laboratory data from the 
Day 28 study visit for at least 10% of planned total subjects (approximately 132 subjects). If the 
DMC recommends proceeding to inclusion of the highest dose (8 mg), subsequent randomization 
will be in a 1:1:1:1 ratio. Based on the staggered randomization as shown in Table 8.1-1 and the 
assumptions above, the study will have at least 80% power to demonstrate a dose-response 
relationship, using a 1-sided type I error rate of 15%. A total sample size of 1312 randomized 
subjects accounts for about 5% of subjects without post-randomization data.
Table 8.1-1:
Randomization Targetsa
Placebo
0.8 mg
4.8 mg
8 mg
Prior to interim safety review by DMC: 
132 subjects
(1:1:1 randomization ratio)
44
44
44
0
Additional subjects randomized while interim 
safety tables are being generated and reviewed 
by the DMC (not included in DMC safety 
interim analysis): 100 subjects
(1:1:1 randomization ratio)
34
33
33
0
After interim safety review by DMC: 1081 
subjects
270
270
270
270
Total: 1312 subjects
348
347
347
270
a Numbers shown for each treatment group are estimates based on randomization ratio. Actual numbers could be 
slightly different based on randomization block size.
8.2
Populations for Analyses

The Enrolled Subjects Data Set will consist of all subjects who sign informed consent.

The Randomized Subjects Data Set will consist of all randomized subjects regardless of 
whether they received treatment. This is also known as the Intent to Treat (ITT) population. 
This will be the primary efficacy data set. Data in this data set will be analyzed based on 
randomized treatment group.

The Treated Subjects Data Set will consist of all subjects who receive at least one dose of 
study medication during the treatment period. This will be the primary safety data set. Data 
in this data set will be analyzed based on randomized treatment, except in the following 
cases:

If a subject received the same incorrect treatment throughout the study (until either 
Day 28 or Day 90, or until discontinuation of the study drug), then the subject will be 
analyzed based on the treatment received.

If a subject received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
subject will be analyzed based on the first treatment received.
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
The Pharmacodynamic analysis dataset will consist of subjects in the Randomized Subject 
Dataset who have at least one pharmacodynamic endpoint assessed.

The Pharmacokinetic analysis dataset will consist of all subjects who receive BMS-986141
and have at least one post dose PK sample. Additionally, the evaluable PK population is 
defined as subjects who have adequate PK profiles on Day 1.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic 
ischemic stroke by Day 28 and unrecognized brain infarction assessed by MRI at Day 28.
8.3.2
Secondary Endpoint(s)
Secondary endpoints include:

The incidence of major adverse cardiovascular events (MACE) by Day 90, defined as a 
composite of adjudicated recurrent stroke, myocardial infarction, or CV death

The incidence of a composite of adjudicated recurrent ischemic stroke, myocardial infarction, 
or CV death

The incidence of adjudicated symptomatic recurrent stroke (including fatal and non-fatal) by 
Day 28

The incidence of the composite of unrecognized brain infarction assessed by MRI at Day 28 
and MACE by Day 90
8.3.3
Exploratory Endpoint(s) 
 
 
 
8.3.4
Safety Endpoints
The primary safety endpoint is incidence of a composite of adjudicated major bleeding and 
adjudicated clinically relevant non-major (CRNM) bleeding during the treatment period.
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Additional safety endpoints include the incidence of adjudicated major bleeding events, all 
bleeding events, intracranial hemorrhage events, as well as the incidence of AEs and markedly 
abnormal standard clinical laboratory test results.
8.4
Analyses
Adjudicated results will be the basis for the primary and secondary analyses, including imaging 
assessments from the IAC and clinical assessments from the CEC.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined. Demographic and baseline variables 
to be summarized include: age, gender, race, geographic region, height, weight, body mass 
index, vital signs (systolic blood pressure, diastolic blood pressure, and heart rate), index event 
(stroke or TIA), and cardiovascular risk factors (cigarette smoking, diabetes mellitus, 
hypercholesterolemia, hypertension, obesity).
Additional baseline variables will include stroke sub-type as assessed by the investigator,
severity (NIH-SS), and time since onset of symptoms detected.
In addition, separate summaries taking into account length of treatment (28 or 90 days) and 
randomization phase (randomized prior to or after DMC safety interim analysis decision) will be 
provided.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Efficacy Endpoint Analysis
To demonstrate the dose-response relationship between BMS-986141 treatment (including 
placebo) and primary endpoint, the primary analysis will be based on a Multiple Comparisons 
and Modeling (MCP-Mod) analysis.15,16 This analysis tests for a dose-response relationship, 
allowing for uncertainty in the dose-response relationship through inclusion of contrasts from
two pre-specified candidate models to assess dose-response. If a dose-response relationship 
exists, then fitted estimates for the incidence of the primary endpoint will be calculated in each 
of the treatment groups using the selected dose-response model, or using a weighted 
model-averaging method if significance is detected using both models. Candidate models will 
include an Emax model and a logistic model, where dose-response will be tested using dose 
levels of 0 (placebo), 1, 2, and 2.3 (corresponding to 0.8 mg, 4.8 mg, and 8 mg)17. The 
parameters used to determine the contrast for testing will include assumed placebo event 
rate 14% and maximum risk reduction of 4.2%. For the Emax model, the parameters used will be 
1.0 for the dose corresponding to half of the maximum effect and 1.0 for a “Hill” parameter that 
determines the steepness of the model at the dose of half effect. For the logistic model, the initial 
parameters used will be 1.0 for the dose corresponding to half effect and 0.1 for the parameter 
that determines the steepness of the curve.
The incidence of the composite of adjudicated symptomatic recurrent ischemic stroke by Day 28 
and unrecognized brain infarction at Day 28 will also be summarized by treatment. Point 
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estimates and 95% CIs for event rates will be presented by treatment, together with point 
estimates and 95% CIs for the relative risk reduction between each BMS-986141 arm and 
placebo. 
A single categorical variable based on study change points (length of treatment [28 or 90 days] 
and randomization phase [randomized prior to or after DMC safety interim analysis decision]) 
will be included as a covariate.
A sensitivity analysis will include subjects who are randomized, treated, and with an evaluable 
MRI at Day 28, or an adjudicated symptomatic recurrent stroke by Day 28.
8.4.2.2
Secondary Efficacy Endpoint Analyses
Similar analysis methods will be used for the secondary endpoint incidence of MACE as for the 
primary endpoint.
A sequential testing approach will be used for the primary and MACE endpoints. Dose-response 
relationship for the primary endpoint will be tested first using a one-sided 0.15 type I error; if the 
p-value for this comparison is < 0.15, then the dose-response relationship for the same endpoint 
will be tested using a one-sided 0.025 type I error. If the p-value for this comparison is < 0.025, 
then the dose-response relationship for the MACE endpoint will be tested using a one-sided 
0.025 type I error.
Other secondary endpoints will use similar analysis methods as the primary and secondary 
endpoint of MACE.
8.4.2.3
Other Efficacy Analyses
Analysis of recurrent ischemic stroke and adjudicated arterial thrombotic events up to 90 days
will use similar analysis methods as the primary and secondary endpoint of MACE.
Analyses of exploratory biomarker data are included in Section 8.4.5, Biomarker Analyses.
8.4.3
Safety Analyses
For safety analyses, separate summaries taking into account length of treatment (28 or 90 days) 
and randomization phase (randomization prior to or after DMC safety interim analysis decision) 
will be provided.
The proportion of subjects with the composite of major bleeding and CRNM bleeding, and 
additional bleeding endpoints such as all bleeding events (including major bleeding, clinically 
relevant non-major bleeding and minor bleeding) and intracranial hemorrhage during the 
treatment period will be summarized by treatment. Point estimates and 95% CIs for event rates 
of each of above safety endpoints will be presented by treatment, together with point estimates 
and 95% CIs for the difference of event rates between each BMS-986141 arm and placebo. A 
single variable based on study change points (length of treatment [28 or 90 days] and 
randomization phase [randomized prior to or after DMC safety interim analysis decision]) will 
be included as a stratum in the calculation of the CIs.
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The number and percent of subjects with at least one adverse event will be summarized for each 
treatment group, including summaries of AEs, SAEs, AEs leading to discontinuation, and AEs of 
special interest. Summaries will include the number of subjects with events by specified system 
organ classes and preferred terms. All endpoint events reported by the investigator as AEs 
(serious or non-serious) will be reported in the safety analyses, regardless of whether the event 
was confirmed by adjudication. The number and percent of subjects with marked laboratory 
abnormalities will be similarly presented.
Values and changes from baseline at each scheduled time point for clinical laboratory 
parameters, vital signs, and ECG will be summarized by treatment group using descriptive 
statistics.
8.4.4
Pharmacokinetic Analyses
Pharmacokinetics of BMS-986141 and BMT-162856 will be explored. 
A population pharmacokinetic model will be developed to understand the pharmacokinetics of 
BMS-986141. The potential effect of covariates (eg, body weight, age, gender, race, renal 
function, liver function, co-administration of other medicine) on the pharmacokinetics of 
BMS-986141 will be also explored. These results will be reported separately.
8.4.5
Biomarker Analyses
Summary statistics will be tabulated for each available biomarker endpoint, including 
corresponding changes from baseline and/or percentage changes from baseline (where 
applicable) by treatment, and time point. Plots of means and standard errors over time and 
change from baseline (and/or percent change from baseline) for each available biomarker versus 
time may be provided. Relationships between exploratory biomarkers and BMS-986141 plasma 
concentrations may be explored. In addition, relationships between polymorphism in genes 
related to PAR4 activity (and/or disposition of BMS-986141) and exploratory biomarkers, 
PK parameters, or efficacy endpoints may be explored. Exploratory biomarker results may be 
reported separately.
8.4.6
Outcomes Research Analyses
Not Applicable.
8.4.7
Other Analyses 
Exploratory exposure response analysis of pharmacodynamics endpoints driven by BMS-986141 
exposure may also be performed and reported separately. 
8.5
Interim Analyses
No interim analyses are planned for efficacy. The DMC will, however, review safety data after 
10% of the total planned subjects for the study (approximately 132 subjects) have been 
randomized and have completed their scheduled Day 28 visit. Additionally, pharmacokinetics of 
BMS-986141 will be explored to assess exposures and potential relationship to safety. Based on 
the results, the DMC will recommend either to expand randomization to include the higher dose 
level (8 mg BMS-986141), to maintain randomization for additional subjects to the original three 
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treatment arms (placebo and the two lower doses), or other modification as necessary to ensure 
subject safety. Details regarding the safety data to be included in the interim safety analysis will 
be provided in the DMC Charter. As noted in Section 4.6, information from pharmacokinetic
analyses may be made available to non-study team members.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
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 

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).
9.1.2
Monitoring
BMS 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.
In addition, the study may be evaluated by BMS 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 BMS or designee.
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9.1.2.1
Source Documentation
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.
9.2
Records
9.2.1
Records Retention
The investigator (or head of 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 study site in Japan) must contact BMS or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator 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.
9.2.2
Study Drug Records 
Records for IP, eg BMS-986141 or matching placebo, (whether supplied by BMS, its vendors, or 
the site) must substantiate IP 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.
For non-IP supplies, eg ASA, the investigator is not required to maintain records for 
substantiation of IP integrity and traceability from receipt, preparation, administration, and 
through destruction or return the non-investigational product. 
For ASA, subject level dispensation, administration and drug accountability records are required 
to ensure patient medication compliance.
If...
Then...
Supplied by BMS (or its vendors):

Records or logs must comply with applicable regulations and 
guidelines and should include
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If...
Then...
BMS-986141 or matching placebo

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

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)
Not Applicable for this study, all IP 
is provided by BMS.  See above for 
instruction for non-IP, Aspirin 
(ASA)
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable under law and the SOPs/standards of the sourcing 
pharmacy.
These records should include:

label identification number or batch number

amount dispensed to and returned by each subject, including 
unique subject identifiers

dates and initials of person responsible for Investigational 
Product dispensing/accountability, as per the Delegation of 
Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
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 Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee.
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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, including any paper or electronic 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 BMS electronic data capture tool. The investigator must 
retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to
other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

