A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic Stroke or Transient Ischemic Attack (TIA)
Phase: PHASE2
Conditions: Acute Ischemic Stroke, Transient Ischemic Attack (TIA)
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of 
BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or 
New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute 
Ischemic Stroke or Transient Ischemic Attack (TIA) 
 
PROTOCOL: CV010-031 
 
NCT Number: NCT03766581 
  
Document Date (Date in which document was last revised): October 9, 2020 

Page:
1
Protocol Number:
CV010031
IND Number:
138,848
EUDRACT Number:
2017-005029-19
Date:
13-Jul-2018
Revised Date:
09-Oct-2020
Clinical Protocol CV010031
A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of 
BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or 
New Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute 
Ischemic Stroke or Transient Ischemic Attack (TIA)
AXIOMATIC-SSP
Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute 
Thromboembolic events in Secondary Stroke Prevention
Revised Protocol 06
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l̓Alleud, Belgium
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1327, Japan
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
2
BMS-986177 is being co-developed under a collaboration agreement between Bristol-Myers 
Squibb Company (BMS) and Janssen Pharmaceuticals, Inc. (Janssen)
This document is the confidential and proprietary information of Bristol-Myers Squibb and 
its global affiliates (BMS), and co-development partner Janssen. 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 Janssen 
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 or Janssen is 
requested to return it to BMS or promptly destroy it. All other rights reserved. References 
to BMS in this protocol may also apply to partners to which BMS has transferred obligations, 
eg, a Contract Research Organization (CRO).
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 06
09-Oct-2020

Increased NIHSS score inclusion criterion for qualifying 
event from ≤5 to ≤7.

Removed use of thrombolytic therapy/mechanical 
thrombectomy for treatment of the index event from 
exclusion criteria and added to inclusion criteria to be 
permitted under specified conditions.

Added intracranial artery stenosis requiring angioplasty 
within 90 days to the exclusion criteria.

Clarified that treated aneurysms without history of 
intracranial bleed are permitted.

Clarified that only complete occlusion of a cervical carotid 
artery or an intracranial artery on the ipsilateral site and 
proximal to the index lesion are exclusionary for the study.

Clarified UFH or LMWH for DVT prophylaxis allowance 
prior to enrollment.

Updated INR exclusion requirement from INR >1.7 to INR 
>1.5.

Updated exclusion criteria to include history of 12-lead 
ECG findings requiring exclusion.

Added exclusion criterion of known SARS-CoV-2 infection 
within 4 weeks of screening and associated conditions.

Clarified that a clinical (standard-of-care) MRI scan can be 
used as the baseline MRI provided that the clinical MRI 
protocol and scanner have been pre-approved by the central 
imaging vendor.

Removed requirement of baseline MRI within 48 hours of 
index event and prior to randomization and provided 
instruction regarding instances where the baseline MRI 
cannot be performed within 48 hours of the index event and 
before randomization.

Expanded the available window for the baseline MRI for 
instances where the MRI cannot be performed within 48 
hours of the index event and prior to randomization to up to 
72 hours after the onset of the index event and up to 24 
hours after randomization 

Removed +10 day visit window from Day 90 visit and 
added instruction regarding performance of the Day 90 
MRI when impacted by the COVID-19 pandemic.

Added statement that alternative measures can be 
considered to obtain required visit assessments for 
participants who are unable or not permitted to attend an 
onsite visit due to the COVID-19 pandemic as local 
regulatory requirements permit.

Updated Day 60 visit description to ease telephone contact 
requirement for participants who completed required 
assessments at Day 60 site visit and removed requirement 
of reviewing Day 60 clinical laboratory results with 
participant.
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
4
Document
Date of Issue
Summary of Change

Added statement that the DMC recommendation regarding 
the Day 60 clinical laboratory sample will be 
communicated to the investigator by the Sponsor.

Updated the milestone requirement for DMC review to 
decide on inclusion of the 200-mg BID dose arm.

Removed contrast use restriction for the collection of the 
study MRIs to allow for contrast agent administration as per 
investigator discretion and local clinical practice.

Revised statement that study drug BMS-986177 must be 
permanently discontinued if thrombolytic therapy or 
thrombectomy is used for the treatment of a new stroke 
during the study to allow for only a temporary interruption 
and restart of BMS-986177 if pre-specified conditions are 
met.

Modified required duration of SAE collection from 7 days 
after discontinuation of dosing to through the follow-up 
period.

Simplified pharmacokinetic and pharmacodynamic 
sampling schedules.

Added biomarkers related to SARS-CoV-2 infection status 
or related pathophysiological pathways to exploratory 
biomarker assessments. 

Provided sample size estimations for the study without 
inclusion of the 200-mg BID dose arm.

Updated Appendix 2 to specify that other means of remote 
monitoring approved by the Sponsor and as local regulatory 
requirements permit can be considered.