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 BMS 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 
BMS or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
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Term
Definition
form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to 
forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined 
as complete avoidance of heterosexual intercourse and is an acceptable 
form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. Acceptable 
alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence.
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11
LIST OF ABBREVIATIONS
Term
Definition
ABCD2
neurological assessment scores (age, blood pressure, clinical features, 
duration, diabetes)
ACS
acute coronary syndrome
AE
adverse event
AF
atrial fibrillation
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASA
acetylsalicylic acid
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(0-24)
area under the concentration-time curve from time zero to 24 hours post 
dose
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BT
bleeding time
BUN
blood urea nitrogen
C
Celsius
C(24)
concentration at 24 hours
CEC
Clinical Events Adjudication Committee
CFR
Code of Federal Regulations 
CI
confidence interval
CK
creatine kinase
CK-MB
creatine kinase- myocardial fraction
cm
Centimeter
Cmax, CMAX
maximum observed concentration
COX-2
cyclooxygenase-2
CRF
Case Report Form, paper or electronic
CRNM
Clinically Relevant Non-Major
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Term
Definition
CSF
cerebrospinal fluid
CT
computerized tomography
Ctrough
Trough observed plasma concentration
CV
cardiovascular
CYP
cytochrome P450
D-dimer
fibrin degradation product
D/C
Discontinue
DDI
drug-drug interaction
DILI
drug induced liver injury
dL
Deciliter
DMC
Data Monitoring Committee
DWI
Diffusion-weighted imaging MRI
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
ethylenediaminetetraacetic acid
eg
exempli gratia (for example)
Emax
Asymptotic maximum change from placebo effect
EOT
end of treatment
ESR
Expedited Safety Report
F1.2
F1.2 fragment of prothrombin
FDA
Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GPIIb/IIIa
glycoprotein IIb/IIIa
h
hour
Hb
hemoglobin
HBsAg
hepatitis B surface antigen
HBV, HepB
hepatitis B virus
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Term
Definition
HCG
human chorionic gonadotropin
HCV, HepC
hepatitis C virus
HepA
hepatitis A virus
HIPAA
Health Insurance Portability and Accountability Act
hr, hrs
hour, hours
HR
heart rate
HRT
hormone replacement therapy
IAC
Imaging Adjudication Committee
IB
Investigator Brochure
ICD
International Classification of Diseases
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IST
International stroke trial
ISTH
International Society on Thrombosis and Hemostasis
ITT
intent to treat
IU
International Unit
IUD
intrauterine device
IVRS
Interactive Voice Response System
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
Kg
kilogram

kidney injury molecule-1
z
terminal disposition rate constant
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Term
Definition
L
liter
LACI
Lacunar infarct
LAM
lactation amenorrhea method
LDH
lactate dehydrogenase
LMWH
low molecular weight heparin
MACE
major adverse cardiovascular events
MAD
multiple-ascending dose
MCP-mod
Multiple Comparison Procedure – Modeling
mg
milligram
MI
myocardial infarction
min
minute
mL
milliliter
mmHg
millimeters of mercury
MRI
magnetic resonance imaging (or image)
g
microgram
L
Microliter
N
number of subjects or observations
N/A
Not Applicable
ng
nanogram
NGAL
neutrophil gelatinase-associated lipocalin
NIHSS
National Institutes of Health Stroke Scale
NIMP
non-investigational medicinal products 
NOAEL
no-observed-adverse-effect level
NSAID
nonsteroidal anti-inflammatory drug
OSCP
Oxfordshire Community Stroke Project
PACI
partial anterior circulation infarct
PAR4
protease-activated receptor-4
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
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Term
Definition
POCI
posterior circulation infarct
PT
prothrombin time
PTT
partial thromboplastin time
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAD
single ascending dose
SAE
serious adverse event
sCD40L
soluble CD40 ligand
SD
standard deviation
SI
International system of units
SOP
Standard Operating Procedures
sP-selectin
soluble P-selectin
T1WI
T1-weighted images
T2WI
T2-weighted images
TACI
Total anterior circulation infarct
TAT
thrombin-antithrombin III
TB
total bilirubin
T-HALF
Half life
TIA
transient ischemic attacks
TSH
thyroid stimulating hormone
Tx
Treatment
ULN
upper limit of normal
US
Ultrasound
VTE
venous thromboembolism
WOCBP
women of childbearing potential
wt
Weight
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12
REFERENCES
1
Geeganage, C. M., et al. Dual or mono antiplatelet therapy for patients with acute ischemic 
stroke or transient ischemic attack: a systematic review and meta-analysis of randomized 
controlled trials. Stroke, 2012; 43: p. 1058-1066.
2
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a 
randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients 
with acute ischemic stroke. The Lancet, 1997; 349: p. 1569-1581.
3
http://www.world-heart-federation.org/cardiovascular-health/stroke/
4
Mozaffarian D, Benjamin EJ, Go AS, et al., on behalf of the American Heart Association 
Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke 
Statistics—2015 Update: A Report from the American Heart Association. Circulation. 
2015;131:e29-e322.[updated reference]
5
Sandercock PAG, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute 
ischaemic stroke. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: 
CD000029. DOI: 10.1002/14651858.CD000029.pub3.
6
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470.
7
Levey AS, Greene T, Kusek J.W., Beck GL, MDRD Study Group. A simplified equation to 
predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol. 2000;11:155A.
8
Bakshi R, Ketonen L. Brain MRI in clinical neurology, in Joynt RJ, Griggs RC (eds): Baker's 
Clinical Neurology on CD-ROM, 2001 Edition. Philadelphia, Lippincott Williams & 
Wilkins, 2001.
9
Brant-Zawadzki M, Atkinson D, Detrick M, Bradley WG, Scidmore G. Fluid-attenuated 
inversion recovery (FLAIR) for assessment of cerebral infarction. Initial clinical experience 
in 50 patients. Stroke 1996; 27: 1187-1191.
10 Spilker J, Kongable G, Barch C, Braimah J, Brattina P, Daley S, Donnarumma R, Rapp K, 
Sailor S. Using the NIH Stroke Scale to assess stroke patients. The NINDS rt-PA Stroke 
Study Group. J Neurosci Nurs. 1997 Dec;29(6):384-92.
11 Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein AL, Sidney 
S. Validation and refinement of scores to predict very early stroke risk after transient 
ischaemic attack. Lancet. 2007 Jan 27;369(9558):283-92.
12 Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of 
clinically identifiable subtypes of cerebral infarction. Lancet. 1991 Jun 22;337(8756):1521-6.
13 Asdaghi N, Jeerakathil T, Hameed B, Saini M, McCombe JA, Shuaib A, Emery D, Butcher 
K. Stroke. 2011;42:2143-2148.
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14 Bornkamp B, Pinheiro J, Bretz F. DoseFinding: planning and analyzing dose finding 
experiments. R package, http://www.cran.rproject. org/web/packages/DoseFinding/.
15 Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics 2005; 61:738–748.
16 Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model 
uncertainty using general parametric models. Statistics in Medicine 2014; 33:1646-1661.
17 Bornkamp B, Pinheiro J, Bretz F. DoseFinding: planning and analyzing dose finding 
experiments. R package, http://www.cran.r-project.org/web/packages/DoseFinding/.
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APPENDIX 1
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause 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.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators should use 
their 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.
At a minimum, subjects must agree to use one highly effective OR one less effective method of 
contraception as listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to 
use one of the highly effective methods of contraception listed below. Male subjects must inform 
their female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as 
follows:
1. Nonhormonal IUDs, such as ParaGard
2. Bilateral tubal occlusion
3. Vasectomised partner with documented azoospermia 90 days after procedure
a.
Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success.
4. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse. (refer to Glossary of Terms)
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b. Complete abstinence is an acceptable form of contraception for all study drugs 
and must be used throughout the duration of the study treatment (plus 5 half-lives 
of the investigational drug plus 30 days).
c.
It is not necessary to use any other method of contraception when complete 
abstinence is elected.
d. Subjects who choose complete abstinence must continue to have pregnancy tests.
e.
Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence.
f.
The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.
LESS EFFECTIVE METHODS OF CONTRACEPTION
1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
4. Male or female condom with or without spermicide*
* A male and a female condom must not be used together.
UNACCEPTABLE METHODS OF CONTRACEPTION
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2. Withdrawal (coitus interruptus)
3. Spermicide only
4. Lactation amenorrhea method (LAM)
Female partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they will not be receiving 
study drug.
Local laws and regulations may require use of alternative and/or additional contraception
methods.
REFERENCES FOR THE USE OF CONDOMS WITH SPERMICIDE.
Kestelman P. et. al., Efficacy of the Simultaneous Use of Condoms and Spermicides Family 
Planning Perspectives.Vol 23 (5); October 1991.
Gabbay MB, Thomas J, Gibbs A, Hold P. A Randomized Crossover Trial of The Impact of 
Additional Spermicide on Condom Failure Rates. Sex Transm Dis 2008; 35: 862-8.
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Page:
1
Protocol Number:
CV006004
IND Number:
122,675
EUDRACT Number
2015-003959-22
Date:
07-Jul-2016
Protocol CV006004: A Phase 2, Placebo Controlled, Double-Blind, Parallel-Arm Study to 
Evaluate Efficacy and Safety of BMS-986141 For the Prevention of Recurrent Brain Infarction 
in Subjects receiving acetylsalicylic acid (ASA) following Acute Ischemic Stroke or Transient
Ischemic Attack
Amendment Number 06
Site Number: All
Study Director
Principal Investigator
 