Other changes made related to typographical errors, 
clarifications, changes in terminology, and alignment to 
other key study documents.
Revised Protocol 05
24-Aug-2019
Removed 3 QD doses groups (lowest 25 mg QD dose is 
maintained); keeping all BID doses. Accordingly, the sample 
size of the study is reduced and primary objective is updated 
(dose-response trend is retained; MED and ED90 assessment 
is removed)
Primary analysis MCP-MOD (include placebo and 25 mg QD 
as lowest dose)
o Additional exploratory analyses using the 25 mg QD dose 
and control
Response-adapted randomization (RAR) initially proposed has 
been replaced with a non-RAR randomization schema
Title of the protocol was changed to reflect the new design
Removed RAR interim analyses, added administrative interim 
analyses
Removed RNA and miRNA sample collection and testing
Revised Protocol 04
03-May-2019
Updated exclusion criteria to exclude participants with 
arteriovenous malformation (AVM)
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
5
Document
Date of Issue
Summary of Change
Revised Protocol 03
05-Apr-2019
Allow clopidogrel loading doses of 300 mg to 600 mg prior to
signing informed consent
Removal of aortic arch atheroma >4 mm in thickness from 
vascular imaging criteria and updated criteria for 
atherosclerotic plaque
Added exploratory objective to assess the incidence and 
characteristics of cerebral microbleeds (CMBs), hemorrhagic 
transformation of ischemic stroke and asymptomatic 
intracranial bleeding on Day 90
Added specifics regarding petechiae on brain imaging
Clarified that MRI is not required to determine study 
eligibility
Clarified assessments to be completed for participants who 
discontinue study treatment
Updated PK characteristics table to include estimate of renal 
clearance and impact of renal impairment
Added instructions for missed doses
Added details for brief physical exam
Provided guidance for the management of bleeding events
Modified the PK and PD sample collection window for the 
12-hour post-first dose time point and the requirement of a 12-
and 24-hour PK/PD sample collection for TIA subjects on 
Day 1.
Clarified assessments to be completed at screening vs. prior to 
dosing on Day 1
Added scenarios where the DMC and the RAR vendor will 
receive unblinded data for safety assessment
Added new appendices for strong CYP3A inhibitors and 
inducers
Added guidance for use of thrombolytic therapy for the 
treatment of new stroke, including availability of unblinding
Reduced the window for collection of information on 
medications taken prior to study drug from 30 days to 7 days
Reduced the window for SAE collection after discontinuation 
of study medication from 30 days to 7 days
Reorganized statistical analysis sections to tabular form 
matching endpoint with statistical method
Corrected/clarified discrepant items
Administrative Letter 01
27-Nov-2018
Correcting a typo in the summary of Change column of the 
document history
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
6
Document
Date of Issue
Summary of Change
Revised Protocol 02
31-Oct-2018
Appendix 3 updated for Adverse Events (AE) definitions and 
details
Day 60 7 central clinical laboratory sample collection added
DMC review for the first 450 and 600 subjects added to make 
recommendation regarding collection of clinical laboratory 
samples
Corrected/clarified items (IP designation, PK/PD sample time 
and collection window)
Revised Protocol 01
20-Sep-2018
Updated based on 
 Steering Committee 
feedback
Study Design changes for clopidogrel loading dose and 
staggered approach for high dose groups randomization
Corrected/clarified discrepant items
Original Protocol
13-Jul-2018
Not applicable
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
OVERALL RATIONALE FOR REVISED PROTOCOL 06:
The purpose of Revised Protocol 06 is to incorporate Steering Committee and investigator 
feedback for modification of selected study eligibility criteria. This includes increasing the 
National Institute of Health Stroke Scale (NIHSS) at randomization from ≤5 to ≤7 and permitting 
intravenous thrombolytic therapy, as well as mechanical thrombectomy, for the index event 
provided conditions are met. These modified criteria reflect a broader population that is closer to 
clinical practice. In addition, the international normalized ratio (INR) threshold prior to study 
treatment administration has been lowered from ≤ 1.7 to < 1.5 for all participants to ensure the 
safety of the study population, which is now permitted to receive thrombolytic therapy and/or 
mechanical thrombectomy for acute treatment of the index stroke. To accommodate for potential 
instances where the baseline study MRI cannot be completed within 48 hours, the window for the 
baseline study MRI has been expanded to up to 72 hours after the onset of the index event with 
the condition that subjects will need to be dosed within the 48-hour randomization window. To 
accommodate for regional and institutional practices in study-related MRI acquisition, the 
administration of contrast agents is permitted as per investigator discretion. Specific to COVID-
19, an exclusion criterion was added for the safety of study participants and site personnel. In 
addition, exploratory research was modified to include biomarkers related to severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to support advancing the 
understanding of the impact of SARS-CoV-2 on the study population, BMS-986177, and 
cardiovascular disease.
Based on site feedback, the pharmacokinetic and pharmacodynamic sampling requirements have 
been simplified to facilitate sample collection. 
In addition, the SAE collection period has been extended through the follow-up period in order to 
standardize post-randomization SAE collection with NSAE collection. Previously, SAEs were to 
be collected for 7 days after discontinuation of dosing.
In an effort to enable flexibility and preserve collection of key study assessments that may be 
impacted by the COVID-19 pandemic, instructions were added to provide guidance regarding 
study assessments, including performance of the Day 90 MRI, collection of other onsite
assessments that can be conducted remotely (eg, central laboratory tests), and remote monitoring 
considerations. 
Other changes are administrative changes such as typographical errors, clarifications, changes in 
terminology, and alignment to other key study documents.
The changes made to the protocol are not anticipated to have a significant impact on the 
benefit-risk of the trial participants, and do not impact the integrity of the study.
The table below highlights the key changes made to the body of the protocol. The changes made 
in the body of the protocol were also implemented in the Synopsis, where applicable. 
Revised Protocol No.: 06
Date: 09-Oct-2020
7
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Title page
Revised Sponsor contact 
information.
To update clinical team members.
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural
Outline)
Clarified that 100-mg aspirin 
dosing can start on Day 2 for
participants who received at least 
75 mg as standard of care on the 
same day as randomization.
To accommodate for regional or 
institutional practices regarding 
aspirin administration during acute 
management of stroke/TIA.
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Clarified that following a 
standard-of-care clopidogrel 
loading dose, the standard-of-care 
clopidogrel daily dose of 75 mg 
may be taken prior to 
randomization.
To accommodate for regional or 
institutional practices regarding 
clopidogrel administration during 
acute management of stroke/TIA.
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Added note: A clinical (standard-
of-care) MRI scan can be used as 
the baseline MRI provided that 
the clinical MRI protocol and 
scanner have been pre-approved 
by the central imaging vendor. 
Removed note: Study-specific, 
pretreatment (Day 1) MRI must 
be performed within 48 hours of 
the onset of the index event and 
prior to randomization.
To clarify conditions when it is 
acceptable to utilize a standard-of-care
MRI protocol as the baseline MRI. 
The timing of the baseline MRI 
relative to the onset of the index event 
and randomization is outlined in the 
study-specific MRI row on Table 2-2. 
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Specified the anatomical location 
where complete occlusion of a 
cervical carotid or an intracranial 
artery will require exclusion 
(proximal to the index lesion). 
To clarify the required evidence for 
exclusion of participants with 
complete occlusion of a cervical 
carotid or an intracranial artery. 
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Updated the notes to include a list 
of screening laboratory tests that 
are required be performed locally 
to assess eligibility.
To provide clarification to sites as to 
what screening labs need to be 
performed locally to assess eligibility.
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Modified required duration of 
SAE collection from 7 days after 
discontinuation of dosing to 
through the follow-up period.
To enable SAE collection through the 
follow-up period for participants who 
discontinue study treatment early and 
align with post-randomization NSAE 
collection.
Section 2 (Schedule of
Activities), Table 2-1
(Screening Period Procedural 
Outline)
Added guidance as to where 
results of local labs performed for 
assessment of SAEs should be 
sent.
To provide clarification to sites as to 
where results of local labs performed 
for assessment of SAEs should be 
sent.
Section 2 (Schedule of
Activities), Table 2-2
Updated “brief physical 
examination” to “brief physical 
assessment.”
To enable performance of the physical 
assessment by delegated non-
physician study staff on Day 21.
Revised Protocol No.: 06
Date: 09-Oct-2020
8
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
(Post-Screening Period Procedural 
Outline)
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Provided instruction regarding
instances where the baseline MRI 
cannot be performed within 48 
hours of the index event and 
before randomization. Removed 
study-specific MRI sequences and 
referenced that sequences will be 
defined in imaging manual.
To enable flexibility without delaying 
randomization. The required MRI 
sequences are defined in the imaging 
manual.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Added instruction regarding 
performance of the Day 90 MRI 
when impacted by the COVID-19
pandemic.
To enable flexibility and preserve 
collection of the Day 90 MRI when 
impacted by the COVID-19 pandemic.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Clarified that participants may not 
be taking study medication past 
Day 96.
To accurately reflect consideration of 
study medication supply relative to 
obtaining the Day 90 MRI. 
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Clarified that 100-mg aspirin 
dosing can start on Day 2 for 
participants who received at least 
75 mg as standard of care on the 
same day as randomization.
To accommodate for regional or 
institutional practices regarding 
aspirin administration during acute 
management of stroke/TIA. 
Section 2 (Schedule of
Activities), Table 2-2
(Screening Period Procedural 
Outline)
Clarified that following a 
standard-of-care clopidogrel 
loading dose, the standard-of-care 
clopidogrel daily dose of 75 mg 
may be taken prior to
randomization.
To accommodate for regional or 
institutional practices regarding 
clopidogrel administration during 
acute management of stroke/TIA.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
NIHSS score for qualifying event 
was increased from ≤5 to ≤7.
The NIHSS score for qualifying event 
was increased based on review of 
aggregate safety data to date and 
Steering Committee feedback.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Updated the notes to include 
pregnancy requirements.
To provide clarity to the sites on the 
pregnancy testing expectations.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Modified required duration of 
SAE collection after 
discontinuation of dosing from 7 
days to through the follow-up 
period.
To enable SAE collection through the 
follow-up period for participants who 
discontinue study treatment early and 
align with post-randomization NSAE 
collection.
Revised Protocol No.: 06
Date: 09-Oct-2020
9
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Added guidance as to where 
results of local labs performed for 
assessment of SAEs should be 
sent.
To provide clarification to sites as to 
where results of local labs performed 
for assessment of SAEs should be 
sent.
Section 2 (Schedule of
Activities), Table 2-2
(Post-Screening Period Procedural 
Outline)
Provided instruction to clarify 
that the timing of first dose of 
study medication remains 
unchanged in instances when the 
baseline MRI is completed after 
48 hours from the onset of the 
index event.
To reaffirm unchanged first dose 
requirements relative to onset of the 
index event even when study-specific 
MRI cannot be completed within 
48 hours from the onset of the index 
event. 
Section 2 (Schedule of Activities), 
Table 2-2
(Post-Screening Period Procedural 
Outline)
Modified table footnotes to reflect 
changes in the table and protocol 
body.
To accurately reflect protocol body 
content. 
Section 3.2.1 (Phase 1 and 2a 
studies with BMS-986177), Table 
3.2.1-1 (Highlights of Clinical 
Pharmacology)
Clarified that Tmax was in fasted 
state and that Accumulation Index 
was for QD dosing only.
To provide clarification on the 
conditions where the PK properties 
were determined.
Section 5.1 (Overall Design)
Removed ±10-day visit window 
and added instruction regarding 
performance of the Day 90 MRI 
when impacted by the COVID-19 
pandemic.
To enable flexibility and preserve 
collection of Day 90 MRI when 
impacted by the COVID-19 pandemic.
Section 5.1 (Overall Design)
Updated enrollment period 
duration from 26 months to 36 
months. 
To reflect updated enrollment 
projections. 
Section 5.1 (Overall Design, 
Screening Period)
Provided instruction regarding 
instances where the baseline MRI 
cannot be performed within 48 
hours of the index event and 
before randomization. 
To enable flexibility without delaying 
randomization.
Section 5.1 (Overall Design, 
Screening Period)
Specified the anatomical location 
for the assessment of complete 
occlusion of a cervical carotid or 
an intracranial artery (proximal to 
the index lesion).
To clarify the required evidence for 
exclusion of participants with 
complete occlusion of a cervical 
carotid or an intracranial artery. 
Section 5.1 (Overall Design,
Double-Blind Treatment Period)
Restructured order of activities to 
be performed during the double-
blind treatment period.
To clarify the sequence of activities to 
be performed during the double-blind 
treatment period.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Added statement that the DMC 
recommendation regarding the 
Day 60 clinical laboratory sample 
will be communicated to the 
investigator by the Sponsor. 
To provide clarity regarding 
communication of the DMC 
recommendation to the investigator
without the need for a protocol 
amendment.
Revised Protocol No.: 06
Date: 09-Oct-2020
10
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 5.1 (Overall Design, 
Double-Blind Treatment Period, 
and Figure 5.1-1 Study Design 
Schematic)
Updated the milestone 
requirement for DMC review 
prior to decision on inclusion of 
the 200-mg BID dose arm. 
In light of modifications to the 
inclusion/exclusion criteria, the DMC 
milestone requirements were updated 
to enable safety evaluation of study 
population prior to the inclusion of the 
200-mg BID arm.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Clarified that following a 
standard-of-care clopidogrel 
loading dose, the standard-of-care 
clopidogrel daily dose of 75 mg 
may be taken prior to 
randomization.
To accommodate for regional or 
institutional practices regarding 
clopidogrel administration during 
acute management of stroke/TIA.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Clarified that 100-mg aspirin 
dosing can start on Day 2 for 
participants who received at least 
75 mg as standard of care on the 
same day as randomization.
To accommodate for regional or 
institutional practices regarding 
aspirin administration during acute 
management of stroke/TIA.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Added statement that alternative 
measures can be considered to 
obtain required visit assessments 
for participants who are unable or 
not permitted to attend an onsite 
visit due to the COVID-19 
pandemic as local regulatory 
requirements permit. 
To preserve study assessment 
collection for participants who are 
unable or not permitted to attend an 
onsite visit due to the COVID-19 
pandemic.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Updated Day 60 visit description 
to ease telephone contact 
requirement for participants who 
reviewed required assessments at 
Day 60 site visit and removed 
requirement of reviewing Day 60 
clinical laboratory results with 
participant.
To provide flexibility to sites and 
participants who are able to conduct 
all required assessment at Day 60 site 
visit.
Section 5.1 (Overall Design, 
Double-Blind Treatment and 
Follow-Up Period)
Clarified when the Day 97 end-
of-study follow-up phone visit 
should occur for participants not 
completing treatment or not 
obtaining the Day 90 MRI.
To provide clear instruction on the
requirement of the Day 97 end-of-
study follow-up phone visit.
Section 5.1 (Overall Design, 
Double-Blind Treatment Period)
Added statement encouraging 
sites to perform follow-up phone 
call 7 days after permanent 
discontinuation.
To encourage follow-up contact is 
made with participants who 
permanently discontinue study 
medication. 
Revised Protocol No.: 06
Date: 09-Oct-2020
11
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.1 (Data Monitoring 
and Other External Committees)
Updated the milestone 
requirements for DMC review 
prior to decision on inclusion of 
the 200-mg BID dose arm. 
In light of modifications to the 
inclusion/exclusion criteria, the DMC 
milestone requirements were updated 
to enable safety evaluation of study 
population prior to the inclusion of the 
200-mg BID arm.
Section 5.1.1 (Data Monitoring 
and Other External Committees)
Added statement that the DMC 
recommendation regarding the 
Day 60 clinical laboratory sample 
will be communicated to the 
investigator by the Sponsor.
To provide clarity regarding 
communication of the DMC 
recommendation to the investigator
without the need for a protocol 
amendment.
Section 5.1.1 (Data Monitoring 
and Other External Committees)
Removed statement: 
“Recommendations for criteria to 
stop the clinical trial for safety 
concerns will be defined in the 
DMC charter.”
Added statement: “The DMC will 
use their clinical and statistical 
judgment to evaluate pertinent 
trial data and may recommend 
early termination of an individual 
study arm or the entire trial for 
important safety concerns that are 
felt to outweigh potential benefits. 
Details of the DMC activities will 
be described in a DMC charter.
To clarify that the Sponsor will not 
provide trial stopping criteria because 
the independent DMC is tasked to 
evaluate if the trial should
be terminated early based on their 
clinical judgement of benefit-risk.
Section 6.1 (Inclusion Criteria)
NIHSS score for qualifying event 
was increased from ≤5 to ≤7.
The NIHSS score for qualifying event 
was increased based on review of 
aggregate safety data to date and 
feedback from Steering Committee.
Section 6.1 (Inclusion Criteria)
Specified the anatomical location 
where complete occlusion of a 
cervical carotid or an intracranial 
artery will require exclusion 
(proximal to the index lesion).
To clarify the required evidence for 
exclusion of participants with 
complete occlusion of a cervical 
carotid or an intracranial artery. 
Section 6.1 (Inclusion Criteria)
Removed language regarding 
performance of baseline MRI 
within 48 hours of index event 
and prior to randomization and 
added statement that baseline
MRI is required in this study in 
line with Section 9.2.12. 
To reflect baseline MRI requirements 
in line with Section 9.2.12.
Revised Protocol No.: 06
Date: 09-Oct-2020
12
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 6.1 (Inclusion Criteria)
Permitted the use of thrombolytic 
therapy/mechanical 
thrombectomy for treatment of 
the index event under specified 
conditions.
Based on aggregate safety data to date 
and feedback from Steering 
Committee, thrombolytic 
therapy/mechanical thrombectomy are 
now permitted provided that specified 
conditions are met in order to study a 
broader population that is closer to 
clinical practice.
Section 6.2 (Exclusion Criteria)
Added intracranial artery stenosis
requiring angioplasty within 90 
days to the exclusion criteria.
To clarify exclusion criteria regarding
planned vascular treatment of 
intracranial artery stenosis.
Section 6.2 (Exclusion Criteria)
Removed use of thrombolytic 
therapy/mechanical 
thrombectomy from exclusion 
criteria.
Based on aggregate safety data to date
and feedback from Steering 
Committee, thrombolytic 
therapy/mechanical thrombectomy are
now permitted provided that specified 
conditions are met in order to study a 
broader population that is closer to 
clinical practice.
Section 6.2 (Exclusion Criteria)
Clarified that treated aneurysms 
without history of intracranial 
bleed are permitted. 
To allow for enrollment of participants 
who present with treated aneurysms 
without history of intracranial bleed. 
Section 6.2 (Exclusion Criteria)
Clarified UFH or LMWH for 
DVT prophylaxis allowance prior 
to enrollment.
To provide clear instruction on UFH 
or LMWH for DVT prophylaxis 
allowance prior to enrollment.
Section 6.2 (Exclusion Criteria)
Updated classification of strong 
CYP3A4/P-gp inhibitors and 
strong CYP3A4/P-gp inducers to 
combined P-gp and strong 
CYP3A4 inhibitors and combined
P-gp and strong CYP3A4 
inducers, respectively.
To reflect current classification of 
compounds with combined P-gp and 
CYP3A modulation properties.
Section 6.2 (Exclusion Criteria)
Updated INR exclusion 
requirement from INR >1.7 to 
INR >1.5.
The INR threshold was lowered for 
the safety of the study population that 
may receive thrombolytic therapy
prior to randomization while also 
aligning laboratory exclusion 
requirements for all study participants.
Section 6.2 (Exclusion Criteria)
Updated criteria to include history 
of 12-lead ECG findings 
requiring exclusion.
Added clarification to also exclude 
participants with a history of ECG 
abnormalities as these participants 
have an increased risk for detection of 
an ECG finding during the study 
which may prompt early drug 
discontinuation.
Revised Protocol No.: 06
Date: 09-Oct-2020
13
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 6.2 (Exclusion Criteria)
Addition of SARS-CoV-2 
infection within 4 weeks of 
screening and associated 
conditions regarding symptom 
resolution, investigator 
assessment, and consultation with 
Medical Monitor/Clinical Trial 
Physician.
To ensure safety of study participants 
and site personnel.
Section 7.2 (Method of Treatment 
Assignment)
Updated the milestone 
requirement for DMC review 
prior to decision on inclusion of 
the 200-mg BID dose arm.
In light of modifications to the 
inclusion/exclusion criteria, the DMC 
milestone requirements were updated 
to enable safety evaluation of study 
population prior to the inclusion of the 
200-mg BID arm.
Section 7.3 (Selection and Timing 
of Dose for Each Participant)
Clarified that following a 
standard-of-care clopidogrel 
loading dose, the standard-of-care 
clopidogrel daily dose of 75 mg 
may be taken prior to 
randomization.
To accommodate for regional or 
institutional practices regarding 
clopidogrel administration during 
acute management of stroke/TIA.
Section 7.3 (Selection and Timing 
of Dose for Each Participant)
Restructured language regarding
clopidogrel loading dose 
instructions.
To clarify 3 scenarios for 
administration of the clopidogrel 
loading dose.
Section 7.3 (Selection and Timing 
of Dose for Each Participant)
Clarified that 100-mg aspirin 
dosing can start on Day 2 for 
participants who received at least 
75 mg as standard of care on the 
same day as randomization.
To accommodate for regional or 
institutional practices regarding 
aspirin administration during acute 
management of stroke/TIA.
Section 7.3 (Selection and Timing 
of Dose for Each Participant)
Provided instruction to clarify 
that the timing of first dose of 
study medication remains 
unchanged in instances when the 
baseline MRI is completed after 
48 hours from the onset of the 
index event.
To reaffirm unchanged first dose 
requirements relative to onset of the 
index event even when baseline MRI 
cannot be completed within 48 hours 
from the onset of the index event. 
Section 7.3 (Selection and Timing 
of Dose for Each Participant)
Updated study medication 
duration of resupply on Day 21 
from 70 days to 64 days.
To accurately reflect the study 
medication re-supply that participant 
is receiving. 
Section 7.3 (Selection and Timing
of Dose for Each Participant)
Updated the consideration that 
participant may not be taking 
study medication past Day 96 
when Day 90 MRI is performed 
past ± 6-day window due to the 
COVID-19 pandemic.
To accurately reflect consideration of 
study medication supply relative to 
obtaining Day 90 MRI when impacted 
by the COVID-19 pandemic.
Revised Protocol No.: 06
Date: 09-Oct-2020
14
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 7.4 (Blinding)
Clarified that designated staff of 
Bristol-Myers Squibb Research & 
Development not involved in the 
study will provide assistance for 
analyses needed for DMC in 
scope of the DMC charter. 
To provide clarification on unblinding 
of designated Bristol-Myers Squibb 
staff not involved in the study who are 
performing analyses needed for DMC 
in scope of the DMC charter.
Section 7.7.1 (Prohibited and/or 
Restricted Treatments)
Included all prohibited treatments 
from exclusion criteria.
To provide clarity on the prohibited 
treatments from exclusion criteria 
instead of referencing the section.
Section 7.7.2.1 (Imaging 
Restrictions and Precautions)
Updated contrast restriction to 
allow for contrast administration 
as per investigator discretion and 
local clinical practice.
To accommodate for regional or 
institutional practices regarding 
contrast administration for MRIs.
Section 8.4 (Emergency 
Procedures)
Removed statement that study 
drug BMS-986177 must be 
discontinued if thrombolytic 
therapy or thrombectomy is used. 
Added statement that study drug 
BMS-986177 must be interrupted 
after thrombolytic therapy or 
thrombectomy and specified 
conditions that need to be met to 
permit re-start.
Based on aggregate safety data and 
feedback from the Steering 
Committee, study drug BMS-986177 
must be interrupted and can be 
restarted if thrombolytic therapy is 
administered or thrombectomy is 
performed provided that specified 
conditions are all met.
Section 8.5 (Other Reasons for 
Permanent Discontinuation from 
Study Treatment)
Removed statement that study 
drug BMS-986177 must be
permanently discontinued if 
thrombolytic therapy or 
thrombectomy is used.
Based on aggregate safety data and 
feedback from the Steering 
Committee, study drug BMS-986177 
can be restarted if thrombolytic 
therapy or thrombectomy were used 
during the treatment period, provided 
that all specified conditions are met.
Section 8.6 (Discontinuation from 
Study)
Clarified the Day 90 and Day 97 
visit assessment requirements if 
end-of-treatment visit is 
completed.
To provide clear instruction to sites 
regarding participants who discontinue 
early and complete end-of-treatment 
visit requirements. Specifically, that 
for these participants only the Day 90 
MRI is required on the Day 90 visit 
and that the Day 97 visit should be 
completed.
Section 8.6 (Discontinuation from 
Study)
Added statement encouraging 
sites to perform follow-up phone 
call 7 days after permanent 
discontinuation.
To encourage follow-up contact is 
made with participants who 
permanently discontinue study 
medication. 
Section 8.6 (Discontinuation from 
Study)
Clarified conditions when Day 97 
end-of-study follow-up phone 
visit should occur.
To provide clear instruction on 
requirement of Day 97 end-of-study 
follow-up phone visit.  
Revised Protocol No.: 06
Date: 09-Oct-2020
15
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 8.7 (Post-Study Treatment 
Follow-up)
Added instruction regarding 
performance of the Day 90 MRI 
when impacted by the COVID-19 
pandemic.
To enable flexibility and preserve 
collection of Day 90 MRI when 
impacted by the COVID-19 pandemic.
Section 9.1 (Efficacy Assessments)
Provided instruction regarding 
instances where the baseline MRI 
cannot be performed within 48 
hours of the index event and 
before randomization.
To enable flexibility without delaying 
randomization. 
Section 9.1 (Efficacy Assessments)
Provided instruction to clarify 
that the timing of first dose of 
study medication remains 
unchanged in instances when the 
baseline MRI is completed after 
48 hours from the onset of the 
index event.
To reaffirm unchanged first dose 
requirements relative to onset of the 
index event even when baseline MRI 
cannot be completed within 48 hours 
from the onset of the index event. 
Section 9.2.3 (Time Period and 
Frequency for Collecting AE and 
SAE information)
Clarified that nonserious AE 
collection should begin at 
randomization. 
To align with adverse event reporting 
in Table 2-2 (Post-Screening 
Procedural Outline).
Section 9.2.3 (Time Period and 
Frequency for Collecting AE and 
SAE information)
Modified required duration of 
SAE collection after 
discontinuation of dosing from 7 
days to through the follow-up 
period.
To enable SAE collection through the 
follow-up period for participants who 
discontinue study treatment early and 
align with post-randomization NSAE 
collection.
Section 9.2.3 (Time Period and 
Frequency for Collecting AE and 
SAE information)
Added guidance as to where 
results of local labs performed for 
assessment of SAEs should be 
sent.
To provide clarification to sites as to 
where results of local labs performed 
for assessment of SAEs should be 
sent.
Section 9.2.12 (Magnetic 
Resonance Imaging)
Clarified that a clinical (standard-
of-care) MRI scan can be used as 
the baseline MRI provided that 
the clinical MRI protocol and 
scanner have been pre-approved 
by the central imaging vendor. 
To clarify conditions when it is 
acceptable to utilize a standard-of-care 
MRI protocol as the baseline MRI.
Section 9.2.12 (Magnetic 
Resonance Imaging)
Provided instruction regarding 
instances where the baseline MRI 
cannot be performed within 48 
hours of the index event and 
before randomization.
To enable flexibility without delaying 
randomization. 
Section 9.2.12 (Magnetic 
Resonance Imaging)
Removed ±10-day window and 
added instruction regarding 
performance of the Day 90 MRI 
when impacted by the COVID-19 
pandemic.
To enable flexibility and preserve 
collection of Day 90 MRI when 
impacted by the COVID-19 pandemic.
Revised Protocol No.: 06
Date: 09-Oct-2020
16
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.12 (Magnetic 
Resonance Imaging)
Updated the consideration that 
participant may not be taking 
study medication past Day 96 
when Day 90 MRI is performed 
past ± 6-day window due to the 
COVID-19 pandemic.
To accurately reflect consideration of 
study medication supply relative to 
obtaining Day 90 MRI when impacted 
by the COVID-19 pandemic.
Section 9.2.12 (Magnetic 
Resonance Imaging)
Restructured language for clarity.
To provide clear guidance on MRI 
requirements for investigators.
Section 9.2.13 Physical 
Examinations
Updated “brief physical 
examination” to “brief physical 
assessment.”
To enable performance of the physical 
assessment by delegated non-
physician study staff on Day 21.
Section 9.3 (PK, PD, Biomarkers 
and PK/PD Assessments), Table  
9.3.1.1-1 (Pharmacokinetic 
Sampling Schedule)
Simplified pharmacokinetic 
sampling schedule.
To enable flexibility to sites for PK 
sampling based on feedback from 
investigators.
Section 9.3 (PK, PD, Biomarkers 
and PK/PD Assessments), Section 
9.3.2.1 (Exploratory Biomarker 
Assessments)
Added biomarkers related to 
SARS-CoV-2 infection status or 
related pathophysiological 
pathways.
SARS-CoV-2 serologic status may 
help advance the understanding of the 
impact of SARS-CoV-2 on BMS-
986177 and cardiovascular disease. 
Section 9.3 (PK, PD, Biomarkers 
and PK/PD Assessments), Table 
9.3.2.1-1 (Biomarker sampling 
Schedule)
Simplified biomarker sampling 
schedule. 
To enable flexibility to sites for 
biomarker sampling based on 
feedback from investigators.
Section 9.4 (Other Assessments), 
Section 9.4.1 (Assessment of Index 
Stroke and New Strokes)
NIHSS score for qualifying event 
was increased from ≤5 to ≤7.
The NIHSS score for qualifying event 
was increased based on review of 
aggregate safety data to date and 
feedback from Steering Committee.
Section 10.1 (Sample Size 
Determination)
Provided sample size estimations 
for the study without inclusion of 
the 200-mg BID dose arm.
To provide an additional statistical 
sample size determination in case the 
200-mg BID dose arm is not included 
in the randomization scheme.
Appendix 2 (Study Governance 
Considerations)
Added statement to specify that 
other means of remote monitoring 
approved by the Sponsor and as 
local regulatory requirements 
permit can be considered.
To clarify conditions where remote 
monitoring can be considered. 
Appendix 11 (Strong CYP3A 
inhibitor list)
Updated classification in title and 
body to combined P-gp and 
strong CYP3A4 inhibitors.
To reflect current classification of 
compounds with combined P-gp and 
CYP3A modulation properties.
Appendix 12 (Strong CYP3A 
inducer list)
Updated classification in title and 
body to combined P-gp and 
strong CYP3A4 inducers.
To reflect current classification of 
compounds with combined P-gp and 
CYP3A modulation properties.
Revised Protocol No.: 06
Date: 09-Oct-2020
17
Approved
8.0
v
Approved
1.0
v

TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 06: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 06 ......................... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Novel Antithrombotic Mechanism of BMS-986177 ................................. 
3.1.2 More Potent Antiplatelet Therapy ........................................................... 
3.1.3 Dual Mechanisms of Thrombosis Inhibition ............................................ 
3.1.4 Selection of Treatments ............................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Phase 1 and 2a Studies with BMS-986177 .............................................. 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring and Other External Committees .................................. 
5.2 Participants ........................................................................................................ 
5.3 End-of-Study Definition ................................................................................... 
5.4 Justification for Doses....................................................................................... 
5.4.1 Identification of Effective Doses of BMS-986177 .................................... 
5.4.2 BMS-986177 with Aspirin + Clopidogrel ................................................ 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.5 Retesting During Screening or Lead-In Period ................................................. 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Selection and Timing of Dose for Each Participant .......................................... 
7.4 Blinding............................................................................................................. 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
7.8 Treatment After the End-of-Study .................................................................... 
8 DISCONTINUATION OR INTERRUPTION CRITERIA ...................................... 












































&OLQLFDO3URWRFRO
%06-1-
&9
)DFWRU;,D,QKLELWRU
5HYLVHG3URWRFRO1R
'DWH2FW

Approved
8.0
v
Approved
1.0
v

8.1 Bleeding ............................................................................................................ 
8.2 Elevated Liver Function Tests .......................................................................... 
8.3 Elective Procedures or Surgery ......................................................................... 
8.4 Emergency Procedures...................................................................................... 
8.5 Other Reasons for Permanent Discontinuation from Study Treatment ............ 
8.6 Discontinuation from the Study ........................................................................ 
8.7 Post-Study Treatment Follow-up ...................................................................... 
8.8 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Primary Efficacy Assessments ................................................................. 
9.1.2 Secondary Efficacy Assessments .............................................................. 
9.2 Safety Assessments ........................................................................................... 
9.2.1 Bleeding ................................................................................................... 
9.2.2 Adverse Events ......................................................................................... 
9.2.3 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.4 Method of Detecting AEs and SAEs ......................................................... 
9.2.5 Follow-up of AEs and SAEs ..................................................................... 
9.2.6 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.7 Pregnancy ................................................................................................ 
9.2.8 Overdose .................................................................................................. 
9.2.9 Laboratory Test Result Abnormalities ..................................................... 
9.2.10 Other Safety Considerations .................................................................. 
9.2.11 Potential Drug Induced Liver Injury (DILI) .......................................... 
9.2.12 Magnetic Resonance Imaging ................................................................ 
9.2.13 Physical Examinations ........................................................................... 
9.2.14 Vital Signs .............................................................................................. 
9.2.15 Electrocardiograms ............................................................................... 
9.2.16 Clinical Safety Laboratory Assessments ................................................ 
9.3 PK, PD, Biomarkers and PK/PD Assessments ................................................. 
9.3.1 PK Assessments ........................................................................................ 
9.3.1.1 PK Sample Analyses ....................................................................... 
9.3.2 PD and Biomarker Assessments .............................................................. 
9.3.2.1 Exploratory Biomarker Assessments .............................................. 
9.3.3 Additional Research Collection ............................................................... 
9.4 Other Assessments ............................................................................................ 
9.4.1 Assessment of Index Stroke and New Strokes .......................................... 
9.4.2 Assessment of Risk for Subsequent Stroke Associated with Index TIA .... 
9.4.3 Assessment of Clinical Severity of Stroke ................................................ 
9.4.4 Assessment of Cognitive Function ........................................................... 
9.4.5 Assessment of Bleeding Severity .............................................................. 
10 STATISTICAL CONSIDERATIONS .................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Demographics and Baseline Characteristics......................................... 














































&OLQLFDO3URWRFRO
%06-1-
&9
)DFWRU;,D,QKLELWRU
5HYLVHG3URWRFRO1R
'DWH2FW

Approved
8.0
v
Approved
1.0
v

10.3.2 Efficacy Analyses ................................................................................... 
10.3.3 Safety Analysis ....................................................................................... 
10.3.4 Pharmacokinetic Analysis ...................................................................... 
10.3.5 Pharmacodynamic and Biomarker Analysis .......................................... 
10.3.6 Exposure-Response Analyses ................................................................. 
10.3.7 Interim Analyses ..................................................................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 NATIONAL INSTITUTES OF HEALTH STROKE SCALE (NIHSS)
................................................................................................................................. 
APPENDIX 6 ABCD2 SCORE ASSESSMENT TOOL.............................................. 
APPENDIX 7 MODIFIED RANKIN SCORE ............................................................. 
APPENDIX 8 MONTREAL COGNITIVE ASSESSMENT (MOCA) ........................ 
APPENDIX 9 WAIS-IV DSST CODING SUBTEST ................................................. 
APPENDIX 10 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
APPENDIX 11 COMBINED P-GP AND STRONG CYP3A INHIBITOR LIST ....... 
APPENDIX 12 COMBINED P-GP AND STRONG CYP3A4 INDUCER LIST ....... 
 




