Medical Monitor
Fraz Ismat, M.D.
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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2
Amendment Rationale:
The purpose of this amendment is to implement changes to several aspects of the study that are 
intended to further ensure the safety of subjects participating in the study. Changes to the 
protocol are being implemented before any subjects have been enrolled.
These changes are being made in response to recent data from a 90 day toxicology study in 
monkeys that showed moderate degeneration/regeneration of the tubular epithelium of the 
kidneys with pale eosinophilic material and multinucleated giant cells at 75 mg/kg/day 
(approximately 4 x the projected AUC in subjects at 16 mg QD). Full recovery of the renal 
pathology was evident after a 1-month post-dose evaluation. Refer to the BMS-986141 
Investigator Brochure, Version 3 for additional information.
This amendment modifies the study design to allow initiation of the study with subjects being 
randomized to placebo, 0.8, or 4.8 mg BMS-996141, with no subjects randomized to the top dose 
until after a DMC review of safety and laboratory data from the Day 28 study visit for at least 
10% of the planned total subjects. In addition, after this review the top dose will be 8 mg of 
BMS-986141 instead of 16 mg. Changes have also been made to exclusion criteria related to 
renal function and factors that may influence exposures to the drug, as well as to criteria that 
require discontinuation of subjects who are on treatment. Guidance around the use of CYP3A4 
inhibitors has been further clarified as the use of CYP3A4 substrates may increase 
concentrations of BMS-986141. In addition, the laboratory tests included in the study have been 
modified to include urinalysis at all treatment period visits and the assessment of renal 
biomarkers to more closely assess renal function of the study subjects. The statistical section and 
sample size calculations have been updated to correspond to these changes.
Additional changes include: expansion of time windows for PK sample collection to reduce 
challenges in collecting samples when subjects are randomized outside of routine working hours;
changing requirements for contraception to allow the use of one highly effective method of 
contraception or one less effective method of contraception to be consistent with BMS SOPs as 
BMS-986141 is currently considered unlikely to be a teratogen since BMS-986141 produced no 
developmental toxicity in rats and rabbits when dosed up the maximal feasible dose, 
150 mg/kg/day, in expanded range-finding studies; clarified that women enrolled in the study 
cannot use hormonal contraception as their sole means of contraception; added a statement in 
Appendix 1 that local laws and regulations may require use of alternative and/or additional 
contraception methods; added pregnancy test to be done at Day 90 in Part 2; clarified genotyping 
testing to include the types of genes that will be studied and the location and duration of sample 
storage; updated protocol to provide further clarifications to assist with study implementation 
and reflect recent changes in the BMS protocol model document template; corrected
typographical errors.
This protocol amendment applies to all subjects to be enrolled in the study.
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3
Changes to the Protocol:
1. Synopsis, Investigational Product(s), Dose and Mode of Administration, Duration of 
Treatment with Investigational Product(s)
a) All treatments: removed approximate number of subjects per treatment arm
b) Treatment D: dose changed from 16 mg QD to 8 mg QD
2. Synopsis, Study Design
a) Removed the randomization ratio
b) Added text stating that initially randomization will be limited to the placebo and the two 
lower dose treatment groups (0.8 mg QD and 4.8 mg QD), randomization to the highest 
dose treatment arm (8 mg) will only be initiated after DMC review of safety data from the 
Day 28 study visit for at least 10% of the planned total subjects.
c) Study Schematic: 
i) Parts 1 and 2 - changed 16.0 mg dose group to 8.0 mg; added note that 8 mg dose group 
will only be initiated after DMC review of initial safety
ii) Part 1 - updated Day 28 to clarify this is end of treatment.
3. Synopsis, Study Assessments, Safety: Added text describing that initially randomization will 
be limited to the placebo and two dose lower treatment groups (0.8 mg QD and 4.8 mg QD) 
with no randomization to the 8 mg dose. Randomization to the 8 mg treatment arm will only 
be initiated after DMC review of safety data from at least 10% of the planned total subjects
that have completed their scheduled Day 28 visit. As a result of this review, the DMC can 
recommend expansion of the randomization to all 4 study arms or other modifications as 
needed to ensure subject safety.
4. Synopsis, Statistical Considerations, Sample Size: Updated paragraph to state that initially 
randomization will be limited to the placebo, 0.8 and 4.8 treatment groups until DMC review 
of the Day 28 safety data from the first 10% of subjects. Initially, the randomization will be 
in a 1:1:1 ratio. If the DMC recommends proceeding to the inclusion of the highest dose 
group the randomization ratio will then become 1:1:1:1. Changed the 16 mg dose group to 8 
mg.
5. Synopsis, Primary Efficacy Endpoint Analysis: update text of 3rd bullet to state that a single 
categorical variable based on study change points (length of treatment [28 or 90 days] and 
randomization phase [randomized prior to or after DMC safety interim analysis decision]) 
will be included as a covariate.
6. Synopsis, Safety Analysis:
a) Added a new 1st bullet to state that for safety analyses, separate summaries taking into 
account length of treatment (28 or 90 days) and randomization phase will be provided.
b) Former 1st bullet, now 2nd bullet: added text at the end of the paragraph to state that a 
single categorical variable based on study change points (length of treatment [28 or 90 
days] and randomization phase [randomized prior to or after DMC safety interim analysis 
decision]) will be included as a stratum in the calculation of the CIs.
7. Section 1.3.4, Exploratory Objectives
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8. Section 1.4.1 Clinical Pharmacology and Safety
a) 1st paragraph, 1st sentence: updated number of subjects that received single doses in the 
study
b) 2nd paragraph, 1st sentence: added BUN and creatinine.
9. Section 1.5, Overall Risk/Benefit Assessment, 3rd paragraph
a) after first sentence added information from the 3 month toxicity studies in monkeys.
b) Previous 2nd sentence and information that follows becomes new 4th paragraph.
10. Section 3.1, Study Design and Duration,
a) 2nd paragraph, removed randomization ratio and number of subjects per treatment arm.
b) 3rd paragraph, 1st sentence: update to state the 90 day non-clinical toxicology studies 
were recently completed.
c) Study Schematic:
i) Parts 1 and 2 - changed 16.0 mg dose group to 8.0 mg; added note that 8 mg dose group 
will only be initiated after DMC review of initial safety.
ii) Part 1 - updated Day 28 to clarify this is end of treatment.
11. Section 3.3.1, Inclusion Criteria
a) 1a: added note that consent by a LAR will only be allowed if permitted by local 
regulations.
b) 3a: updated to state subjects must be a minimum of 18 years old or age of majority (if 
local age of majority is >18 years of age) to participate in the study as per the model 
document.
c) 3g: added criterion to state that women of child-bearing potential who use hormonal 
contraception must agree to use an additional method of birth control but female partners 
of male subjects may use hormonal contraceptives as they are not taking study medication.
d) 3, 2nd paragraph after lettered list: changed to state, at a minimum subjects must use one 
highly effective method of contraception OR one less effective method.
e) 3rd, paragraph: All text related to contraceptive methods is removed from protocol and 
now in Appendix 1 as per the model document.
f)
Added a statement in Appendix 1 that local laws and regulations may require use of 
alternative and/or additional contraception methods.
12. Section 3.3.2, Exclusion Criteria
a) 2c: added that subjects with acute gastrointestinal ulcers are to be excluded from the study.
b) 2f: changed to exclude subjects with moderate or severe hepatic impairment, defined as 
Child-Pugh Class B or C, and added reference to Appendix 5.
c) 2g: changed to exclude subjects with moderate to severe renal impairment defined as an 
estimated glomerular filtration rate (eGFR)< 45 mL/min.
d) 2o: added exclusion of subjects who have received intravenous or intra-arterial 
thrombolysis or mechanical thrombectomy within the past 48 hours or who are currently 
eligible and able to receive these treatments for their current stroke.
e) 3a, v): removed exclusion of QTcF450 msec as these subjects are expected to be 
excluded based on uncorrected QT interval
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f)
6e: deleted this exclusion as it is now addressed in exclusion criteria 2o. 
g) 6g: added that use of strong CYP3A4 inhibitors or strong CYP3A4 inducers are prohibited 
in the 7 days prior to randomization and during the study.
13. Section 3.3.3, Women of Childbearing Potential: Section deleted. This information is now in 
Appendix 1.
14. Section 3.4.1, Prohibited and/or Restricted Treatments
a) 2nd paragraph, first bullet: added that low molecular weight heparin (LMWH) can be used 
to maintain patency of indwelling catheters or for prophylaxis of VTE.
b) 2nd paragraph, third bullet: deleted any intravenous or intra-arterial thrombolysis as this is 
more clearly stated in exclusion criterion 2o) above
c) 2nd paragraph, 4th bullet: updated to state that concomitant oral or intravenous therapy
with strong CYP3A4 inhibitors or inducers is prohibited.
d) 5th paragraph: added that subjects requiring treatment with strong CYP3A4 inhibitors or
strong CYP3A4 inducers must be discontinued from study treatment and that is 
recommended the CYP3A4 inhibitor or inducer is not started for at least 24 hours after the 
last dose of study medication.
15. Section 3.5, Discontinuation of Subjects following an Treatment with Study Drug
a) 6th bullet: deleted that subjects will be discontinued if unblinded for any reason, as per the
model document
b) 10th bullet: Changed definition of severe renal impairment to severe or moderate renal 
impairment with a eGFR<45 mL/min for more than 7 days.
c) added 12th bullet: added that subjects requiring treatment with strong CYP3A4 inhibitors 
or strong CYP3A4 inducers will have study treatment discontinued. 
d) added 13th bullet: added that subjects treated with any intravenous or intra-arterial 
thrombolysis or mechanical thrombectomy will be discontinued from study treatment
e) 3rd paragraph: wording changes per new protocol model document. Reference to BMS 
Medical Monitor changed to Sponsor or designee and 2nd sentence deleted.
16. Section 4.3, Storage of Study Drug and Dispensing:
a) Section title changed to 4.3 Storage of Study Drug
b) 3rd paragraph deleted per the model document
c) Added new 3rd paragraph referencing Section 9.2.2 for guidance on IP records and 
documentation.
17. Section 4.4, Method of Assigning Subject Identification, 2nd paragraph: 
a) changed 16 mg treatment group to 8 mg
b) added that randomization will be limited to the two lower doses of BMS-986141 or 
placebo in a 1:1:1 ratio until after DMC review of safety and laboratory data from the Day 
28 study visit for at least 10% of the planned total subjects. If the DMC recommends 
proceeding to inclusion of the highest dose, subsequent randomization will be in a 1:1:1:1 
ratio.
18. Section 4.5, Selection and Timing of Dose for Each Subject, 3rd paragraph. Updated to note 
that initially each daily dose of study medication will consist of 4 tablets, however, drug 
supplies that may be available in early 2017 may allow for dosing with 2 tablets daily. Sites 
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will be provided with instructions and guidance on how to implement this change if it is to 
occur.
19. Section 4.6, Blinding/Unblinding
a) 7th paragraph: added that designated senior staff of BMS Research and Development 
independent from the study oversight team will be unblinded to pharmacokinetic results
and may make recommendations to enroll additional participants to specific dosage tiers 
in order to obtain sufficient exposures. Any such recommendations will be considered by 
the Steering Committee and DMC.
b) 8th paragraph: added that the pharmacokineticist or designate in Clinical Pharmacology 
and Pharmacometrics; and programmers in Data Sciences may be unblinded in order to 
prepare preliminary summaries of pharmacokinetic, and safety data, as needed before data 
is more generally unblinded.
c) 10th paragraph: clarified that a BMS biomarker representative and/or their designate may 
be unmasked to review the platelet aggregation data.
20. Section 4.8, Destruction of Study Drug:
a) Section title changed to 4.8 Destruction or Return of Investigational Product;
b) added table after 1st paragraph providing guidelines for investigational product 
destruction;
c) content of this section has been rearranged per the model document.
21. Section 4.9, Return of Study Drug: section deleted and text moved to Section 4.8 per model 
document
22. Section 4.10, Retained Samples for Bioavailability/Bioequivalence: section number changed 
to 4.9.
23. Section 5.1 Flow Chart/Time and Events Schedule
a) Table 5.1-1, Screening Procedural Outline
i) Local Laboratory Tests: clarified all screening laboratory tests are analyzed locally
ii) Follicle Stimulating Hormone (FSH) Test: clarified this is only done for post-
menopausal women under the age of 55
iii) Deleted comment for Urinalysis
iv) TSH testing deleted as there were no increases in TSH observed in the phase 1 study of 
BMS-986141
b) Tables 5.1-2 and 5.1-3, Part 1 and Part 2 Procedural Outlines
i) Central Laboratory: clarified that chemistry and hematology samples will be sent to the 
central laboratory for analysis throughout the study. 
ii) Added Urinalysis tests, to be done locally, at the Day 1, Day of Hospital Discharge and 
Day 28 visits (and Day 56 and Day 90 for Part 2). 
iii) Deleted TSH testing
iv) Serial/Sparse Blood PK Sampling and Platelet Aggregation: updated collection 
window for Day 1 24 hour post-dose PK sample 
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v)
 
 
 
 
vi)
 
 
vii)
Pregnancy Test, Part 2, Day 90: Added an additional X and comment to indicate 
the a pregnancy test must be done at the Day 90 visit in addition to the home test done 
at Day 84. 
24. Section 5.3.7, Laboratory Test Assessments: 
a) Inserted new paragraph between paragraphs 1 and 2 to clarify that unexpected abnormal 
results on urinalysis should be confirmed by retesting a new, carefully obtained sample.
b) 4th paragraph, clarified that any abnormal laboratory test will evaluated as clinically 
indicated.
25. Table 5.3.7-1, Laboratory Assessments: 
a) Deleted bicarbonate testing at Screening
b) Clarified FSH is only done for post-menopausal women under the age of 55 
c) Deleted TSH testing
d) Clarified urinalysis will be done locally at all required time points
26. Section 5.4.1, Symptomatic Stroke, 2nd paragraph, 1st sentence: clarified requirements for 
diagnosis of stroke
27. Table 5.5-1: Pharmacokinetic Sampling Schedule: updated the sample collection windows 
for the Day 1 - 8 hr and Pre-dose Day 2 (Day 1-24 hr) samples.
28. Section 5.6.1, Exploratory Biomarker Assessments: 
 
 
 
 
 
 
 