&OLQLFDO3URWRFRO
%06-1-
&9
)DFWRU;,D,QKLELWRU
5HYLVHG3URWRFRO1R
'DWH2FW

Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
1
SYNOPSIS
Protocol Title:
A Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of 
BMS-986177, an Oral Factor XIa Inhibitor, for the Prevention of New Ischemic Stroke or New 
Covert Brain Infarction in Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic
Stroke or Transient Ischemic Attack (TIA)
AXIOMATIC-SSP: Antithrombotic Treatment with Factor XIa Inhibition to Optimize 
Management of Acute Thromboembolic Events in Secondary Stroke Prevention
Study Phase:
2
Rationale:
Bleeding, especially intracranial hemorrhage (ICH), is the major concern among clinicians when 
considering antithrombotic therapy in patients with stroke and threatened stroke. A major advance 
of the past decade in anticoagulation has been the introduction of selective oral direct thrombin 
and Factor Xa inhibitors (DOACs). The risk of ICH with DOACs is sharply reduced compared 
with warfarin.
BMS-986177 (also known as JNJ-70033093) is a small molecule that binds and inhibits the 
activated form of human coagulation Factor XI (Factor XIa) with high affinity and selectivity. 
According to the scientific evidence accumulated to date, the inhibition of FXI may provide a 
novel mechanism for systemic antithrombotic effects without increasing the risk of clinically 
significant bleeding in a variety of conditions predisposing to high risk of thrombotic events.
The rationale for this study is that Factor XIa inhibition has the potential to reduce thrombin 
generation enough to prevent vascular occlusion and embolism without impairing hemostasis. The 
following observations support this concept: (1) the highest levels of Factor XI activity are 
associated with a heightened risk of ischemic stroke; (2) lower levels of Factor XI activity are 
associated with a reduced risk of ischemic stroke; (3) Factor XI deficiency is rarely associated with 
unprovoked major bleeding; (4) although not done in participants with stroke, a Phase 2 study for 
VTE prophylaxis in participants post total knee replacement with another Factor XIa inhibitor 
provides a proof-of-concept. The study showed that reducing FXI levels to 20% or less than normal 
with an antisense inhibitor of FXI synthesis reduced the risk of postoperative VTE compared to 
enoxaparin, without an increase in bleeding compared to enoxaparin.
The recently-reported POINT and CHANCE studies demonstrated that treatment with aspirin and 
clopidogrel is more effective than aspirin alone in reducing the risk of recurrent stroke. However, 
the residual risk for recurrent stroke remains high, even when patients are treated with combination 
of aspirin and clopidogrel, emphasizes the continuing need for a more effective therapeutic option.  
Two possible strategies for achieving better efficacy are more potent antiplatelet therapy or dual 
pathway inhibition of thrombus formation.
Revised Protocol No.: 06
Date: 09-Oct-2020
21
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
BMS-986177 combined with antiplatelet therapy has the potential to be safe and more effective
than antiplatelet therapy alone. A recently completed drug-drug interaction (DDI) study in healthy 
volunteers was conducted to assess the safety and tolerability of multiple-dose BMS-986177 
200 mg given twice daily (BID) for 5 days with and without dual antiplatelet therapy. Clopidogrel 
was given as 300 mg on Day 1 followed by 4 days of 75 mg clopidogrel, and aspirin 325 mg was 
administered once daily [QD] for 5 days. There were no serious bleeding events reported from any 
of the 113 healthy participants, including 37 participants treated with DAPT + BMS-986177, in 
the DDI study. There were a few minor bleeding events, which showed no trend toward any 
treatment group. These preliminary findings are consistent with the notion that FXIa inhibition is 
associated with a low risk of bleeding, and support the proposed clinical trial with BMS-986177, 
aspirin and clopidogrel.
Finally, the rationale for treating all patients with aspirin + clopidogrel is based on the lack of 
credible clinical trial data to support a net clinical benefit of anticoagulation alone over antiplatelet 
therapy for secondary prevention of non-cardioembolic strokes.  As noted above, this situation is 
reflected in guidelines recommending antiplatelet therapy for secondary stroke prevention in this 
population. The data summarized above support the hypothesis that inhibition of Factor XIa could 
be a promising target for antithrombotic therapy for stroke, potentially providing sufficient 
inhibition of thrombin generation to prevent thrombotic vascular occlusion or embolization 
without impairing hemostasis.
Study Population:
Approximately and up to 2350 participants, ≥40 years of age, identified within 48 hours of onset 
of signs and/or symptoms of stroke or TIA will be included in this study.
Key Inclusion Criteria:
Type of Participant and Target Disease Characteristics

Ischemic stroke: a neurological deficit attributable to a non-lacunar, acute brain infarction 
detected by neuroimaging (CT or MRI) and relevant to the clinical symptoms.
AND
National Institutes of Health Stroke Score (NIHSS) 7 at time of randomization
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or 
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA or
MRA or catheter angiography)
Note: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible.
Participants with complete occlusion of a cervical carotid or intracranial artery that is 
proximal to the index lesion should be excluded.
AND
Modified Rankin Score (mRS) 3 before the index event (pre-morbid)
Revised Protocol No.: 06
Date: 09-Oct-2020
22
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

TIA: acute onset neurological deficit attributable to focal ischemia of the brain by history or 
examination, with complete resolution of the deficit and no brain infarction on 
neuroimaging (CT or MRI)
AND
ABCD2 SCORE ≥6 or motor symptoms
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or 
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA or
MRA or catheter angiography)
Note: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible.
Participants with complete occlusion of a cervical carotid or intracranial artery that is 
proximal to the index lesion should be excluded.
AND
Modified Rankin Score (mRS) 3 before the index event (pre-morbid)

Two MRI scans are required for participation in this study. Therefore, participants must have 
a body habitus suitable for MRI and cannot have any contraindications to the performance of 
the MRI. (eg, weight limit, MRI-incompatible implanted devices, infusion pump that cannot 
be discontinued temporarily for the scan).

No contraindication to clopidogrel or aspirin and suitable for treatment with aspirin 100 mg 
per day for at least 90 days.

Enrollment of subjects who have received  thrombolytic therapy or mechanical thrombectomy
(without stenting) for the treatment of the index event is permitted if all of the following 
conditions are met:
o
At least 24 hours have elapsed between end of IV thrombolytic use/thrombectomy and 
first dose of study medication.
o
Neuroimaging (either clinical imaging or study MRI) after IV thrombolytic therapy/ 
post-thrombectomy excludes any hemorrhagic transformation.
o
NIHSS ≤7 at time of randomization.
o
Post-thrombolytic therapy/post-thrombectomy INR ≤ 1.5, aPTT ≤1.4 prior to study 
treatment administration.
o
No contraindications have been identified that in the opinion of the investigator would 
preclude start of study medication (eg, large infarct volume, procedure-related 
bleeding).
o
All other study criteria are met.
In addition, we recommend following local practice and considering fibrinogen > 150 mg/dL 
before initiation of study treatment.
Revised Protocol No.: 06
Date: 09-Oct-2020
23
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Key Exclusion Criteria:

Predicted inability to swallow study medication

Women who are pregnant or breastfeeding

Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy or 
would have an unacceptable risk of bleeding such as a large infarct volume (per investigator 
discretion) or uncontrolled hypertension.

Hemorrhage, tumor, arteritis, large vessel dissection, arteriovenous malformation (AVM), or 
other pathology that could account for index symptoms must be excluded by CT or MRI 
interpreted locally.

Symptomatic carotid stenosis or intracranial artery stenosis for which endarterectomy or 
angioplasty is planned within 90 days.

Any condition for which chronic anticoagulation is indicated and expected to be initiated 
(eg, NVAF, DVT, PE)

Requirement for continued use of dual antiplatelet therapy (DAPT) for more than 21 days or 
non-aspirin antiplatelet therapy or anticoagulant for another medical condition 
(eg, prophylaxis for venous thromboembolism).
Note: Treatment with clopidogrel, aspirin, dipyridamole or another P2Y12 inhibitor prior to 
enrollment is allowed. Treatment with aspirin at a different dose before enrollment is 
also allowed. All participants must transition to the protocol-defined treatments and 
doses at randomization. No clopidogrel loading dose is needed for participants who 
received a clopidogrel loading dose prior to randomization. Participants who report 
taking chronic clopidogrel also require a 300-mg clopidogrel loading dose unless the 
investigator can verify that the participant has taken the daily dose for at least the 
preceding 3 days. Participants who have received dipyridamole or another P2Y12 
inhibitor must receive the clopidogrel loading dose after discontinuing the 
non-clopidogrel P2Y12 inhibitor or dipyridamole/dipyridamole-containing treatment.

History of hemorrhage into the brain, subarachnoid hemorrhage, subdural hematoma or spinal 
cord hemorrhage except cerebral microbleeds (CMB) and minor hemorrhagic transformation 
of prior infarct manifesting as scattered petechiae (Hemorrhagic Infarction Type 1 [HI1] 
according to Heidelberg classification).
Note: CMBs are defined as rounded foci of <10 mm in size that appear hypointense and distinct 
from vascular flow voids, leptomeningeal hemosiderosis, or non-hemorrhagic 
subcortical mineralization on T2* weighted MRI.

History of clinically meaningful hepatic disease and/or clinically significant abnormal liver 
function.

Any of the following laboratory results outside of the ranges specified below prior to study 
treatment administration, confirmed by repeat:

Hemoglobin <9 g/dL

Platelet count <100,000 mm3

aPTT >1.4x upper limit of normal (ULN)

INR 1.5

AST or ALT >3x ULN
Revised Protocol No.: 06
Date: 09-Oct-2020
24
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Intracranial tumor (except meningioma, which is permitted) or aneurysm >5 mm or AVM
(except treated aneurysm without history of intracranial bleed, which is permitted.)

History of end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73m2, or requiring 
dialysis 

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.
Note: Participants who received UFH or LMWH for DVT prophylaxis prior to randomization 
can be enrolled. The use of anticoagulants for post-stroke DVT prophylaxis after 
randomization is prohibited. For post-stroke DVT prophylaxis, non-pharmacological 
prophylaxis (i.e. intermittent pneumatic compression) is recommended.

Anticipated concomitant chronic (>14 days) use of systemic nonsteroidal anti-inflammatory 
drugs (NSAIDs). NSAID (including COX-2 inhibitors) use prior to randomization is allowed.

Use of combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors or combined P-gp and 
strong CYP3A4 inducers in the 7 days prior to randomization, or the need for ongoing 
treatment with concomitant oral or intravenous therapy with combined P-gp and strong 
CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inducers during the study. A list of 
combined P-gp and strong CYP3A4 inhibitors is attached as Appendix 11. A list of combined 
P-gp and strong CYP3A4 inducers is attached as Appendix 12.

Planned concomitant use of omeprazole or esomeprazole after randomization for the duration 
of clopidogrel treatment (eg, H2 blockers [except cimetidine] and other PPIs are allowed).

History of or any of the following findings on 12-lead ECG prior to study drug administration: 
atrial fibrillation, atrial flutter, complete heart block, or Mobitz 2 second-degree heart block.