 
29. Section 5.8.2, ABCD2: clarified this will be source document
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30. Section 6, Adverse Events; Section 6.1.1, Serious Adverse Event Collection and Reporting; 
Section 6.4, Pregnancy; Section 9.2.3, Case Report Forms; Section 9.3, Clinical Study Report 
and Publications
a) Changed BMS or BMS Medical Monitor to Sponsor or designee as per the model 
document
31. Section 6.4, Pregnancy, 5th paragraph: clarified that a pregnancy in a female partner of a 
male study subject will require the female partner to provide informed consent to disclose 
pregnancy related information.
32. Section 7.1, Data Monitoring Committee: added 2nd paragraph describing that the DMC will 
review the safety data from the at least 10% of the total planned subjects randomized to the 
0.8, 4.8 or placebo groups and will make their recommendation before randomizations to the 
8 mg treatment arm can begin. 
33. Section 8.1, Sample Size Determination
a) 1st paragraph, 3rd sentence: changed 16 mg dose to 8 mg
b) Updated 2nd paragraph to describe randomizations ratios and sample size calculations 
based on the possible staggered randomization from 3 treatment groups to 4 treatment 
groups.
c) Added Table 8.1-1: Randomization Targets
34. Section 8.3.3 Exploratory Endpoint(s):
a) 2nd bullet: Deleted NR-2 peptide
b) Added 3rd bullet to state change from baseline on renal biomarkers is a new exploratory 
endpoint
c) former 3rd bullet, now 4th bullet: added that polymorphisms in genes related to platelet 
activity will also be studied. 
35. Section 8.4.1 Demographics and Baseline Characteristics
a) 2nd paragraph: deleted summaries of baseline variable by study phase
b) added 3rd paragraph stating separate summaries taking into account the length of 
treatment and randomization phase will be provided.
36. Section 8.4.2.1, Primary Efficacy Endpoint Analysis: 
a) 1st paragraph, 4th sentence: updated the dose levels to reflect change from 16 mg to 8 mg 
treatment arm. 
b) 3rd paragraph: deleted. 
c) new 3rd paragraph added to address new covariate.
37. Section 8.4.3, Safety Analyses: 
a) Added new 1st paragraph describing that for safety analyses separate summaries taking 
into account length of treatment and randomization phase will be provided.
b) 1st paragraph (now 2nd paragraph): added a 3rd sentence stating that a single variable 
based on study change points (length of treatment and randomization phase) will be 
included as a stratum in the calculation of the CIs.
c) 2nd paragraph (now 3rd paragraph): delete 4th sentence stating AE summaries will be 
presented by treatment length.
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38. Section 8.4.4, Pharmacokinetic Analyses, 1st paragraph: deleted reporting of Cmax, 
AUC(0-24), C(24) after first dose, and C(24) on Day 28 due to the need to expand PK 
sample collection windows.
39. Section 8.5, Interim Analyses: Updated to state no interim analyses are planned for efficacy. 
Description of review of safety data after 10% of the total planned subjects for the study have 
completed the Day 28 visit and that pharmacokinetics will be explored to assess exposure.
40. Section 9.1.1, Compliance with Protocol and Protocol Revisions
a) Deleted 1st sentence as per the model document
b) 1st paragraph, 2nd sentence: added statement that if applicable, local health authority of 
approval/favorable opinion must be received prior to implementing a protocol amendment 
and additional wording changes per the model document
c) 2nd paragraph: updated wording per the model document
d) 3rd paragraph: added statement that if applicable, local health authority of 
approval/favorable opinion must be sent to BMS
41. Section 9.1.2, Monitoring
a) Reference to BMS changed to BMS or designee per the model document
42. Section 9.1.3, Investigational Site Training
a) Section deleted per the model document
43. Section 9.2.1 Records Retention
a) 1st paragraph: added that investigator or head of study site in Japan must retain all study 
all study records
b) All paragraphs: changed BMS to BMS or designee per the model document
44. Section 9.2.2, Study Drug Records: 
a) Clarified that records for IP, eg, BMS-986141 or matching placebo must be maintained as 
described in this section. Clarified ASA is considered non-IP and described the records 
that must be maintained for ASA.
b) Table inserted that describes the records required to be maintained
c) Added statement that sites are not required to retain records that substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or 
return of the non-investigational product, ASA used in this study. Subject level 
administration and drug accountability records are required. 
d) additional wording updated per the model document
45. Section 9.2.3, Case Report Forms, 5th paragraph: Added that subinvestigators in Japan may 
not be delegated the CRF approval task as per the model document
46. Section 11, List of Abbreviations
a) Deleted NR2 peptide
b) Added: KIM-1, NGAL, 
47. Added the following Appendices:
a) Appendix 1, Women of Childbearing Potential Definitions and Methods of Contraception
b) Appendix 2 - NIH Stroke Scale
c) Appendix 3 - ABCD2 Assessment Source Document
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d) Appendix 4 - Oxfordshire Community Stroke Project Classification
e) Appendix 5 - Child-Pugh Classification Criteria
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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AMENDMENT ACKNOWLEDGMENT
I have read this Amendment and agree that it contains all necessary details for carrying out the 
changes described. I understand that it must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion by all necessary Health Authorities before implementation unless to eliminate 
an immediate hazard to subjects.
If this Amendment substantially alters the study design or increases potential risk to subjects, the 
consent form will be revised and submitted to the Institutional Review Board/Independent Ethics 
Committee for approval/positive opinion. I will use the new consent form for any new subjects 
prior to enrollment, and for subjects currently enrolled in the study if they are affected by the 
Amendment.
___________________________________
_______________
Investigator's printed name and signature
Date
___________________________________
_______________
Medical Monitor/Study Director
Date
(If required by applicable regulations and guidelines.)
Protocol Number: CV006004
Site Number:
Amendment Number: 06
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SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 2, PLACEBO CONTROLLED, RANDOMIZED, DOUBLE-BLIND, 
PARALLEL-ARM STUDY TO EVALUATE EFFICACY AND SAFETY OF BMS-986141 
FOR THE PREVENTION OF RECURRENT BRAIN INFARCTION IN SUBJECTS
RECEIVING ACETYLSALICYLIC ACID (ASA) FOLLOWING ACUTE ISCHEMIC 
STROKE OR TRANSIENT ISCHEMIC ATTACK
PROTOCOL(S) CV006004
VERSION # 1.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND AND RATIONALE......................................................................7
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................8
2.2
Treatment Assignment..............................................................................................9
2.3
Blinding and Unblinding.........................................................................................10
2.3.1
Blinding..................................................................................................................10
2.3.2
Unblinding .............................................................................................................11
2.4
Protocol Amendments.............................................................................................11
3
OBJECTIVES ........................................................................................................11
3.1
Primary...................................................................................................................11
3.2
Secondary...............................................................................................................11
3.3
Safety.....................................................................................................................12
3.4
Exploratory.............................................................................................................12
4
ENDPOINTS..........................................................................................................12
4.1
Primary Efficacy Endpoint......................................................................................12
4.1.1
Symptomatic Stroke ................................................................................................12
4.1.2
Unrecognized Brain Infarction ...............................................................................13
4.2
Secondary Efficacy Endpoints ................................................................................13
4.3
Exploratory Endpoints............................................................................................13
4.4
Primary Safety Endpoint.........................................................................................14
4.5
Additional Safety Endpoints ...................................................................................14
5
SAMPLE SIZE AND POWER...............................................................................14
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................15
6.1
Study Periods..........................................................................................................15
6.2
Treatment Regimens...............................................................................................15
6.3
Populations for Analyses ........................................................................................15
7
STATISTICAL ANALYSES..................................................................................16
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7.1
General Methods ....................................................................................................16
7.1.1
General Methods for Study Periods ........................................................................16
7.1.2
General Methods for Efficacy Analyses...................................................................17
7.2
Study Conduct........................................................................................................19
7.2.1
Accrual...................................................................................................................19
7.2.2
Relevant Protocol Deviations..................................................................................19
7.3
Study Population ....................................................................................................20
7.3.1
Subject Disposition.................................................................................................20
7.3.2
Demographic and Baseline Characteristics ............................................................20
7.3.3
Medical History......................................................................................................21
7.4
Extent of Exposure .................................................................................................21
7.4.1
Administration of Study Therapy.............................................................................21
7.4.2
Study Therapy Compliance .....................................................................................21
7.4.3
Modifications of Study Therapy ..............................................................................22
7.4.4
Concomitant Medications.......................................................................................22
7.5
Efficacy..................................................................................................................22
7.5.1
Primary Efficacy Analysis.......................................................................................22
7.5.1.1
Sensitivity Analyses.................................................................................................23
7.5.1.2
Subgroup Analyses .................................................................................................23
7.5.2
Secondary Efficacy Analyses...................................................................................24
7.5.3
Other Efficacy Analyses..........................................................................................25
7.6
Safety Analyses ......................................................................................................25
7.6.1
Major Bleeding and Clinically Relevant Non-Major Bleeding.................................25
7.6.2
Deaths ....................................................................................................................26
7.6.3
Serious Adverse Events...........................................................................................26
7.6.4
Adverse Events .......................................................................................................26
7.6.5
Clinical Laboratory Evaluations.............................................................................27
7.6.6
Electrocardiograms................................................................................................28
7.6.7
Vital Signs ..............................................................................................................28
7.6.8
Physical Examination Findings...............................................................................29
7.7
Pharmacokinetic Analyses ......................................................................................29
7.8
Biomarker Analyses ...............................................................................................29
8
CONVENTIONS....................................................................................................30
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8.1
Decimal Places .......................................................................................................30
8.2
Pharmacokinetic Summaries...................................................................................30
8.3
Day Ranges for Analysis of Time Points.................................................................30
8.4
Multiple Measurements ..........................................................................................31
9
CONTENT OF REPORTS .....................................................................................32
APPENDIX 1
MARKED ABNORMALITY CRITERIA FOR LABORATORY 
TEST RESULTS - CONVENTIONAL (US) UNITS..............................33
APPENDIX 2
MARKED ABNORMALITY CRITERIA FOR LABORATORY 
TEST RESULTS -- SI UNITS................................................................37
10
REFERENCES.......................................................................................................41
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LIST OF TABLES
Table 5-1:
Randomization Targets...........................................................................14
Table 7.2.2-1:
List of Relevant Protocol Deviations ......................................................19
Table 7.4.1-1:
Extent of Exposure Categories for Summarization..................................21
Table 7.5.1.2-1:
Subgroups of Interest for Efficacy Assessments......................................23
Table 7.6.7-1:
Out of Range Vital Signs Criteria ...........................................................29
Table 8.3-1:
Analysis Windows for Laboratory Parameters & Vital Signs (Part 
1)............................................................................................................31
Table 8.3-2:
Analysis Windows for Laboratory Parameters & Vital Signs (Part 
2)............................................................................................................31
Table 8.3-3:
Analysis Windows for ECG Results .......................................................31
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LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic for Part 1............................................................9
Figure 2.1-2:
Study Design Schematic for Part 2............................................................9
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1
BACKGROUND AND RATIONALE
 
 
 
 
 
 
 
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.
Research Hypothesis:  
BMS-986141 is effective in reducing the recurrence of stroke in subjects with recent TIA or
stroke.
Schedule of Analyses:
No interim analyses are planned to assess efficacy.  The DMC will, however, review safety data 
after 10% of the total planned subjects for the study (approximately 132 subjects) have been 
randomized and have completed their scheduled Day 28 visit.  Additionally, pharmacokinetics of 
BMS-986141 will be explored to assess exposures and potential relationship to safety.  There are 
no other planned interim analyses for this study. 
The final analyses for the clinical study report will be performed following the database lock 
after all subjects have completed the study.
2
STUDY DESCRIPTION
2.1
Study Design
This study is a randomized, double-blind, placebo-controlled, parallel arm clinical trial in 
subjects receiving acetylsalicylic acid (ASA) with a recent Acute Ischemic Stroke (AIS) or 
Transient Ischemic Attack (TIA).
The study consists of two parts.  Part 1 will have a treatment duration of 28 days.  Part 2 will 
begin once results from ongoing toxicology studies are reviewed, and will have a treatment 
period of 90 days.  Subjects enrolling in Part 1 will not be allowed in Part 2.  The figures below 
illustrate the treatment plan for both study parts.
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Figure 2.1-1:
Study Design Schematic for Part 1
Figure 2.1-2:
Study Design Schematic for Part 2
2.2
Treatment Assignment
At the screening visit each subject will be assigned a unique sequential subject number by the
Interactive Voice Response System (IVRS). The subject number will consist of 5 digits which
are assigned sequentially (00001, 00002, 00003, etc.) by the IVRS. This number will be used for
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identification throughout the study and will not be used for any other participant. Screening of
subjects with lacunar infarcts will be capped at approximately 20%.
In addition to the two Parts of the study noted above, which are related to treatment duration, the 
study also consists of two phases, each with a slightly different method of assigning study 
treatment.  In Phase A, subjects will be randomized 1:1:1 using IVRS to one of two doses of 
BMS-986141 (0.8 mg or 4.8 mg) or placebo.  In Phase B, subjects will be randomized 1:1:1:1 
via IVRS to one of three doses of BMS-986141 (0.8 mg, 4.8 mg, or 8 mg) or placebo.  The 
transition from Phase A to Phase B of the study will only occur after an Independent Data 
Monitoring Committee (DMC) has reviewed data from the first 10% of the planned subjects 
(approximately 132 subjects with 28 days of data). As of the time of the writing of this SAP, the 
decision to move from Part 1 to Part 2 of the study has been made.  Some sites will continue to 
enroll subjects in to Part 1 of the study until Part 2 can be fully implemented.  As a result, there 
will be no subjects randomized in Phase B during Part 1 of the study.
Randomization schedules will be generated by BMS and kept by the IVRS vendor.  All subjects 
will receive open-label ASA at a dose from 75 to 162 mg per day beginning at a time consistent 
with local standards of care for patients with AIS or TIA.  As mentioned in section 2.1, the 
planned study dosing duration is 28 days for Part 1 of the study and 90 days for Part 2 of the 
study.
At all study visits when study drug is dispensed, each subject will be assigned a container
number by the IVRS. Container numbers will be assigned non-sequentially and will correspond
to the numbers printed on the packages and bottles containing study drug, and will be recorded
on the appropriate eCRF. The IVRS will be available 24 hours per day, 7 days a week.
2.3
Blinding and Unblinding
2.3.1
Blinding
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 
investigational product is critical to the subject’s management, procedures are in place to have 
the blind broken for an individual subject.
Except as noted, BMS Research and Development personnel, as well as all vendors responsible
for the conduct of the trial (protocol team) will remain blinded for the duration of the trial. The
Data Monitoring Committee (DMC) will assess safety on an ongoing basis, and will have access
to unblinded treatment codes. An analysis team, including a reporting statistician and
programming support, who are not involved with the conduct of the study, will provide analyses
to the DMC. This unblinded analysis team will not provide any information from unblinded
analyses to the protocol team until after the trial has been completed.
The Bioanalytical Sciences section or its designate will be unblinded to the randomized
treatment assignments in order to minimize unnecessary analysis of samples from control group
subjects. Likewise, the Biotransformation section or its designate may be unblinded, if
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metabolite profiling work is conducted. This unblinded analysis team will not provide any
information from unblinded analyses to the protocol team until after the trial has been completed.
Platelet aggregation data will be collected and reviewed for QC purposes by hospital and vendor
personnel not associated with the clinical conduct of the study. During the double-blind
treatment period, platelet aggregation will be masked to the Investigator and protocol team. One
biomarker representative, may be unmasked to review the platelet aggregation data, and will not
provide any information that can potentially be unblinding to the protocol team until after the
trial completes. The unmasked platelet aggregation data will be provided to the study team after
the trial has been completed.  
2.3.2
Unblinding
For this study, the method of unblinding for emergency purposes is IVRS.  Details are included 
in the IVRS manual.
2.4
Protocol Amendments
A protocol revision was formally issued on 07-July-2016, incorporating several design changes
into the study.  Most notably, the original planned high dose of BMS-986141 was reduced from 
16 mg to 8 mg, and this arm of the study is to be closed off until the Data Monitoring Committee 
is able to evaluate sufficient safety data from the 2 lower dose groups (0.8 mg and 4.8 mg).  To 
that effect, the randomization scheme was updated to keep the 8mg arm closed until the DMC 
convened.  Pending the outcome of the DMC meeting, the 8mg arm would open and 
randomization would proceed in a 1:1:1:1 fashion from there forward to one of the three BMS-
986141 doses or placebo (see Table 5-1).
Additional updates were made to clarify various aspects of the study and can be found in the 
protocol revision.  No further updates had a significant impact to the statistical methods planned 
for this study.
3
OBJECTIVES
3.1
Primary
The primary objective of the study is to determine the dose-response relationship of BMS-
986141 on the recurrence of brain infarction at 28 days as assessed by a composite of 
symptomatic ischemic stroke and unrecognized brain infarction as assessed by MRI in subjects 
with ischemic stroke or TIA treated with ASA.
3.2
Secondary