Known SARS-CoV-2 infection within 4 weeks prior to screening.
Note: To be considered for enrollment, symptoms must have completely resolved and based 
on investigator assessment in consultation with the Medical Monitor/Clinical Trial Physician, 
and there are no sequelae that would place the participant at a higher risk of receiving 
investigational treatment.
The following table outlines the objectives and endpoints for the study. Definitions and details 
related to study endpoints can be found in the Study Events Assessment Manual.
Objective
Endpoints
Primary
To estimate the dose-response relationship of 
BMS-986177 in participants with ischemic stroke or 
TIA treated with aspirin and clopidogrel
Composite of new ischemic stroke during the treatment 
period and new covert brain infarction (FLAIR + DWI) 
detected by MRI at Day 90 (MRI assessed by central 
review)
Revised Protocol No.: 06
Date: 09-Oct-2020
25
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Objective
Endpoints
Secondary
To assess the rate of major bleeding after treatment 
with BMS-986177 relative to placebo
Event rate based on bleeding according to Bleeding 
Academic Research Consortium (BARC) Type 3 and 5
To assess the rate of all bleeding after treatment with 
BMS-986177 relative to placebo
Event rate based on BARC, ISTH and PLATO-defined 
criteria
To compare the rate of the composite of new ischemic
stroke and new covert brain infarction detected by 
MRI at Day 90 during treatment with BMS-986177 
compared to placebo
Rate of the composite of new ischemic stroke during the 
treatment period and new covert brain infarction 
(FLAIR + DWI) detected by MRI at 90 days
To assess the effect of BMS-986177 on characteristics 
of brain lesions on Day 90 MRI
Location, number, and volume of new FLAIR + DWI 
lesions
To compare the rate of the composite of new ischemic
stroke, myocardial infarction (MI) and all-cause 
mortality during treatment with BMS-986177 vs.
placebo
Event rates for new ischemic, non-fatal stroke, non-fatal 
MI, and all-cause death during the treatment period
To assess stroke severity, neurological, and cognitive 
function following BMS-986177 treatment vs.
placebo
National Institutes of Health Stroke Scale (NIHSS), 
Modified Rankin Scale (mRS), Montreal Cognitive 
Assessment (MoCA), and Digit Symbol Substitution 
Test (subtest of WAIS-IV) at baseline, on Days 21 and 
90, and at the time of a new stroke event
To assess the safety and tolerability of BMS-986177
Adverse events, vital signs, physical exams, 
electrocardiogram (ECG) and clinical laboratory results
To assess the pharmacokinetics (PK) of BMS-986177 
and potential effects of covariates on exposure
Estimated clearance (CL) and volume of distribution 
(Vd) and effect of body weight, age, gender, race, renal 
function, liver function, concomitant medications
To assess the dose-response of BMS-986177 on 
pharmacodynamic (PD) biomarkers
% change from baseline in aPTT and Factor XI clotting 
activity during treatment
Exploratory
To assess the effect of BMS-986177 on characteristics 
of cerebral microbleeds (CMBs), hemorrhagic 
transformation of ischemic stroke and asymptomatic 
intracranial bleeding on Day 90 MRI
Incidence and characteristics of CMBs, hemorrhagic 
transformation of ischemic stroke and asymptomatic 
intracranial bleeding on Day 90 MRI
To explore the exposure-response (E-R) relationship 
of BMS-986177 on efficacy endpoints
New ischemic, non-fatal stroke, non-fatal MI, and all-
cause death during the treatment period
To explore the E-R relationship of BMS-986177 on 
major bleeding
Bleeding according to BARC Type 3 and 5 definitions
To assess the PK of clopidogrel (and metabolites), 
aspirin and salicylic acid
Clopidogrel (and metabolites), aspirin and salicylic acid
plasma concentrations
To explore the E-R relationship of BMS-986177 on 
aPTT and Factor XI clotting activity
Change from baseline in aPTT and Factor XI clotting 
activity during treatment
To explore biomarkers related to FXI pathway, stroke, 
thrombosis/hemostasis, inflammation and 
cardiovascular diseases, and their relationship to 
BMS-986177 treatment and selected endpoints
These markers may include, but are not limited to: 
plasma D-dimer, PT, F1.2, and Factor XI antigen.
Revised Protocol No.: 06
Date: 09-Oct-2020
26
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Overall Design:
The study is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, dose-ranging 
trial. Eligible participants will be screened for potential inclusion into the study as soon as possible 
after presentation and randomized within 48 hours of the index event.
Following signing of informed consent, participants will be randomized to receive BMS-986177 
or placebo, plus open-label uncoated aspirin 100 mg in combination with clopidogrel (a loading 
dose followed by maintenance doses) for the next 21 days. Participants will continue treatment 
from Day 22 through Day 90 with BMS-986177 or placebo, plus open-label 100-mg uncoated 
aspirin only. 
Aspirin and clopidogrel will be given open-label as a background therapy according to the 
following scenarios:
1) Prior to signing informed consent:

Participants who have received a single open-label clopidogrel loading dose of between 
300 mg and 600 mg as standard-of-care prior to obtaining informed consent can be enrolled 
in the study. No additional loading dose of clopidogrel is required for such participants
after randomization. 

Following a standard-of-care clopidogrel loading dose, the standard-of-care clopidogrel 
daily dose of 75 mg will be taken the next day, and it can be taken prior to randomization. 

Participants who report taking chronic clopidogrel also require a 300-mg clopidogrel 
loading dose unless the investigator can verify that the participant has taken the daily dose 
for at least the preceding 3 days.
2) Prior to randomization and after signing informed consent:

Following signing of informed consent, a 300-mg loading dose of clopidogrel and 100 mg 
aspirin may be assigned for immediate treatment upon consenting the participant and 
registering the participant in Interactive Response Technology (IRT), if considered 
clinically appropriate. Daily 75 mg clopidogrel and 100 mg daily aspirin will be started the 
next day.
3) After randomization:

A clopidogrel loading dose of 300 mg along with 100 mg aspirin will be administered after 
randomization on Day 1 for participants who have not received any clopidogrel loading 
dose. 
For participants who have received at least 75 mg aspirin as standard of care before randomization, 
and if this dose was taken on the same day as randomization, then no additional aspirin is required 
on Day 1. In this case, 100 mg daily aspirin should be started in the morning of Day 2.
A baseline MRI will be performed within 48 hours of the onset of the index event, and prior to 
randomization. The first dose of double-blind study medication (BMS-986177 or placebo) should
be taken as soon as possible after the baseline MRI assessment, preferably within 2 hours, but no 
Revised Protocol No.: 06
Date: 09-Oct-2020
27
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
longer than 6 hours. If outside of the 6-hour post-MRI window, the investigator should call the 
Medical Monitor for guidance. In instances where the baseline MRI is completed after 48 hours 
from the onset of the index event, the first dose of study medication should still be taken 
immediately after randomization and within 48 hours from the onset of the index event.
BMS-986177 or placebo will be taken twice daily (BID), once in the morning (between
6AM - 9AM) and again in the evening (between 6PM - 9PM).
An MRI of the brain will be performed on Day 90 ± 6 days (based on randomization on Day 1) 
All participants should remain on study treatment until the Day 90 MRI is performed up to Day 
96. 
Screening Period:

All study assessments should occur within the first 48 hours of the index event, following 
participant consent.

Within 48 hours of the onset of the index event, and prior to randomization, participants will 
have a baseline MRI (may be same as clinical MRI) whenever possible. If the baseline MRI 
cannot be performed within 48 hours of the index event and before randomization, it can be 
performed after randomization but must be performed within 72 hours of the index event and 
up to 24 hours after randomization. In instances where the baseline MRI is completed after 
48 hours from the onset of the index event, the first dose of study medication should still be 
taken immediately after randomization within 48 hours from the onset of the index event.

Within 48 hours of the onset of the index event, and prior to randomization, all participants 
will have a Doppler ultrasound, CTA, MRA, or catheter angiography to assess for the presence 
of intracranial or cervical arterial atherosclerotic plaque, ulceration, or thrombus that is 
proximal to the index lesion. Use of available vascular imaging showing a qualifying lesion 
prior to the stroke event is allowed for participants who cannot complete the vascular imaging 
within 48 hours of the index event.

At screening, the following will be obtained: physical examination, physical measurements, 
local clinical laboratory tests (including pregnancy test for WOCBP), vital signs, ECG, and 
medical history.

The following functional/disease severity assessments are to be completed at screening: 
ABCD2, NIHSS, mRS for eligibility assessment.
Double-blind Treatment Period:

The double-blind treatment period will be from Day 1 to Day 90.

During the initial phase of the study, a minimum of 800 participants will be randomized to one 
of the following 4 doses of BMS-986177: 25 mg daily (QD), 25 mg, 50 mg, or 100 mg twice 
daily (BID), or placebo. Twenty-five percent (25%) of the participants will be randomized to 
the placebo arm and the rest of participants will be randomized equally to the 4 doses of 
BMS-986177.
Revised Protocol No.: 06
Date: 09-Oct-2020
28
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

All participants will be treated with open-label uncoated aspirin, 100 mg QD and clopidogrel, 
75 mg QD (after a single 300 mg clopidogrel loading dose + aspirin 100 mg one day prior), 
for 21 days followed by aspirin alone from Day 22 to Day 90.

On Day 1, prior to the initial dose of study medication, the following will be obtained: central 
clinical laboratory tests for safety, PD samples, exploratory biomarker samples, and optional 
pharmacogenomic samples.

National Institutes of Health Stroke Score (NIHSS), Modified Rankin Scale (mRS), Montreal 
Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (DSST; subtest of 
WAIS-IV) will be collected at baseline (at randomization for NIHSS), on Days 21 and 90, and 
at the time of a new stroke. MoCA and DSST (subset of WAIS-IV) will be read by a third-
party central laboratory blinded to treatment.

A Day 60 visit is required for central clinical safety laboratory sample within a 7-day visit 
window for approximately 450 participants, after which the DMC will determine if such safety 
laboratory assessment will be continued, reduced, or discontinued. The DMC will review 
safety data, including clinical laboratory and any available imaging results when 
approximately 450 participants have completed the Day 21 visit. The DMC will recommend
if further monitoring of Day 60 laboratory samples is needed. The DMC recommendation 
regarding the Day 60 clinical safety laboratory sample will be communicated to investigators
by the study Sponsor.

A telephone contact is required on Day 60 if all the respective assessments have not been 
completed onsite.

Onsite visits will be required on Days 21 and 90 (end-of-treatment visit). At these visits, the 
following will be obtained: central laboratory tests for safety, PK, PD, and exploratory 
biomarkers. 

In the event participants are unable or not permitted to attend an onsite visit due to the 
COVID-19 pandemic, alternative measures can be considered to obtain required visit 
assessments as local regulatory requirements permit.

The randomization of participants to the 200-mg BID dose may occur in a staggered approach 
after a minimum of 800 participants have been randomized. The decision to proceed with the 
200-mg BID dose group will depend on the evaluation of the population, the DMC review of 
efficacy and safety data, and an assessment of whether it is safe to randomize participants to 
that dose group. When approximately 800 participants have been randomized, randomization 
for the placebo group will be used to achieve a 2:1 ratio relative to each treatment arm by the 
end of the study. Once a decision to add the 200-mg BID dose group has been made, 
randomization will be revised to achieve a target 2:1:1:1:1:1 (placebo: 25 mg QD: 25 mg BID: 
50 mg BID: 100 mg BID: 200 mg BID) by the end of this study.

All participants will also have an MRI assessment on Day 90 (6 days) while continuing study 
drug treatment. In the event participants are unable or not permitted to attend the Day 90 visit 
due to the COVID-19 pandemic, the Day 90 MRI may be performed at a local facility provided 
that the study-specific MRI protocol is performed on a scanner pre-approved by the central 
imaging vendor. If the Day 90 MRI cannot be performed at a local facility, it may be performed 
when the participant is able or permitted to access the study site. For these participants, it is 
understood that they may not be taking study medication past Day 96.
Revised Protocol No.: 06
Date: 09-Oct-2020
29
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

A telephone contact to assess efficacy and safety events will be required for all participants.  
For participants completing treatment, this contact will be timed within 7 days after the end of 
the treatment period and after the Day 90 MRI. For participants not completing treatment, an 
MRI is to be scheduled at Day 90, with a telephone contact scheduled 7 days after the Day 90 
MRI; if for any reason a Day 90 MRI is not obtained, then a telephone contact is to be 
performed at Day 97 ± 2. Participants who permanently discontinue study treatment early 
should complete the end-of-treatment assessments, except MRI, at time of study drug 
discontinuation. For these participants, the Day 90 MRI as well as Day 97 visit must be 
completed at the planned visit days. Other Day 90 visit assessments do not need to be 
performed if they already were completed at the end-of-treatment visit. In addition, a follow-
up telephone contact between discontinuation and Day 90 MRI is encouraged for participants 
who permanently discontinue study treatment early.

For participants who withdraw consent for follow-up, there should be documentation of the 
reason for withdrawal. Study staff should explicitly seek information about the possible 
contribution of AEs to the participant’s desire to withdraw and document any AEs that are 
identified in the AE section of the CRF.

Early permanent discontinuation of study medication should be distinguished from withdrawal 
of consent for follow-up visits, telephone contacts, or medical records checks. Participants 
requesting withdrawal from the follow-up should be informed that withdrawal of consent for 
follow-up will result in loss of important information about the benefits and risks of BMS-
986177.
Follow-up Period:

To be discharged from the study, a telephone contact to assess efficacy and safety events will 
be required for all participants. For participants completing treatment, this contact will be timed 
within 7 days after the end of the treatment period and after the Day 90 MRI. For participants 
not completing treatment, an MRI is to be scheduled at Day 90, with a telephone contact 
scheduled 7 days after the Day 90 MRI. If for any reason a Day 90 MRI is not obtained, then 
a telephone contact is to be performed at Day 97 ± 2.
Number of Participants:
Approximately and up to 2350 participants from approximately 30 countries and approximately
380 clinical research sites will be randomized using a competitive enrollment approach.
Treatment Arms and Duration:
Study Drugs for CV010031
Medication
Dose Strength
IP/Non-IP
BMS-986177 Capsule
25 mg
IP
100 mg
IP
Revised Protocol No.: 06
Date: 09-Oct-2020
30
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Study Drugs for CV010031
Medication
Dose Strength
IP/Non-IP
Placebo For BMS-986177 Capsule
NA
IP
Clopidogrel Tablets
75 mg
IP
Uncoated Aspirin Tablets
100 mg
IP
Study Design Schematic:
The enrollment period for this trial will last approximately 36 months.
Data Monitoring Committee (DMC)
An independent DMC, whose activities will be described in a charter, will monitor the study. The 
DMC will be comprised of experienced clinicians, trialists and statistical experts. The DMC will 
review efficacy and safety data at designated times during the trial with the purpose of each review 
defined in the DMC charter. After approximately 450 participants have completed the Day 21 visit, 
the DMC will recommend if the Day 60 central laboratory samples are still needed. The DMC 
recommendation regarding the Day 60 clinical safety laboratory sample will be communicated to
the investigator by the study Sponsor.
The DMC will review efficacy and safety data after a minimum of 800 participants have been 
randomized, and assess whether it is safe to randomize participants to the 200-mg BID dose group.
A list of drug discontinuation criteria for individual participants will be provided in the study 
protocol. Such criteria will include serious bleeding. The DMC will use their clinical and statistical 
judgment to evaluate pertinent trial data and may recommend early termination of an individual 
study arm or the entire trial for important safety concerns that are felt to outweigh potential 
benefits. Details of the DMC activities will be described in a DMC charter.
Revised Protocol No.: 06
Date: 09-Oct-2020
31
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Steering Committee (SC)
The SC will consist of the Lead Investigator, who will serve as SC Chair. Other members will 
include: national leaders from other countries, other experts, and Sponsor representatives. The SC 
will be responsible for scientific aspects of the study and will ensure that the study execution and 
management are of the highest quality. The SC will convene regularly to discuss and report on 
ongoing supervision of the study.
Statistical Considerations
Sample Size: The primary endpoint for this study is the incidence of events within a composite of 
new ischemic stroke during the treatment period and new covert brain infarction (FLAIR + DWI) 
detected by MRI at 90 days. Sample size calculations were performed for detecting a dose-
response effect with the MCP-MOD methodology using simulations with the Dose-Finding 
package in R statistical analysis software. Simulations of 2500 clinical trials were performed, 
assuming a true incidence for placebo of 15%, a plateau shaped dose response relationship with 
maximum relative risk reduction of 32% for BMS-986177 100 or 200 mg BID relative to placebo, 
and reductions of 10%, 17.5%, and 27% for the 25 mg QD, 25 mg BID, and 50 mg BID doses, 
respectively. Candidate models included an Emax model, a logistic model, and an exponential 
model.
Using these assumptions, a total of 2100 participants allocated in a 2:1:1:1:1:1 ratio to placebo and 
BMS-986177, 25-mg QD, 25-mg BID, 50-mg BID, 100-mg BID, and 200-mg BID groups provide 
approximately 80% power to demonstrate a dose-response relationship, with a 1-sided type I error 
of 0.049. Without the 200-mg group, a total of 1800 participants allocated in a 2:1:1:1:1 ratio to 
placebo and BMS 986177, 25-mg QD, 25-mg BID, 50-mg BID, and 100-mg BID groups would 
provide approximately 79% power to demonstrate a dose-response relationship with similar 
pattern, but risk reduction of 32% for BMS-986177 50- or 10-mg BID relative to placebo and 
reductions of 17.5%, and 27% for the 25-mg QD and 25-mg BID doses, respectively. Allowing up 
to 10% of participants who do not have a clinical event and also do not have a Day 90 imaging 
assessment, approximately and up to 2350 participants may be randomized. The frequency and 
reasons for missing data will be evaluated in blinded fashion during the course of the study.
Statistical Analyses: Dose-response relationship will be analyzed based on a generalized Multiple 
Comparisons and Modeling (gMCP-Mod) analysis for the BMS-986177 dose regimens, with 
placebo, and 25 mg QD as the lowest dose added to the ordered BID dose regimens. 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. An Emax 
model, a logistic model, and an exponential model will be used as the candidate models for the 
gMCP-Mod analysis.
Point estimates with 95% confidence intervals for the following event rates will be summarized 
by treatment group.

Composite of new ischemic stroke during the treatment period and new covert brain infarction 
detected by MRI at 90 days
Revised Protocol No.: 06
Date: 09-Oct-2020
32
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Composite of new ischemic non-fatal stroke, non-fatal MI, and all-cause mortality

New ischemic stroke during the treatment period

New covert brain infarction detected by MRI at Day 90

All-cause death

Non-fatal myocardial infarction (MI)
Dose-response analysis for new ischemic non-fatal stroke and the composite of new non-fatal 
stroke, non-fatal MI, and all-cause death will be assessed similar to the primary endpoint analysis.
Location, number, and volume of new FLAIR + DWI lesions will be summarized descriptively by 
treatment group.
Functional/disability/cognitive status assessed by the National Institutes of Health Stroke Score 
(NIHSS), modified Rankin Score (mRS), Montreal Cognitive Assessment (MoCA) and Digit
Symbol Substitution Test (DSST; subtest of WAIS-IV) will be summarized by treatment group.
The event rates for all bleeding will be summarized by treatment group, including point estimates 
with 95% confidence intervals within group. Bleeding events will be summarized by BARC 
category, ISTH (major and CRNM bleeding), and PLATO criteria (major, including life-
threatening and other; minor, and minimal).
Adverse events, vital signs, ECGs, and clinical laboratory results will be summarized by treatment 
group.
Except as otherwise noted, descriptive summaries will use data from all randomized groups, while 
dose-response analyses of primary and secondary endpoints will use data from participants 
randomized to placebo, 25 mg QD, and 25 mg, 50 mg, 100 mg, and 200 mg BID groups.
Revised Protocol No.: 06
Date: 09-Oct-2020
33
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
2
SCHEDULE OF ACTIVITIES
Study assessments and procedures are presented in Table 2-1 and Table 2-2.
Table 2-1:
Screening Period Procedural Outline (CV010031)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Must be signed before any study procedures are initiated. See Appendix 2.
Participant Enrollment
X
Contact Interactive Response Technology (IRT) for participant number assignment and treatment 
assignment.
Inclusion/Exclusion Criteria
X
See Protocol Section 6.1 and 6.2.
Clopidogrel Loading Dose and Aspirin
X
Interactive web/voice response system (IRT) will dispense a 21-day supply of 75 mg clopidogrel and 
100 mg aspirin, inclusive of the initial 300 mg clopidogrel loading dose and 100 mg aspirin.
Upon consenting and registering participant in IRT, a 300 mg loading dose and 100 mg aspirin may 
be assigned for immediate treatment along with daily 75 mg clopidogrel and 100 mg daily aspirin, if 
considered clinically appropriate. For participants who have received at least 75 mg aspirin as standard 
of care before randomization, and if this dose was taken on the same day as randomization, then no 
additional aspirin is required on Day 1. In this case, 100 mg daily aspirin should be started in the 
morning of Day 2. Participants who have received a single loading dose of open-label clopidogrel 
between 300 mg to 600 mg as standard-of-care prior to obtaining informed consent can also be enrolled 
in the study. No additional loading dose of clopidogrel is required for such participants after 
randomization. Following a standard-of-care clopidogrel loading dose, the standard-of-care 
clopidogrel daily dose of 75 mg may be taken prior to randomization. Participants who report taking 
chronic clopidogrel also require a 300 mg clopidogrel loading dose unless the investigator can verify 
that the participant has taken the daily dose for at least the preceding 3 days.
Medical History
X
Revised Protocol No.: 06
Date: 09-Oct-2020
34
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-1:
Screening Period Procedural Outline (CV010031)
Procedure
Screening
Visit
Notes
Assessment of Signs and Symptoms
Clinical MRI or CT for Exclusionary 
Pathology
X
Local assessment of magnetic resonance imaging (MRI) or computed tomography (CT) used to 
identify exclusionary pathology such as lacunar stroke, hemorrhage, arteriovenous malformation 
(AVM) or tumor.
Note: A clinical (standard-of-care) MRI scan can be used as the baseline MRI provided that the clinical 
MRI protocol and scanner have been pre-approved by the central imaging vendor.a
Clinical Vascular Imaging
X
Doppler Ultrasound, CTA, MRA or Catheter Angiography to ascertain the presence of intracranial or 
cervical arterial atherosclerotic plaque, ulceration or thrombus in feeding artery. Use of available 
vascular imaging showing a qualifying lesion prior to the stroke event is allowed for participants who 
cannot complete the vascular imaging within 48 hours of the onset of the index event.