To assess the effect of BMS-986141 on the occurrence of major adverse cardiovascular 
events (MACE, including all stroke, myocardial infarction, and CV death) by Day 90

To assess the effect of BMS-986141 on the occurrence of the composite of ischemic stroke, 
myocardial infarction, and CV death by Day 90

To assess the effect of BMS-986141 on incidence of symptomatic recurrent ischemic stroke 
up to 28 days of treatment
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
To assess the effect of BMS-986141 on the occurrence of the composite of unrecognized 
brain infarction assessed by MRI at Day 28 and MACE by Day 90
3.3
Safety

To assess the effect of BMS-986141 on the composite of Major and Clinically Relevant Non-
Major (CRNM) Bleeding

To assess the effect of BMS-986141 on all reported bleeding

To evaluate safety and tolerability of BMS-986141
3.4
Exploratory

 
 
 
 
 
 
 
 
4
ENDPOINTS
4.1
Primary Efficacy Endpoint
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic
ischemic stroke by Day 28 and unrecognized brain infarction assessed by MRI at Day 28.  Each 
of these will be assessed by an adjudication committee.  If a subject experiences any of these 
events, the subject will be counted as having experienced a composite event in the analysis.
In the event that one, but not both of the components of the primary endpoint cannot be 
ascertained, then the remaining component will be evaluated.  In this case, if the remaining 
component is counted as an event, the composite event will be considered as having occurred.  
If, however, the remaining component is not counted as an event, or if both of the components of 
the primary endpoint cannot be ascertained, the resulting primary endpoint will be considered as 
missing.
4.1.1
Symptomatic Stroke
All cases of suspected recurrent stroke will be adjudicated by a blinded Clinical Events
Adjudication Committee (CEC). Diagnosis of stroke will require the abrupt onset of focal 
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neurological symptoms lasting at least 24 hours. Evaluation and treatment of strokes will be 
according to the local standard of care. It is strongly recommended (but not required) that an
imaging procedure such as a CT scan or MRI be performed to evaluate events of suspected 
stroke or TIA. 
Adjudicated strokes will be categorized by the CEC as definite ischemic, definite hemorrhagic, 
hemorrhagic transformation or type uncertain. Additional classification of stroke subtypes will 
be specified in the CEC charter.
4.1.2
Unrecognized Brain Infarction
MRI of the brain will be obtained in all subjects no later than within 24 hours of randomization
and at the Day 28 visit. The baseline and Day 28 MRIs for each subject will be reviewed 
independently by the blinded neuroradiologists of the Imaging Adjudication Committee (IAC) to 
determine if any new areas of infarction have developed since the baseline MRI. These 
independent assessments will undergo adjudication according to the processes described in the 
Imaging Charter with a single, adjudicated determination recorded for each subject.
4.2
Secondary Efficacy Endpoints
Secondary endpoints include:

The incidence of Major Adverse Cardiovascular Events (MACE) by Day 90, defined as a 
composite of adjudicated recurrent stroke, myocardial infarction, or cardiovascular-related 
death (CV death)

The incidence of a composite of adjudicated recurrent ischemic stroke, myocardial infarction, 
or CV death by Day 90 

The incidence of adjudicated symptomatic recurrent stroke (including fatal and non-fatal) by 
Day 28

The incidence of the composite of unrecognized brain infarction assessed by MRI at Day 28
and MACE by Day 90
Myocardial Infarction and cardiovascular death will be adjudicated by the Clinical Events 
Adjudication Committee (CEC).  As the composite secondary endpoints are each defined in the 
list above, if a subject experiences any of these events, the subject will be counted as having 
experienced a composite event in the analysis.
4.3
Exploratory Endpoints
 
 
  
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
 
4.4
Primary Safety Endpoint
The primary safety endpoint is incidence of a composite of adjudicated major bleeding and 
adjudicated Clinically Relevant Non-Major (CRNM) bleeding during the treatment period.  If a 
subject experiences any of these events, the subject will be counted as having experienced a 
composite event.
4.5
Additional Safety Endpoints
Additional safety endpoints include the incidence of adjudicated major bleeding events, all 
bleeding events, intracranial hemorrhage events, as well as the incidence of AEs and markedly 
abnormal standard clinical laboratory test results.  As well, vital signs, ECG results, physical 
exam findings, and certain renal parameters and biomarkers, including estimated glomular 
filtration rate (eGFR), Cystatin-C, NGAL, and KIM-1 may be considered as additional safety 
endpoints.
5
SAMPLE SIZE AND POWER
The primary efficacy endpoint of the study is the incidence of a composite of symptomatic
ischemic stroke by Day 28 and unrecognized brain infarction at Day 28. Sample size calculations
were performed for detecting a dose-response effect with the MCP-MOD methodology using
simulations with the DoseFinding package in R4. Simulations of 1000 clinical trials were 
performed, assuming a true incidence for placebo of 14%, a maximum relative risk reduction of
30% for BMS-986141 8 mg relative to placebo, and relative reductions of 75% and 90% of the
maximum for the 0.8 and 4.8 mg doses, respectively. Candidate models included an Emax model
and a logistic model.
Initially, randomization will be limited to the two lower doses of BMS-986141 (0.8 mg or 4.8 
mg) or placebo in a 1:1:1 ratio until after the DMC review of safety and laboratory data from the
Day 28 study visit for at least 10% of planned total subjects (approximately 132 subjects). If the
DMC recommends proceeding to inclusion of the highest dose (8 mg), subsequent randomization
will be in a 1:1:1:1 ratio. Based on the staggered randomization as shown in in the table below
and the assumptions above, the study will have at least 80% power to demonstrate a dose-
response relationship, using a 1-sided type I error rate of 15%. A total sample size of 1312 
randomized subjects accounts for about 5% of subjects without post-randomization data.
Table 5-1:
Randomization Targets
Placebo
0.8 mg
4.8 mg
8 mg
Prior to interim safety review by the DMC: 132 
subjects
(1:1:1 randomization ratio)
44
44
44
0
Additional subjects randomized while interim safety 
reports are being generated and reviewed by the DMC 
(not included in the DMC safety interim analysis): 100 
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Table 5-1:
Randomization Targets
Placebo
0.8 mg
4.8 mg
8 mg
subjects
(1:1:1 randomization ratio)
After interim safety review by DMC: 1081 subjects
270
270
270
270
Total: 1312 subjects
348
347
347
270
Note: Numbers shown for each treatment group are estimates based on randomization ratio.  Actual numbers could 
be slightly different based on randomization block size and rate of enrollment.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
As outlined in section 2.1, the study will be conducted in two parts.
In Part 1 of the study, the treatment period will be 28 days. Part 2 of the study will only be
initiated after regulatory review of reports from 90-day nonclinical toxicology studies that are
currently ongoing. The treatment period in Part 2 will be 90 days. Subjects that are entered into 
Part 1 of the study will not be allowed to enter into Part 2.
Periods for each part of the study include pre-treatment, on-treatment, and post-treatment.  
Schematics for each study part are provided in Section 2.1.
6.2
Treatment Regimens
Study treatments will be assigned according to the details provided in section 2.2 of this SAP.
6.3
Populations for Analyses
The analyses will use several populations as defined below.
1) All Enrolled Subjects: Includes all subjects who signed informed consent.
2) All Randomized Subjects / Intent to Treat (ITT) Population: Includes all subjects who were 
randomized to a treatment, regardless of whether they received study drug or not.  This 
population will be analyzed according to the treatment assigned at randomization.
3) All Evaluable Subjects: Includes All Randomized Subjects as above, excluding those 
subjects’ visits where relevant protocol deviations occurred, as defined in Section 7.2.2.
4) All Treated Subjects: Includes all subjects who received at least one dose of study 
medication.  This will be the primary population used in safety analyses and will be analyzed 
according to the treatment assigned at randomization, except in the following cases:

If a subject received the same incorrect treatment throughout the study (until either Day 
28 or Day 90, or until discontinuation of the study drug), then the subject will be 
analyzed based on the treatment received.
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
If a subject received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
subject will be analyzed based on the first treatment received.
5) Pharmacodynamics (PD) Population: A subset of the ITT Population that includes subjects 
with at least one pharmacodynamic endpoint assessed following the first dose of BMS-
986141.
6) Pharmacokinetic (PK) Population: Includes all subjects treated with BMS-986141 who also 
have at least one post-dose PK sample.  The Evaluable PK Population is further defined as a 
subset of the PK Population including subjects who have adequate PK profiles on Day 1.
7
STATISTICAL ANALYSES
SAS® version 9 or higher will be used for statistical analyses, tabulations and graphical 
presentations. The DoseFinding package for R (version 3.1.3 or higher) will also be used in the 
conduct of the multiple comparisons modelling analyses.
7.1
General Methods
Descriptive summaries will be presented for continuous variables using number of subjects (N), 
mean, standard deviation (SD), median, minimum and maximum. Geometric mean and 
coefficient of variation (%CV) will also be presented for sample plasma concentration-time data 
and PK parameters. Descriptive summaries for categorical variables will utilize counts and 
percentages. 
Adverse events will be coded according to the most recent Medical Dictionary for Regulatory 
Activities (MedDRA) version.  Adverse events will be summarized according to the MedDRA 
coded Preferred Terms (PT) by System Organ Class (SOC). Previous and concomitant 
medications will be coded using the WHO Drug Dictionary version. 
Unless otherwise specified, baseline is defined as the last non-missing result with a collection 
date-time prior to the date-time of the first active dose of study medication.
7.1.1
General Methods for Study Periods
Given the different planned study treatment durations between Part 1 (treatment duration of 28 
days) and Part 2 (treatment duration 90 days) and time at which randomization will be extended 
to include the high dose of BMS-986141 (8 mg) following review of safety data by the DMC, 
select summaries will be tabulated by the following three applicable study time periods with 
respect to study part and study phase:

Part 1, Phase A  (1A)

Part 2, Phase A  (2A)

Part 2, Phase B  (2B)
Summaries will also be tabulated for Part 2 overall, to include data from all subjects with a 
planned treatment duration of 90 days.  The following summaries will be tabulated as indicated 
above.
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
Demographics

Baseline characteristics

Relevant protocol deviations

Disposition

Concomitant medications, including CYP3A4 inhibitor use

Study drug exposure and compliance

Bleeding events

Adverse events, including overall AEs, SAEs, AEs leading to discontinuation, related AEs, 
and deaths