Note: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible. 
Participants with complete occlusion of a cervical carotid or an intracranial artery that is proximal 
to the index lesion should be excluded.
ABCD2 for TIA
X
ABCD2 Score ≥6 or motor symptoms (see Section 9.4.2 and Appendix 6).
Modified Rankin Scale (mRS)
X
Pre-morbid mRS must be 3 (ie, before index event); to assess degree of disability or dependence in 
daily activities (see Section 9.4.3 and Appendix 7)
Full Physical Examination
X
See Protocol Section 9.2.13.
Physical Measurements
X
Height (screening only) and weight.
Vital Signs
X
Seated blood pressure and heart rate measured after the participant has been resting quietly for at least 
5 minutes and before blood collection (see Section 9.2.14).
Concomitant Medication Use
X
All medications within 7 days prior to randomization (see Section 7.7).
Revised Protocol No.: 06
Date: 09-Oct-2020
35
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-1:
Screening Period Procedural Outline (CV010031)
Procedure
Screening
Visit
Notes
Clinical Laboratory Tests
X
Screening clinical laboratory tests to assess eligibility, per inclusion/exclusion criteria, to be conducted 
locally and listed below (see Section 6 and Section 9.2.16). Laboratory samples collected as standard-
of-care after the onset of the index event and prior to signing informed consent can be used to assess 
eligibility if meeting protocol-specified requirements. Results from the screening labs should be faxed 
or scanned and emailed to 
.
The following screening laboratory tests should be performed locally to assess eligibility and review 
should be documented prior to randomization:
eGFR ≥15 ml/min/1.73m2
Hemoglobin ≥9 g/dL
Platelets count ≥100,000 mm3
aPTT ≤1.4 x ULN
INR < 1.5
AST or ALT ≤3 x ULN
Negative urine pregnancy test for WOCBP
Pregnancy Test (WOCBP Only)
X
Pregnancy test to be done locally at screening.
All WOCBP must have a negative pregnancy test every 30 days (see Protocol Section 6.1 and 
Appendix 4).
Electrocardiogram (ECG)
X
12-lead ECG should be recorded after the participant has been supine or recumbent for at least 5 
minutes and before blood collection (see Section 9.2.15).
Serious Adverse Event (SAE)
X
All SAEs should be collected from the date of written consent through the follow-up period (see Table 
2-2, Section 9.2.2, and Appendix 3). Labs performed locally for assessment of SAEs should have 
reports faxed or scanned and emailed to 
.
Revised Protocol No.: 06
Date: 09-Oct-2020
36
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
Study-specific MRI
Xe
X
The baseline MRI should be acquired within 
48 hours of the index event and prior to 
randomization on Day 1. If the baseline MRI 
cannot be performed within 48 hours of the 
index event and before randomization, it can 
be acquired after randomization but must be 
performed within 72 hours of the index event 
and up to 24 hours after randomization. In 
order to randomize a participant prior to the 
baseline MRI, other neuroimaging (CT or 
MRI) must be performed to assess eligibility.
The protocol-required MRI sequences will be 
defined in the imaging manual.
A second MRI will be performed on Day 90 
± 6 days (based on randomization on Day 1) 
to accommodate scheduling and scanner 
availability. Sites are encouraged to schedule 
the Day 90 MRI at the time of the baseline 
visit. All participants should remain on study 
treatment until the Day 90 MRI is performed 
up to Day 96. 
In the event that participants are unable or 
not permitted to attend the Day 90 visit at the 
study site due to the COVID-19 pandemic, 
the Day 90 MRI may be performed at an 
external facility provided that the MRI 
protocol and scanner have been pre-approved 
by the central imaging vendor. In the event 
Revised Protocol No.: 06
Date: 09-Oct-2020
37
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
the Day 90 MRI cannot be performed within 
the + 6-day window, the Day 90 MRI can be 
performed after the + 6-day window using 
the study site or an external facility MRI 
scanner. For these participants, it is 
understood that they may not be taking study 
medication past Day 96 (see Section 9.2.12).
Central Safety Laboratory Tests
Xf
X
X
X
Safety labs: Serum chemistry and 
hematology (see Section 9.2.16).
Clopidogrel Loading Dose and 
Aspirin
X
A clopidogrel loading dose is required for 
study participation. More specifically:
Clopidogrel loading dose of 300 mg and 100 
mg aspirin will be administered after 
randomization on Day 1.
Clopidogrel loading dose of 300 mg and 100
mg aspirin may be assigned for immediate 
treatment along with daily 75 mg clopidogrel 
and 100
mg aspirin upon consenting 
participant and registering participant in IRT, 
if considered clinically appropriate
Participants who have received a single 
loading dose of open-label clopidogrel 
between 300 mg to 600 mg as standard of care 
prior to obtaining informed consent can also 
be enrolled in the study. No additional loading 
dose of clopidogrel is required for such 
participants after randomization. Following a 
Revised Protocol No.: 06
Date: 09-Oct-2020
38
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
standard-of-care clopidogrel loading dose, the 
standard-of-care clopidogrel daily dose of 75 
mg may be taken prior to randomization.
Participants who report taking chronic 
clopidogrel also require a 300 mg clopidogrel 
loading dose unless the investigator can 
verify that the participant has taken the daily 
dose for at least the preceding 3 days.
Participants who have received at least 75 mg 
aspirin 
as 
standard 
of 
care 
before 
randomization and this dose was taken on the 
same day as randomization, then no additional 
aspirin is required on Day 1. In this case, 100
mg daily aspirin should be started in the 
morning of Day 2.
Randomize Participant
X
Participant MUST be randomized within 48 
hours of the onset of the index event.
Full Physical Examination
X
See Section 9.2.13.
Brief Physical Assessment
X
Includes organ systems pertinent to the 
participant’s signs, symptoms, or adverse 
events, 
e.g., 
assessment 
of 
signs 
of 
thromboembolism and bleeding.
Physical Measurements
X
Weight only.
Revised Protocol No.: 06
Date: 09-Oct-2020
39
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
Vital Signs
X
X
Seated blood pressure and heart rate measured 
after the participant has been resting quietly 
for at least 5 minutes, and before blood 
collection (see Section 9.2.14).
Concomitant Medication Use
X
X
X
See Section 7.1.
National Institutes of Health 
Stroke Scale (NIHSS)g
Xe
X
X
To assess neurological impairment
(see 
Section 9.4.1 and Appendix 5); must be at 
time of randomization.
Modified Rankin Scale (mRS)g
X
X
To assess degree of disability or dependence 
in daily activities (see Section 9.4.3 and 
Appendix 7).
Montreal Cognitive Assessment 
(MoCA)g
Xh
X
X
To assess cognitive dysfunction, the MoCA 
instrument will be completed by the clinical
site and sent to a third-party central laboratory 
for evaluation (see
Section
9.4.4
and 
Appendix 8).
Digit Symbol Substitution Test 
(subtest of WAIS-IV)g
Xh
X
X
To assess cognitive dysfunction, the DSST 
(subset of WAIS-IV) instrument will be 
completed by the clinical site and sent to a 
third-party central laboratory for evaluation
(see Section 9.4.4 and Appendix 9).
Pregnancy Test
(WOCBP Only)
X
X
All WOCBP must have a negative pregnancy 
test every 30 days (see Section 6.1 and 
Appendix 4).  
Revised Protocol No.: 06
Date: 09-Oct-2020
40
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
ECG
X
X
12-lead ECG should be recorded after the 
participant has been supine or recumbent for 
at least 5 minutes and before blood collection 
(see Section 9.2.15).
Adverse Event (AE) Reporting
X
X
X
X
X
NSAE collection begins after randomization 
through the follow-up period (see Section 
9.2.2 and Appendix 3).
Serious Adverse Event (SAE) 
Reporting
X
X
X
X
X
SAEs collection after written consent through 
the follow-up period. SAEs must be followed 
up until resolution or stabilization (see 
Sections 9.2.2, 9.2.3, and 9.2.5 and Appendix 
3). Labs performed locally for assessment of 
SAEs should have reports faxed or scanned 
and emailed to 
.
Pharmacokinetic (PK)
Assessment for BMS-986177i
X
X
X
See Section 9.3.1.
Pharmacokinetic (PK) 
Assessment for Clopidogrel and 
Aspirini
X
Xj
See Section 9.3.1.
Pharmacodynamic (PD) 
Biomarker Sampling (PT, aPTT,
and FXI Clotting Activity)i
Xf
X
X
See Section 9.3.2.
Revised Protocol No.: 06
Date: 09-Oct-2020
41
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
Blood for F1.2 and D-dimer
Xf
X
X
See Section 9.3.2.
Plasma and Serum Exploratory 
Biomarker Assessments
Xf
X
X
See Section 9.3.2.
FXI Antigen 
Xf
See Section 9.3.2.
Whole Blood for DNA 
X
Day 1 pre-dose. If sample is not collected on 
Day 1, it can be collected at any time during 
the study; only one sample is required per 
participant (see Section 9.3.2).
Note:
Collected only in participants in 
countries and
sites where genetic 
testing is allowed and who opt in to 
genetic testing as captured on an ICF.
Study Medication Compliance
X
X
X
BMS-986177, 
placebo,
clopidogrel and 
aspirin (see Section 7.6).
Dispense Study Medication
X
Xk
The first dose of study medication (BMS-
986177 or placebo) should be taken as soon 
as possible after the baseline MRI 
assessment, preferably within 2 hours, but no 
longer than 6 hours. If outside of the 6-hour 
post-MRI window, the investigator should 
call the Medical Monitor for guidance.
If the baseline MRI is completed after 
48 hours from the onset of the index 
Revised Protocol No.: 06
Date: 09-Oct-2020
42
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 2-2:
Post-Screening Procedural Outline (CV010031)
Procedure
Day 1
Onsite
Visit
Day 21
Onsite
Visita
(2 days)
Day 60
Onsite/Phone 
Visita,b
(7 days)
Day 90 
Onsite Visita,c
(6 days)
(End-of-
Treatment)
Day 97
Phone Visitd
(2 days)
(End-of-Study)
Notes
event,the first dose of study medication 
should still be taken immediately after 
randomization within 48 hours from the 
onset of the index event.
Study Medication Collection
X
Participant 
should 
return 
all 
study 
medication/supplies.
a  In the event participants are unable or not permitted to attend an onsite visit due to the COVID-19 pandemic, alternative measures can be considered to obtain required visit 
assessments as local regulatory requirements permit.
b  Day 60 site visit for central clinical safety laboratory testing can occur separate from the phone visit within the ±7-day visit window. If all Day 60 required assessments can be 
completed onsite, then a phone visit is not required. If the DMC makes a recommendation to discontinue Day 60 lab assessments at the milestone defined in Section 5.1.1, the 
Day 60 visit will only be a telephone contact. The Sponsor will notify investigators on the decision of the DMC.
c  If study treatment is discontinued early, the participant is expected to complete the end-of-treatment assessments, except MRI, at time of study drug discontinuation. For these 
participants, the Day 90 MRI (± 6 days) as well as Day 97 (± 2 days) visit must be completed at the planned visit days. Other Day 90 visit assessments do not need to be performed 
if they already were completed at an end-of-treatment visit.
d  7 days after Day 90 MRI. If for any reason a Day 90 MRI is not obtained, then a telephone contact is to be performed at Day 97 ± 2.
e To be conducted prior to randomization. Refer to notes regarding study-specific MRI for instances where the baseline MRI is performed outside of the 48-hour window and the 
Day 90 MRI is performed outside of the 6-day window.
f  To be conducted prior to first dose of study medication.
g  In addition to the times specified in this table, assessments are to be obtained at the time of a new stroke (see Appendix 5, 7, 8, and 9).
h  May be collected within 48 hours of Day 1.
i Sample should be obtained within 48 hours of new stroke or major bleeding event.
Revised Protocol No.: 06
Date: 09-Oct-2020
43
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
j Sample to be collected for aspirin only.
k  Unused Day 1 blister card of study medication and open-label aspirin must be re-dispensed at Day 21.
Revised Protocol No.: 06
Date: 09-Oct-2020
44
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
3
INTRODUCTION
Stroke is a leading cause of death and disability worldwide. Ischemic brain infarction is the most 
common type of stroke (~80%). Primary brain hemorrhage is a less common cause of stroke 
(~20%) but is associated with considerable morbidity and mortality. Stroke incidence is strongly 
linked to age and stroke prevalence is increasing due to the ageing global population. 
Thromboembolism is common to almost all types of ischemic strokes so that inhibition of 
thrombosis is a pivotal intervention for stroke prevention. About 1.5 million people have ischemic 
strokes annually in North America and Europe and about 18 million people worldwide.1
The risk of recurrent cerebrovascular events is high in patients who have had a stroke or transient 
ischemic attack (TIA). The risk of recurrent stroke is particularly high during the initial 90 days 
following ischemic stroke or TIA. Pooled analyses of observational studies completed in 2007,
suggested the early risk of stroke was 9.9%, 13.4%, and 17.3% at 2, 30, and 90 days, 
respectively.2,3 Development of specialized acute stroke centers and preventive services have 
decreased the recurrence rate but it remains unacceptably high. In two recent clinical trials that 
investigated patients with acute ischemic stroke, the risk of recurrent stroke was 7 to 12% despite 
treatment with aspirin and other secondary prevention interventions.4,5 In patients with acute TIA, 
the rate of subsequent ischemic stroke is somewhat lower, but still high, 4% to 9% at 90 days.2,3,5
The clinical, time-based definition of TIA has been updated to now include imaging to exclude 
evidence of tissue damage, but the traditional time-based definition is still commonly used in 
practice.6 Clinically defined TIA and stroke form part of a risk continuum and risks of early 
recurrent stroke, MI and vascular death are similar.7,8,9
Accumulating evidence suggests that for patients with strokes associated with large vessel 
atherosclerosis (CARESS10, CLAIR11) and for patients in whom treatment can be initiated within 
12-24 hours after an acute minor stroke or TIA (CHANCE12, POINT13), treatment with aspirin 
and clopidogrel is more effective than aspirin alone in reducing asymptomatic microembolic 
signals and the risk of recurrent stroke.
A meta-analysis of data from the CARESS and CLAIR trials below (Figure 3-1) shows that the 
combination of aspirin and clopidogrel is more effective than monotherapy in reducing the risk of 
ischemic stroke associated with large vessel atherosclerosis.
Figure 3-1:
Meta-analysis Number of Patients with Recurrent Stroke in CARESS 
and CLAIR for Dual Antiplatelet Therapy vs Monotherapy
Revised Protocol No.: 06
Date: 09-Oct-2020
45
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
As shown in Table 3-1, the risk of recurrent ischemic stroke at 90 days with aspirin and clopidogrel 
was considerable in both CHANCE and POINT and the rate of bleeding was higher with 
combination therapy than with aspirin alone.
Table 3-1:
Rates of Ischemic Stroke and Bleeding in POINT and CHANCE 
Studies
Study
Event
Aspirin (%)
Aspirin + Clopidogrel (%)
CHANCE12
Ischemic Stroke
11.4
7.9
Severe Bleeding
0.2
0.2
Any Bleeding
1.6
2.3
POINT13
Ischemic Stroke
6.3
4.6
Symptomatic ICH
0.1
0.1
Major Hemorrhage not ICH
0.3
0.7
Minor Bleeding
0.5
1.6
Despite the improved efficacy of aspirin and clopidogrel compared to aspirin alone, the residual 
high risk of recurrent stroke and the higher risk for bleeding with combination therapy highlight 
the need for a safe and more effective treatment option.
3.1
Study Rationale
A pooled analysis of individual patient data from all randomized trials of aspirin vs. control for 
secondary prevention after TIA or ischemic stroke as a function of time after the index event, 
confirmed that medical treatment reduces the risk and severity of early recurrent stroke and that 
aspirin was the key intervention. Intensification of antiplatelet therapy by adding a P2Y12 inhibitor 
to aspirin treatment resulted in increased efficacy, but at the cost of more bleeding complications.
Factor Xa inhibitors have recognized therapeutic impact on thrombotic diseases through dose-
dependent inhibition of the tissue factor-activated coagulation process. Increasing doses of FXa 
inhibitors cause progressively more inhibition of hemostasis and efficacy, until bleeding risks limit 
further increases in FXa doses. Adding a FXa inhibitor to maximized antiplatelet treatment 
improves efficacy outcomes (as seen below with the COMPASS results) but, again, at the cost of 
additional bleeding which is a major concern among clinicians when considering antithrombotic 
therapy in patients with stroke and threatened stroke.
3.1.1
Novel Antithrombotic Mechanism of BMS-986177
BMS-986177 (also known as JNJ-70033093) is a small molecule that binds and inhibits the 
activated form of human coagulation Factor XI (Factor XIa) with high affinity and selectivity. The
Revised Protocol No.: 06
Date: 09-Oct-2020
46
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
scientific evidence accumulated to date suggest that inhibition of FXIa may provide a novel 
mechanism for inhibiting intravascular thrombus formation with limited impact on hemostasis.14
The rationale for this study is that Factor XIa inhibition has the potential to reduce thrombin 
generation enough to prevent vascular occlusion and embolism without impairing hemostasis.
Whereas Factor Xa inhibitors block the tissue factor-activated coagulation process required for 
hemostasis, Factor XIa inhibition blocks thrombus formation through the “contact” system, which
is not required for normal hemostasis but appears to contribute to pathological thrombus formation.
The following observations support this concept: (1) the highest levels of Factor XI activity are
associated with a heightened risk of ischemic stroke15,16,17; (2) lower levels of Factor XI activity
are associated with a reduced risk of ischemic stroke18,19,20; (3) Factor XI deficiency is rarely 
associated with unprovoked major bleeding21; (4) although not done in patients with stroke, a 
Phase 2 study for VTE prophylaxis in patients post total knee replacement provides a proof of 
concept. The study showed that reducing FXI levels to 20% or less than normal with an antisense 
inhibitor of FXI synthesis reduced the risk of postoperative VTE compared to enoxaparin, without 
an increase in bleeding compared to enoxaparin.14 In patients with ESRD on hemodialysis, single 
doses of 100 mg and 300 mg BMS-986177 reduced clot formation in the hemodialysis circuits, 
and was not associated with serious bleeding.22
The high residual risk for recurrent stroke seen in the POINT and CHANCE studies (see Table 3-
1), even when patients are treated with combination of aspirin and clopidogrel, emphasizes the 
continuing need for a more effective therapeutic option. Two possible strategies for achieving 
better efficacy are: (1) more potent antiplatelet therapy. (2) dual pathway inhibition of thrombosis.
3.1.2
More Potent Antiplatelet Therapy
The SOCRATES trial23 tested the hypothesis that treatment with more potent antiplatelet therapy
with ticagrelor would be more effective than treatment with aspirin in patients with TIA or acute 
minor ischemic stroke. The trial compared ticagrelor (a direct-acting P2Y12 receptor inhibitor 
antiplatelet agent) vs. aspirin 100 mg/day. The 11% reduction in the primary outcome (stroke, 
myocardial infarction, cardiovascular death) with ticagrelor compared to aspirin was not 
statistically significant (p = 0.07).
A pre-specified exploratory subgroup analysis of the data from the SOCRATES trial23 showed a 
significant treatment-by-subgroup interaction suggesting that the risk for the composite endpoint 
of stroke, myocardial infarction, or death was lower with ticagrelor than aspirin in patients with 
symptomatic ipsilateral stenosis than in those without ipsilateral stenosis in whom the risk for the 
composite endpoint was similar with ticagrelor and aspirin. The investigators suggested that this 
analysis provides empirical evidence of the importance of an understanding of the stroke 
mechanism and cause in the selecting therapy for early stroke prevention
3.1.3
Dual Mechanisms of Thrombosis Inhibition
Support for this strategy was provided by the recently published results of the Cardiovascular 
Outcomes for People Using Anticoagulation Strategies (COMPASS24) trial in which 27,395
Revised Protocol No.: 06
Date: 09-Oct-2020
47
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
patients with stable coronary artery atherosclerosis or peripheral artery atherosclerosis (but without 
recent stroke) were randomly assigned to receive rivaroxaban 5 mg twice daily (BID), rivaroxaban 
2.5 mg BID plus aspirin, or aspirin alone. An analysis for the tertiary outcome of ischemic stroke 
or uncertain type of stroke showed a relative risk reduction of 49% (absolute risk 
reduction = 0.7%) with low-dose rivaroxaban plus aspirin vs. aspirin alone (nominal p <0.001). 
Major bleeding increased by 70% (absolute risk increase = 1.2%) with rivaroxaban 2.5 mg BID 
plus aspirin compared to aspirin alone.24
A recent analysis of the patients in COMPASS who had a prior stroke (3.8%=1,041) showed that 
the annual rate of ischemic stroke was reduced from 3.4% with aspirin alone compared to 0.7%
with rivaroxaban plus aspirin [HR = 0.42 (0.19-0.92), nominal p = 0.03)].25 In addition to a 
reduction in MACE, a substantial reduction in recurrent ischemic stroke in COMPASS was also 
observed indicating that the combination of antiplatelet therapy with an anticoagulant has the 
potential to be more effective than antiplatelet therapy or anticoagulation alone for secondary 
stroke prevention.
Although the combination of a low dose of rivaroxaban combined with aspirin showed superior 
efficacy, the risk of bleeding increased more than the risk reduction for ischemic stroke. This result 
is attributable to the mechanism by which rivaroxaban and other Factor Xa inhibitors reduce 
thrombosis: dose-dependent inhibition of the tissue factor-activated coagulation process which is 
required for hemostasis. Increasing doses of FXa inhibitors cause progressively more inhibition of 
hemostasis which can predispose to bleeding. In contrast to FXa inhibition which impairs 
hemostasis, FXIa inhibition blocks thrombus formation without impairing hemostasis. The rarity 
of serious bleeding in people with severe FXI deficiency is consistent with the lack of a significant 
effect of severely reduced FXI activity on hemostasis.20
Accordingly, the combination of BMS-986177 with antiplatelet therapy has the potential to 
provide superior efficacy for reducing thromboembolic events without predisposing to serious 
bleeding.
3.1.4
Selection of Treatments
Identification of the putative mechanism of stroke is critical for selecting the treatment that is most 
likely to be effective. The totality of evidence from clinical trials to date support the use of more 
intensive antiplatelet therapy than treatment with aspirin alone to reduce the risk of stroke 
associated with atherosclerosis in the major cerebral arteries and aortic arch.
Accordingly, in this study, in a population with acute ischemic stroke associated with large vessel 
atherosclerosis, the combination of aspirin and clopidogrel will be used as a background therapy. 
The combination of a wide range of doses of BMS-986177 with aspirin and clopidogrel is expected 
to provide a robust dose-response relationship and to identify one or more doses that will provide 
improved efficacy without an increased risk of bleeding that exceeds absolute risk reduction for 
the composite endpoint of new ischemic stroke and new covert brain infarction.
Revised Protocol No.: 06
Date: 09-Oct-2020
48
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
3.2
Background
3.2.1
Phase 1 and 2a Studies with BMS-986177
BMS-986177 is currently being investigated in a number of studies in humans including: (1) single 
ascending and multiple ascending dose study; (2) drug-drug interactions with itraconazole, 
diltiazem, rifampin, aspirin, and aspirin plus clopidogrel; (3) clinical pharmacology studies of 
special populations including participants with end-stage renal disease (ESRD) undergoing 
hemodialysis, participants with renal impairment, and participants with hepatic impairment; (4) 
relative bioavailability and (5) Japanese PK study. To date, no dose-limiting safety findings have 
been observed in these studies.
The first-in-human (FIH) study with BMS-986177 investigated single oral doses between 4 - 500 
mg and multiple oral doses between 5 - 500 mg over a 14-day period. In the single-dose portion 
of the study, dose-proportionality was observed between 20 - 200 mg QD with no greater increase 
in exposure observed at 300 mg, believed to be due to solubility-limited absorption. 
Co-administration of a high-fat diet at 200 mg and 500 mg was associated with ~1.2-fold and ~2-
fold increases in exposure, respectively. Table 3.2.1-1 summarizes the clinical pharmacology of 
BMS-986177.
Table 3.2.1-1:
Highlights of Clinical Pharmacology after Oral Administration of 
Single and Multiple Doses of BMS-986177 to Healthy Participants 
and Participants with Renal or Hepatic Impairment
PK Properties
BMS-986177 Clinical PK Results
Tmax
2 to 4 hours in a fasted state with rapid absorption and quick onset of PD effect
Half-life (T1/2)
~11 hours (terminal T1/2); supports BID or QD dosing
Accumulation 
Index (AI)
Minimal accumulation: AI = 1.13 to 1.40 for AUC (dose range 20 to 200 mg in MAD 
study; for QD dosing only)
Exposure
Average Cmax: 15.4 to 7595 ng/mL;
Average AUC:172 to 95110 nghr/mL
Dose 
Proportionality
Single oral doses: greater than dose proportional from 4 to 20 mg; dose proportional 
between 20 and 200 mg
Multiple oral doses: greater than dose proportional from 5 to 20 mg; dose proportional 
between 20 and 200 mg 
Renal Impairment
(normal renal 
function vs. 
moderate or severe 
renal dysfunction)
Renal Clearance: ~10%
Similar Cmax between all renal function groups
When compared to normal renal function (@ eGFR of 90 mL/min/1.73 m2):
- moderate impairment (@ eGFR of 30 mL/min/1.73 m2): 39%in AUC(0-T);
41%in AUC(0-INF)
- severe impairment (@ eGFR of 15 mL/min/1.73 m2 not on dialysis): 50%in AUC(0-T);
54%in AUC(0-INF)
Revised Protocol No.: 06
Date: 09-Oct-2020
49
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 3.2.1-1:
Highlights of Clinical Pharmacology after Oral Administration of 
Single and Multiple Doses of BMS-986177 to Healthy Participants 
and Participants with Renal or Hepatic Impairment
PK Properties
BMS-986177 Clinical PK Results
Hepatic 
Impairment 
(normal hepatic 
function vs mild or 
moderate hepatic 
impairment)