Abnormal laboratory results, including renal biomarkers

Abnormal ECG results

Out of range vital signs
7.1.2
General Methods for Efficacy Analyses
Generalized Multiple Comparison Modelling (gMCP-Mod)
To demonstrate the dose-response relationship between BMS-986141 treatment (including
placebo) and the primary endpoint, the primary analysis will be based on a generalized Multiple 
Comparisons and Modeling (gMCP-Mod) analysis56. This analysis tests for a dose-response 
relationship, allowing for uncertainty in the dose-response relationship through inclusion of 
contrasts from multiple pre-specified candidate models to assess dose-response. If a dose-
response relationship exists, then fitted estimates for the incidence of the primary endpoint will 
be calculated in each of the treatment groups using the selected dose-response models.
The gMCP-Mod procedure extends the MCP-Mod methodology to non-continuous endpoints.  
This is accomplished by decoupling the dose-response model from the expected response 
through the use of an ANOVA style parameterization of the dose-response parameter.  For the 
binary endpoint used in this study, a logistic regression of the event proportion at each dose level 
will be used, following adjustment for study time period (1A, 2A, 2B) via the inclusion of an 
additive covariate.  After this first step, the mean parameter estimates from the logistic model 
and the corresponding covariance matrix, both of which are on the logit scale, will then be used 
during the rest of the gMCP-Mod procedure.  Point estimates from the selected models will be 
displayed on the proportion scale in all statistical outputs.
Candidate Models and Multiple Testing Procedure
There are two candidate models that will be considered for the primary analysis.  These are an 
Emax model and a logistic model, where dose-response will be tested using dose levels of 0 
(placebo), 1, 2, and 2.3 (corresponding to 0.8 mg, 4.8 mg, and 8 mg)7.
The MCP-Mod procedure requires certain parameter estimates be pre-specified for the candidate 
models based on available information in order to derive optimum contrast coefficients for 
testing the null hypothesis: that a dose-response does not exist in any of the candidate models.  It 
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is through testing this hypothesis that the model which best describes the dose-response 
relationship will be identified8.  The parameters used to determine the contrast for testing will 
assume a placebo event rate of 14% and maximum risk reduction of 4.2%.  For the Emax model, 
the required parameter estimates used will be 1.0 for the dose corresponding to half of the 
maximum effect and 1.0 for a “Hill” parameter that determines the steepness of the model at the 
dose of half effect. For the logistic model, these parameter estimates used will be 1.0 for the dose 
corresponding to half effect and 0.1 for the parameter that determines the steepness of the curve.  
These pre-specified parameter estimates will remain fixed through the contrast testing portion of 
the gMCP-Mod procedure in order to preserve the type I error.
The gMCP-Mod procedure for non-continuous endpoints diverges from the original MCP-Mod 
procedure in the calculation of the optimum contrast coefficients.  The gMCP-Mod methods that 
will be used to calculate the optimum contrast coefficients require the pre-specified model 
parameters from above along with the covariance matrix from the logistic regression in the first 
step.  In practice, since the covariance matrix in the first step is based on actual data, the 
optimum contrast coefficients are recalculated when the actual data become available.  The 
parameter estimates for the candidate models, however, will remain fixed.
These optimal contrast coefficients follow the form given below, and will be recalculated as 
described using the DoseFinding package in R once the actual data are available.
ܿ௠
௢௣௧∝ܵିଵቆߤ௠−ߤ௠′ܵିଵ1
1ᇱܵିଵ1 ቇ
Where µm is the event rate on the logit scale based on the corresponding candidate model m 
(m=1, 2) at the specified dose levels, and S corresponds to the covariance matrix from the 
logistic regression on the actual data in the first step.
In order to demonstrate a dose-response relationship, the following global hypothesis will be 
tested:
H0: ܿ௠
௢௣௧µ ≥0 for all m {1, 2}
H1: ܿ௠
௢௣௧µ < 0 for at least one m {1, 2}
where µ is the true event rate on the logit scale at the specified dose levels.
For each candidate model (m=1, 2), the contrast test statistic (zm) is calculated as standardized 
linear combinations of the estimated event rate on the logit scale from the logistic regression
using the optimal contrast coefficients associated with that candidate model. 
A multiplicity-adjusted critical value will be determined from the joint multivariate normal 
distribution of the contrast test statistics at the overall one-sided alpha level of 0.15.  If either test 
statistic that exceeds this critical value, a dose-response relationship will be demonstrated.
Modelling and Estimation
The model for estimation will be selected from among the two candidate models with a contrast 
test statistic that is greater than or equal to the multiplicity-adjusted critical value.  If both 
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candidate models have such contrast test statistics, then both models will be employed using a 
weighted averaging technique based on their relative Bayesian Information Criteria (BIC), for 
the purposes of estimation.  If neither candidate model has a contrast test statistic that is greater 
than or equal to the multiplicity-adjusted critical value, then the analysis will end, indicating that 
a dose-response relationship cannot be established.
In this manner, the point estimates for the means will be generated from the selected model as 
described in the efficacy analyses in Section 7.5.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site, and per month for all 
randomized subjects. Enrollment date, randomization date, first dosing date, country, 
investigational site will be presented in a by subject listing of accrual.
7.2.2
Relevant Protocol Deviations
Relevant deviations from the study protocol will be documented and accounted for in presenting 
the data summaries, listings and descriptive statistical analyses. Any changes from planned 
protocol-specified analyses will be defined in the SAP and reported in the CSR.  The relevant 
protocol deviations are described in the table below.
Table 7.2.2-1:
List of Relevant Protocol Deviations
Number
RPD Criteria
1
Subject randomized but not dosed
2
Error in treatment assignment (resulting in a subject receiving a treatment other than that 
assigned by the IVRS) during the first 28-day interval
3
Poor treatment compliance for either BMS-986141 or ASA (compliance less than 80% or more 
than 120%) during first 28-day interval
4
Randomized subjects with history of atrial fibrillation (AF) other than transient AF related to 
cardiac surgery at enrollment (per Exclusion Criteria 1a from the protocol)
5
Randomized subjects with unrecognized or misdiagnosed intracranial hemorrhage (ICH) as 
determined by the central reader based on  the baseline study specific MRI (presence of type 1 or 
2 parenchymal hematoma)
6
Randomized subjects who took no dose of ASA or dose of ASA not within limits designated by 
the protocol for ≥ 5 consecutive days in the first 28 days of the treatment period
7
Randomized subjects who took oral anticoagulants or prohibited antiplatelet therapy, other than 
study medication, for > 2 consecutive days during the first 28days of the treatment period
8
Randomized subjects that were treated with a strong CYP3A4 inhibitor for > 5 days during the 
first 28 days of the treatment perioda
a: CYP3A4 inhibitors will be defined in a separate file maintained by the study team and will be classified as weak, 
moderate, or strong.
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7.3
Study Population
All study population summaries will be presented by treatment and overall, as well as by study 
time period (1A, 2A, 2B) and for study part 2.
7.3.1
Subject Disposition
Subject disposition will be listed for all enrolled subjects.  For subjects who are randomized, the 
subject’s study part, gender, age, race, consent date, randomization date, first and last dosing 
date, reason for treatment discontinuation, off-study date, and reason for going off-study will be 
listed.  For subjects who enroll, but are not treated, the subject’s gender, age, race, consent date, 
and reason for not entering the treatment period will be listed.
Summary tables reflecting the number of subjects enrolled, randomized, and treated, reasons for 
not entering the treatment period, and number completing the study will be presented by 
treatment and study time period (1A, 2A, 2B), and for study part 2.
The number of subjects who do not complete treatment and also the number who do not 
complete the study, both overall and according to reasons for discontinuation, will also be 
summarized by treatment and study time period (1A, 2A, 2B), and for study part 2..
7.3.2
Demographic and Baseline Characteristics
The following baseline characteristics will be summarized by treatment group for all randomized 
subjects, overall, as well as by study time period (1A, 2A, 2B), and for study part 2. All baseline 
presentations will identify subjects with missing measurements. 

Age (descriptive statistics)

Age category I, in years (< 65, 65)

Age category II, in years (< 65, 65- < 75, 75)

Gender (male, female)

Race (White, Black or African American, Asian, American Indian  or Alaska Native, Native 
Hawaiian or Other pacific islander, Other)

Ethnicity (Hispanic/Latino, Non Hispanic/Latino) for US subjects

Geographical Region (North America, Europe, Asia / Pacific)

Height, Weight, and BMI

Acute Ischemic Stroke at Entry  (Yes/No)

National Institutes of Health Stroke Score (NIHSS) at Baseline

High-risk Transient Ischemic Attack at Entry  (Yes/No)

Lacunar Infarct

Diabetes mellitus (Yes/No)

Cigarette use (Yes/No)

Hypercholesterolemia (Yes/No)

Hypertension (Yes/No)

BMI Category (<18, 18-25, 25-30, 30-35, >35)
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
Vital signs

Time since onset of symptoms detected to randomization
7.3.3
Medical History
General medical history will be summarized by treatment and study time period (1A, 2A, 2B), 
and for study part 2.
7.4
Extent of Exposure
7.4.1
Administration of Study Therapy
The number of days on study medication received will be calculated as (date of first dose - date 
of last dose) + 1.  The days on study medication will be summarized for all treated subjects by 
treatment and study time period (1A, 2A, 2B), and for study part 2 using descriptive statistics as 
well as categorically as given in the table below.
Table 7.4.1-1:
Extent of Exposure Categories for Summarization
Part 1 Exposure Categories
Part 2 Exposure Categories
1 - 7 days
1 - 14 days
8 - 14 days
15 - 28 days
15 - 21 days
28 - 42 days
22 - 28 days
43 - 56 days
> 28 days
57 - 70 days
71 - 84 days
> 85 days 
A by-subject listing of dosing of study medication and a listing of batch numbers will be also 
provided.
7.4.2
Study Therapy Compliance
Compliance with the protocol-specified study therapy will be summarized by treatment group for 
all treated subjects by treatment and study time period (1A, 2A, 2B), and for study part 2.  
For randomized study therapy, the case report forms collect the number of doses taken per day.  
The kits dispensed for study treatment are expected to contain 4 pills per day during Phase A of 
the study while the high dose arm is closed.  During Phase B, once the high-dose arm has 
opened, the number of pills dispensed to patients who are randomized from that point forward 
will be 2.  Thus, compliance with randomized therapy dosing will be calculated as given below
for each container of study therapy:
% ܥ݋݉݌݈݅ܽ݊ܿ݁ோ௔௡ௗ௢௠௜௭௘ௗ்௛௘௥௔௣௬= 100 ݔܰݑܾ݉݁ݎ݋݂ܾ݈ܶܽ݁ݐݏܶܽ݇݁݊݌݁ݎܦܽݕ
(Phase A: 4 or Phase B: 2)
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Overall compliance will be calculated as the weighted average of the compliance for each 
container, weighted in proportion to the # of days each container was used.
Acetylsalicylic acid (ASA) is an adjuvant therapy that the protocol requires all subjects receive at 
a total daily dose that is between 75mg and 162mg.  Overall compliance with ASA dosing will 
be calculated as given below:
% ܥ݋݉݌݈݅ܽ݊ܿ݁஺ௌ஺= 100 ݔܰݑܾ݉݁ݎ݋݂ܦܽݕݏݓℎ݁ݎ݁݌ݎ݋ݐ݋ܿ݋݈ݏ݌݂݁ܿ݅݅݁݀ܶܦܦݓܽݏݐܽ݇݁݊
(ܮܽݏݐܦܽݐ݁ܦ݋ݏ݁݀−ܨ݅ݎݏݐܦܽݐ݁ܦ݋ݏ݁݀) + 1
In addition, compliance will also be summarized from the first dose date to the lesser of the last 
date dosed and 28 days after the first date dosed.  The above calculations will be repeated using 
only data within this time period.
Summaries of compliance will be presented according to the general methods for continuous 
variables as well as categorically, according to the number and percentage of subjects with 
compliance in each of the following categories:

< 80%

and  


7.4.3
Modifications of Study Therapy
The dosage of double blind study medication may not be increased or decreased during the
treatment period. Double blind study medication may be interrupted if treatment with prohibited
or restricted concomitant therapies is needed as specified in section 3.4.1 of the protocol.
7.4.4
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken 
at any time on-treatment (ie, on or after the first day of study therapy and prior to the last dose of 
study therapy), will be coded using the WHO Drug Dictionary.
Concomitant medications will be summarized (subjects with any concomitant medication, 
subjects by medication class and generic term) for all treated subjects.  Additionally, a separate, 
but similar summary of all concomitant medications that are moderate CYP3A4 inhibitors will 
be created.
7.5
Efficacy
Adjudicated events will be the basis for the primary and secondary analyses, including imaging 
assessments from the Imaging Adjudication Committee (IAC) and clinical assessments from the 
CEC.  All efficacy analyses will be conducted on the Intent-To-Treat (ITT) population.
7.5.1
Primary Efficacy Analysis
Using the general methods for efficacy analyses described in 17, the observed incidence of the 
composite of symptomatic ischemic stroke by Day 28 and unrecognized brain infarction assessed 
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by MRI at Day 28 will be summarized by treatment using the fitted model from the gMCP-Mod 
procedure. It should be noted that the selected model from gMCP-Mod will actually be a model 
for the logit of the incidence rate.  As a result, the point estimate will be converted and presented 
on the probability scale by treatment.  
In addition, the raw proportion of incidence within each treatment group and its associated 95% 
Clopper-Pearson CI will be presented. The relative risk reduction between each BMS-986141 
arm and placebo and the associated 95% CI will be presented as well.  The form of the relative 
risk reduction between each treatment group and placebo is given below.
ܫ݊ܿ݅݀݁݊ܿ݁௉஻ை−ܫ்݊ܿ݅݀݁݊ܿ݁ோ்
ܫ݊ܿ݅݀݁݊ܿ݁௉஻ை
= 1 −ܫ்݊ܿ݅݀݁݊ܿ݁ோ்
ܫ݊ܿ݅݀݁݊ܿ݁௉஻ை
7.5.1.1
Sensitivity Analyses
To assess the robustness of the primary efficacy analysis, additional sensitivity analyses will be 
carried out using the following approaches:

Following the same procedure as the primary analysis, considering the All Evaluable 
Subjects population in place of the All Randomized Subjects population. 

A worst-case analysis that will repeat the primary analysis on the ITT population where any 
missing information that is consequential to the evaluation of the primary endpoint will be 
considered as an event.
7.5.1.2
Subgroup Analyses
All analyses described in this section will be performed on the ITT Population. Table 7.5.1.2-1
below shows the subgroups of interest for analyses of efficacy data.  If the value of the grouping 
variable cannot be determined for a subject, the subject will be excluded from the corresponding 
subgroup analysis.
Table 7.5.1.2-1:
Subgroups of Interest for Efficacy Assessments
Grouping Variable
Subgroups
Event at entry
Acute ischemic stroke
Transient ischemic attack
Time since onset of symptoms detected to 
randomization
< 24 hours
24 - 48 hours
Lacunar infarct at entry
Yes
No
Oxfordshire Community Stroke Project (OCSP) 
Subtype (only for stroke) at entry
Total Anterior Circulation Stroke (TAC)
Lacunar Stroke (LAC)
Partial Anterior Circulation Stroke (PAC)
Posterior Circulation Stroke (POC)
ABCD2a Score (only for TIA) at entry
4-5 (moderate)
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Table 7.5.1.2-1:
Subgroups of Interest for Efficacy Assessments
Grouping Variable
Subgroups
6-7 (high)
Age
< 65 years old
≥ 65 to < 75 years old
≥ 75 years old
Gender
Male
Female
Race
White
Black or African American
Asian
Other
Geographic Region
North America
Europe
Asia / Pacific
a age, blood pressure, clinical features, duration, diabetes
7.5.2
Secondary Efficacy Analyses
The same approach used in the primary analysis will be repeated on the secondary endpoints.

The incidence of major adverse cardiovascular events (MACE) by Day 90, defined as a 
composite of adjudicated recurrent stroke, myocardial infarction, or CV death

The incidence of a composite of adjudicated recurrent ischemic stroke, myocardial infarction, 
or CV death by Day 90

The incidence of adjudicated symptomatic recurrent stroke (including fatal and non-fatal) by 
Day 28

The incidence of the composite of unrecognized brain infarction assessed by MRI at Day 28 
and MACE by Day 90
In addition, a sequential testing procedure will be used for the primary and MACE endpoints as 
described below. 
1) If a dose-response relationship is established for the primary endpoint at the one-sided 0.15 
level, then the primary analysis will be repeated at a one-sided alpha level of 0.025.
2) If this analysis at the one-sided 0.025 level also demonstrates a dose-response relationship, 
then the dose-response relationship for the MACE endpoint will be tested using a one-sided
alpha level of 0.025.
Each of these sequential testing analyses will be performed.  Their interpretation will be guided 
by the sequential testing procedure.
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7.5.3
Other Efficacy Analyses
The primary analysis will be repeated for the composite endpoint of recurrent ischemic stroke or 
any adjudicated arterial thrombotic events up to 90 days.  As well, the primary analysis will be 
repeated using each of its components, individually, as the response variable.
Additionally, the following exploratory analyses may be explored:

 
 
 
 
 
 
7.6
Safety Analyses
Analysis of all safety data will be conducted on all treated subjects and will follow the BMS 
guideline of analysis of safety data9.  Safety will be summarized for each parameter by treatment 
group, as well as for all subjects receiving BMS-986141.  Summaries of the frequency of 
subjects experiencing certain events, such as adverse events, elevated labs or vital signs, or 
elevated ECGs, will be summarized by treatment and study time period (1A, 2A, 2B), and for 
study part 2.
The evaluation of safety is based on adjudicated bleeding events, clinical adverse events (AEs), 
vital signs, ECG results, and clinical laboratory results.
All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), 
using the most current available version of Medical Dictionary for Regulatory Activities 
(MedDRA). Summaries of AEs will use the version of MedDRA that is current at the time of 
database lock. All recorded adverse events will be listed and tabulated by SOC, PT, treatment 
and overall. Values for ECGs, vital signs, and clinical laboratory test results will be summarized 
by treatment. Abnormal results for ECG, vital signs and clinical laboratory tests that fall outside 
the pre-specified criteria will also be listed and summarized. In addition, ECG readings will be 
evaluated by the Investigator and abnormalities, if present, will be listed.
7.6.1
Major Bleeding and Clinically Relevant Non-Major Bleeding
The proportion of subjects with adjudicated bleeding events which occur on or after the first dose 
of study treatment and within 4 days after the last dose of study treatment will be summarized by 
treatment. Point estimates and 95% exact CIs for event rates of each of the below bleeding
endpoints will be presented by treatment, together with point estimates and 95% exact CIs for the 
difference of event rates between each BMS-986141 arm and placebo.  The following bleeding 
endpoints will be analyzed using these methods.
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
The proportion of subjects with the composite of adjudicated major bleeding and CRNM 
bleeding

The proportion of subjects with all reported bleeding

The proportion of subjects with intracranial hemorrhage
All adjudicated bleeding events will be listed.  In addition, the proportion of subjects with 
confirmed major bleeding or clinically relevant non-major bleeding events occurring during the 
treatment period will be summarized by treatment group for each of the following factors.

Stroke severity (based on National Institutes of Health Stroke Scale NIHSS) at study entry

NIHSS Score of 0 (No stroke symptoms)

NIHSS Score of 1-4 (Minor stroke)

NIHSS Score of 5-15 (Moderate stroke)

Lacunar infarct at study entry

Yes

No
7.6.2
Deaths
All reported deaths after a subject is enrolled (i.e., has signed the informed consent) will be listed 
separately by subject.  Deaths will also be summarized by treatment group according to whether 
the death was determined to be CV-related, not CV related, or unknown, following adjudication.
7.6.3
Serious Adverse Events
All reported serious adverse events (SAEs) will be listed for all enrolled subjects.  A summary of 
SAEs occurring from the day of the first dose of study drug through 30 days following the last 
dose of study drug will also be provided for all treated subjects by SOC and PT for each 
treatment group. A separate summary of SAEs related to study drug will also be provided.
7.6.4
Adverse Events
All AEs will be summarized by SOCs and PTs for each treatment group and also listed.
Adverse events which occur on or after the first dose of study treatment and within 4 days after 
the last dose of study treatment will be tabulated.  Events will be assigned to the study treatment 
administered to the subject. The proportion of subjects having an adverse event will be 
calculated as the number of subjects experiencing the event, divided by the total number of 
subjects receiving study treatment.
A high-level summary will be presented by treatment group that counts subjects experiencing 
any of the following:

At least one AE

At least one related AE
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
Deaths

At least one SAE

SAE leading to discontinuation of study drug

AE leading to discontinuation of study drug
The above summary will also be presented by treatment and study time period (1A, 2A, 2B), and 
for study part 2.
All AE listings will indicate the unique subject identifier, age, gender, current treatment, the date 
of onset, the date of resolution, day of onset relative to the start of treatment, action taken, 
investigator’s assessment of severity and relationship to study drug. Additional listings will be 
provided for adverse events leading to discontinuation, serious adverse events, adverse events 
leading to death, and adverse events without a recorded resolution. Summaries of adverse events 
will include adverse events, adverse events by intensity, adverse events leading to 
discontinuation, and adverse events by relationship.  
All adverse events will be further summarized according to demographic factors for each of the 
categories given below:

Age category I, in years (< 65, 65)

Age category II, in years (< 65, 65- < 75, 75)

Gender (male, female)

Race (White, Black or African American, Asian, American Indian  or Alaska Native, Native 
Hawaiian or Other pacific islander, Other)
Where a subject has multiple adverse events within the level of summarization in a single 
analysis period, the subject will only be counted once at that level of summarization in the 
adverse event frequency tables.
When a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:

Relationship to study medication

Intensity of event
When reporting adverse events by intensity, summary tables will be provided based on the most 
intense event during the analysis period - independent of relationship to study medication.  
Similarly, where a subject has multiple adverse events within the level of summarization in a 
single analysis period, the subject will only be counted once at that level of summarization in the 
adverse event frequency tables
7.6.5
Clinical Laboratory Evaluations
Summaries of laboratory test results and the corresponding change from baseline by treatment 
and nominal visit will be provided for those laboratory tests required at each study visit as given 
in Table 5.3.7-1 of the protocol.
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The criteria used for classifying laboratory test results as markedly abnormal will be listed. 
These criteria are provided in an appendix to this SAP.
Laboratory results for subjects with any marked laboratory abnormality (scheduled and 
unscheduled) will be listed. This listing will include all observations for the specific laboratory 
test and subject, not only the marked laboratory abnormalities. The frequency of subjects with 
any marked laboratory abnormality will be presented by treatment and study time period (1A, 
2A, 2B), and for study part 2. 
In addition to the analysis of standard laboratory results, separate analyses will focus specifically 
on renal parameters.  Renal biomarkers, including Cystatin-C, NGAL, and KIM-1 will be 
summarized according to the number and percentage of subjects in each treatment group with 
levels exceeding the upper limit of normal (ULN) at each study visit where labs are collected per 
protocol.  Additionally, estimated Glomerular Filtration Rate (eGFR) using the Modification of 
Diet in Renal Disease formula (MDRD) will be summarized at each visit by the mean, standard 
deviation, range, and median.
Urinalysis results will also be summarized in the same manner as the laboratory test results.
7.6.6
Electrocardiograms
Summaries of ECG results and the corresponding change from baseline by treatment will be 
provided for the screening, Day 28, and end of treatment visits.  The normality/abnormality of 
the ECG tracing, as determined by the investigator, will be summarized using frequency tables 
on the number of subjects who have a normal/abnormal ECG tracing at Day 28 and at Day 90 
(Part 2 only).  A listing of subjects with Investigator identified ECG abnormalities will also be 
provided.
7.6.7
Vital Signs
Vital sign measurements (systolic BP, diastolic BP, heart rate, respiratory rate and body 
temperature) and their respective changes from baseline will be summarized by nominal visit and 
treatment group.
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The following criteria will be used to determine vital sign results that are out a range, where 
changes from baseline are based on matched postural positions:
Table 7.6.7-1:
Out of Range Vital Signs Criteria
Vital Sign Measurement
Criteria
Heart Rate(bpm)
Value > 100 and change from baseline > 30, or
Value < 55 and change from baseline < -15
Systolic BP(mmHg)
Value > 140 and change from baseline > 20, or
Value < 90 and change from baseline < -20
Diastolic BP(mmHg) 
Value > 90 and change from baseline > 10, or
Value < 55 and change from baseline < -10
Subjects with vital signs out of range will also be listed.
7.6.8
Physical Examination Findings
All physical examination abnormal findings will be listed per subject and visit.
7.7
Pharmacokinetic Analyses
Analyses of pharmacokinetics will be conducted on the Pharmacokinetic Population.  
Pharmacokinetics of BMS-986141 and BMT-162856 will be summarized with descriptive 
statistics for Cmax, AUC(0-24), C(24) after first dose, and C(24) on Day 28.
As well, a
population pharmacokinetic model will be developed to understand the 
pharmacokinetics of BMS-986141. The potential effect of covariates such as body weight, age, 
gender, race, renal function, liver function, and co-administration of other medicines on the 
pharmacokinetics of BMS-986141 will be explored in this analysis.  Details of this analysis and 
its results will be reported in a separate document.
7.8
Biomarker Analyses
 
 
 
 
 
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8
CONVENTIONS
Standard time windowing, imputation rules, and counting rules will be applied according to the 
GBS Requirements for Statistical Outputs10.  Unless otherwise defined, baseline is defined as the 
last non-missing value prior to the first dose of study drug.
8.1
Decimal Places
The number of decimal places displayed in all listings will be determined by the number of 
decimal places in the raw data. 
Unless otherwise specified, minimum and maximum will be reported to the precision as the data 
collected, one more decimal place for the mean and median, and two more decimal places for the 
standard deviation.  The adjusted geometric mean, geometric mean ratio and the lower and upper 
limits of confidence interval will be displayed to three decimal places.
8.2
Pharmacokinetic Summaries
Handling of Non-Quantifiable Concentrations 
For the summaries of plasma concentration-time data, concentrations that are less than the lower 
limit of quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as 
missing in summary tables and plots.  
Summary statistics for PD-concentrations will be calculated by imputing values less than LLOQ 
as ½ * LLOQ.  
8.3
Day Ranges for Analysis of Time Points
Subjects do not always adhere strictly to the visit schedule timing in the protocol. Therefore, the 
designation of visits for analysis of safety outcome measures during the treatment period will be 
based on the day of the start of study medication (Day 1). The day ranges for the analyses of 
laboratory, electrocardiogram (ECG) and vital sign measurements are defined in the following 
tables.
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Table 8.3-1:
Analysis Windows for Laboratory Parameters & Vital Signs (Part 1)
Visit Name
Lower Limit
(Study Day)
Upper Limit
(Study Day)
Day 1
1
1*
Day of Hospital Discharge
2
10
Day 28
11
N/A
* Pre-dose
Table 8.3-2:
Analysis Windows for Laboratory Parameters & Vital Signs (Part 2)
Visit Name
Lower Limit
(Study Day)
Upper Limit
(Study Day)
Day 1
1
1*
Day of Hospital Discharge
2
10
Day 28
11
42
Day 56
43
68
Day 90
69
N/A
* Pre-dose
Table 8.3-3:
Analysis Windows for ECG Results
Visit Name
Lower Limit
(Study Day)
Upper Limit
(Study Day)
Day 28
2
64a
Day 90a
65
N/A
a: Day 90 visit will only be conducted for subjects in Part 2 of the study.  Subjects in Part 1 of the study will only 
have a Day 28 ECG scheduled after beginning treatment, with no applicable upper limit to the analysis window.
8.4
Multiple Measurements
Laboratory Measurements
For tabulations of changes from baseline or shift analyses, if multiple laboratory measurements 
are obtained within the same visit window, then the measurement obtained on the day closest to 
the target day for that visit window will be used; in the case of a tie, the measurement obtained 
on the earlier day will be used in the analyses.
For tabulations of incidence of marked abnormalities (e.g. ALT > 3xULN), if multiple laboratory 
measurements are obtained within the same visit window, then the worst measurement within the
visit window will be used.
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Vital Signs and ECGs
If multiple vital sign or ECG measurements are obtained within the same visit window, then the 
measurement obtained on the day closest to the target day for that visit window will be used; in 
the case of a tie, the measurement obtained on the earlier day will be used in the analyses.
9
CONTENT OF REPORTS
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Pharmacokinetic and exploratory biomarker results may be reported 
separately.
Details of the tables, listings, and figures to be prepared for the final CSR will be included in a 
study-specific Data Presentation Plan (DPP).
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APPENDIX 1
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS - CONVENTIONAL (US) UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
HEMATOLOGY
Hemoglobin
g/dL
> 2 g/dl decrease compared to pre-
dose or value ≤ 8 g/dl
Hematocrit
%
< 0.75 x pre-dose
Erythrocytes
x106
cells/µL
< 0.75 x pre-dose
Platelet Count
x109
cells/µL
< 100,000/mm3 (or < 100x 109
cells/L)
Leukocytes
x103
cells/µL
< 0.75 x LLN, or
if pre-dose < LLN then use < 0.8 x 
pre-dose
if pre-dose > ULN then use < LLN
> 1.25 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.2 x 
pre-dose
Neutrophils (absolute)
x103
cells/µL
< 1.0 x 103 cells/µL
Neutrophils + Bands 
(absolute)
x103
cells/µL
< 1.0 x 103 cells/µL
Eosinophils (absolute)
x103
cells/µL
> 0.750 x 103 cells/µL
Basophils (absolute)
x103
cells/µL
> 400/mm3 (or > 0.4 x 103
cells/µL)
Monocytes (absolute)
x103
cells/µL
> 2000/mm3 (or > 2 x 103
cells/µL)
Lymphocytes (absolute)
x103
cells/µL
< 0.750 x 103 cells/µL
> 7.50 x 103 cells/µL
LIVER/KIDNEY
Alkaline Phosphatase
U/L
> 2 x ULN
Aspartate 
Aminotransferase
U/L
> 3 x ULN
Alanine 
Aminotransferase
U/L
> 3 x ULN
Bilirubin, Total
mg/dL
> 2 x ULN
Bilirubin, Direct
mg/dL
> 1.5 x ULN
Blood Urea Nitrogen
mg/dL
> 2 x ULN
Creatinine
mg/dL
> 1.5 x ULN
ELECTROLYTES
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APPENDIX 1
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS - CONVENTIONAL (US) UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
Sodium, Serum
mEq/L
< 0.95 x LLN, or
if pre-dose < LLN then use < 0.95 
x pre-dose
if pre-dose > ULN then use < LLN
> 1.05 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.05 
x pre-dose
Potassium, Serum
mEq/L
< 0.9 x LLN, or
if pre-dose < LLN then use < 0.9 x 
pre-dose
if pre-dose > ULN then use < LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.1 x 
pre-dose
Chloride, Serum
mEq/L
< 0.9 x LLN, or
if pre-dose < LLN then use < 0.9 x 
pre-dose
if pre-dose > ULN then use < LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.1 x 
pre-dose
Calcium, Total
mg/dL
< 0.8 x LLN, or
if pre-dose < LLN then use < 0.75 
x pre-dose
if pre-dose > ULN then use < LLN
> 1.2 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.25 
x pre-dose
Bicarbonate
mEq/L
< 0.75 x LLN, or
if pre-dose < LLN then use < 0.75 
x pre-dose
if pre-dose > ULN then use < LLN
> 1.25 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.25 
x pre-dose
Phosphorus
mg/dL
If pre-dose = missing then use < 
0.85 x LLN
If LLN ≤ pre-dose ≤ ULN then use 
< 0.85 x LLN
If pre-dose < LLN then use < 0.85 
x pre-dose
If pre-dose > ULN then use < LLN
If pre-dose = missing then use > 
1.25 x ULN
If LLN ≤ pre-dose ≤ ULN then use 
> 1.25 x ULN
If pre-dose > ULN then use > 1.25 
x ULN
If pre-dose < LLN then use > ULN
OTHER CHEMISTRY
Lactate Dehydrogenase 
(LDH)
U/L
If pre-dose = missing then use > 
1.25 x ULN
If pre-dose ≤ ULN then use > 1.25 
x ULN
If pre-dose > ULN then use > 1. 5 
x pre-dose
Total Protein
g/dL
< 0.9 x LLN, or
if pre-dose < LLN then use 0.9 x 
pre-dose
if pre-dose > ULN then use < LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use 1.1 x 
pre-dose
Albumin
g/dL
If pre-dose = missing then use < 
0.9 x LLN
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APPENDIX 1
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS - CONVENTIONAL (US) UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
if pre-dose ≥ LLN then use < 0.9 x 
LLN
If pre-dose < LLN then use < 0.9 x 
pre-dose
Glucose, Serum Fasting
mg/dL
< 0.8 x LLN, or
if pre-dose < LLN then use < 0.8 x 
pre-dose
if pre-dose > ULN then use < LLN
> 1.5 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 2.0 x 
pre-dose
Uric Acid
mg/dL
> 1.5 x ULN, or
if pre-dose > ULN then use > 2 x 
pre-dose
URINALYSIS
Glucose Urine
N/A
if missing pre-dose then use2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Protein, Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Blood, Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Leukocyte Esterase, 
Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
RBC, Urine
hpf
If missing pre-dose then use 2, or
if value 4, or
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APPENDIX 1
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS - CONVENTIONAL (US) UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
WBC, Urine
hpf
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
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APPENDIX 2
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS -- SI UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
HEMATOLOGY
Hemoglobin
g/L
> 20 g/l decrease compared to 
pre-dose or value ≤g/l
Hematocrit
Vol
< 0.75 pre-dose
Erythrocytes
x1012 c/L
< 0.75 pre-dose
Platelet Count
x109 cells/L
< 100 x109 cells/L
Leukocytes
x109 cells/L
< 0.75 x LLN, or
if pre-dose < LLN then use < 
0.8 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.25 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.2 x 
pre-dose
Neutrophils (absolute)
x109 cells/L
< 1.0 x 109 cells/L
Neutrophils + Bands 
(absolute)
x109 cells/L
< 1.0 x 109 cells/L
Eosinophils (absolute)
x109 cells/L
> 0.750 x 109 cells/L
Basophils (absolute)
x109 cells/L
> 0.4 x 109 cells/L
Monocytes (absolute)
x109 cells/L
> 2 x 109 cells/L
Lymphocytes (absolute)
x109 cells/L
< 0.750 x 103 cells/µL
> 7.50 x 109 cells/L
LIVER/KIDNEY
Alkaline Phosphatase
U/L
> 2 x ULN
Aspartate 
Aminotransferase
U/L
> 3 x ULN
Alanine 
Aminotransferase
U/L
> 3 x ULN
Bilirubin, Total
umol/L
> 2 x ULN
Bilirubin, Direct
umol/L
> 1.5 x ULN
Blood Urea Nitrogen
umol/L
> 2 x ULN
Creatinine
umol/L
> 1.5 x ULN
ELECTROLYTES
Sodium, Serum
mmol/L
< 0.95 x LLN, or
if pre-dose < LLN then use < 
0.95 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.05 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.05 
x pre-dose
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Statistical Analysis Plan
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38
APPENDIX 2
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS -- SI UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
Potassium, Serum
mmol/L
< 0.9 x LLN, or
if pre-dose < LLN then use < 
0.9 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.1 x 
pre-dose
Chloride, Serum
mmol/L
< 0.9 x LLN, or
if pre-dose < LLN then use < 
0.9 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.1 x 
pre-dose
Calcium, Total
mmol/L
< 0.8 x LLN, or
if pre-dose < LLN then use < 
0.75 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.2 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.25 
x pre-dose
Bicarbonate
mmol/L
< 0.75 x LLN, or
if pre-dose < LLN then use < 
0.75 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.25 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 1.25 
x pre-dose
Phosphorus
mmol/L
If pre-dose = missing then use 
< 0.85 x LLN
If LLN ≤ pre-dose ≤ ULN then 
use < 0.85 x LLN
If pre-dose < LLN then use < 
0.85 x pre-dose
If pre-dose > ULN then use < 
LLN
If pre-dose = missing then use > 
1.25 x ULN
If LLN ≤ pre-dose ≤ ULN then use 
> 1.25 x ULN
If pre-dose > ULN then use > 1.25 
x ULN
If pre-dose < LLN then use > ULN
OTHER CHEMISTRY
Lactate Dehydrogenase 
(LDH)
U/L
If pre-dose = missing then use > 
1.25 x ULN
If pre-dose ≤ ULN then use > 1.25
x ULN
If pre-dose > ULN then use > 1. 5 
x pre-dose
Total Protein
g/L
< 0.9 x LLN, or
if pre-dose < LLN then use 0.9 
x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.1 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use 1.1 x 
pre-dose
Albumin
g/L
If pre-dose = missing then use 
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Statistical Analysis Plan
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39
APPENDIX 2
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS -- SI UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
< 0.9 x LLN
if pre-dose ≥ LLN then use < 
0.9 x LLN
If pre-dose < LLN then use < 
0.9 x pre-dose
Glucose, Serum Fasting
mmol/L
< 0.8 x LLN, or
if pre-dose < LLN then use < 
0.8 x pre-dose
if pre-dose > ULN then use < 
LLN
> 1.5 x ULN, or
if pre-dose < LLN then use > ULN
if pre-dose > ULN then use > 2.0 x 
pre-dose
Uric Acid
mmol/L
> 1.5 x ULN, or
if pre-dose > ULN then use > 2 x 
pre-dose
URINALYSIS
Glucose Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Protein, Urine
N/A
f missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Blood, Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Leukocyte Esterase, 
Urine
N/A
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
1.0
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Statistical Analysis Plan
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BMS-986141
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40
APPENDIX 2
MARKED ABNORMALITY CRITERIA FOR LABORATORY
TEST RESULTS -- SI UNITS
Clinical Laboratory 
Variables
Units
Low MA Criterion
High MA Criterion
RBC, Urine
hpf
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
WBC, Urine
hpf
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, 
or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
1.0
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930113650
1.0
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10
REFERENCES
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6
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model 
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7
Bornkamp B, Pinheiro J, Bretz F. DoseFinding: planning and analyzing dose finding 
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8
Bornkamp B, Pinheiro J, Bretz F.  MCPMod: An R Package for the Design and Analysis of 
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9
CT SOP 109, Analysis of Safety Data. Bristol-Myers Squibb Research and Development, 
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10 Bristol-Myers-Squibb Global Biometrics Sciences General Requirements for Statistical 
Outputs, Revision 1.8.5, 06-Nov-2013.
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