Primarily metabolized in the liver

Similar Cmax and AUC(0-INF) between normal, mild and moderate hepatic impairment 
groups

Compared to normal participants

Mild hepatic impairment (Child Pugh A category): 18% in Cmax and AUC(0-INF)

Moderate hepatic impairment (Child Pugh category B): 14% in Cmax and no 
change in AUC(0-INF)

When accounting for changes in protein binding, the differences in normal participants 
compared to: 

Mild hepatic impairment (Child Pugh A category): 30% in Cmax and 29% in 
AUC(0-INF)

Moderate hepatic impairment (Child Pugh category B): 41% in Cmax and 24% 
in AUC(0-INF)
Food Effect
Small food effect at 200 mg (53% in Cmax; 39% for AUC)
Metabolites
No major or active metabolites
CYP3A4 Inhibitors 
or Inducer DDI
Itraconazole:
150% in AUC; 28% in Cmax
Diltiazem: 
38% in AUC; 9% in Cmax
Rifampin: 
85% in AUC; 78% in Cmax
A multicenter, cross-over, randomized, Phase 2a proof-of-concept study in participants
undergoing hemodialysis for ESRD showed that single doses up to 300 mg of BMS-986177 were 
safe and well tolerated; no serious bleeding or other serious adverse events occurred. Exploratory 
efficacy assessment showed that the extent of clot formation in the hemodialysis circuit was similar 
with BMS-986177 and the active comparators (unfractionated heparin and enoxaparin). This result 
suggests that BMS-986177 has clinically meaningful antithrombotic activity at the doses tested. 
Detailed information on BMS-986177 Phase 1 and Phase 2a studies is provided in the 
Investigator’s Brochure.26
BMS-986177 combined with antiplatelet therapy has the potential to be safe and more effective 
than antiplatelet therapy alone. A drug-drug interaction study (CV01002727) showed that 
BMS-986177 200 mg BID taken with aspirin was safe and well tolerated over a 7-day period in 
healthy participants, and bleeding time did not increase significantly. In another drug-drug 
interaction study in healthy participants, BMS-986177 200 mg was given twice daily (BID) for 5 
days, with and without clopidogrel and aspirin. Clopidogrel was given as 300 mg on Day 1 
followed by 4 days of 75 mg clopidogrel, and 325 mg aspirin was administered once daily [QD] 
for 5 days. There were no serious bleeding events reported from any of the 113 healthy participants 
treated in this study28. A few minor bleeding events (e.g., contusion, venipuncture site bruise, 
gingival bleeding, and anal fissure bleeding) occurred in either subjects who received dual 
antiplatelet treatment plus BMS-986177, or in participants who received dual antiplatelet treatment 
Revised Protocol No.: 06
Date: 09-Oct-2020
50
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
without BMS-986177, or in participants who received mono antiplatelet treatment (either 
clopidogrel or aspirin) alone, indicating no trend towards any treatment arms. These findings are 
consistent with the notion that FXIa inhibition is associated with a low risk of bleeding, and support 
the proposed clinical trial with BMS-986177, aspirin and clopidogrel.
3.3
Benefit/Risk Assessment
Anticoagulation has the potential to cause major bleeding which has been demonstrated in all
clinical trials (SPIRIT29, WARSS30, WASID31, ESPRIT32, ARISTOTLE33, RELY34, ROCKET 
AF35, COMPASS). And the risk of bleeding associated with anticoagulation is heightened by 
concomitant use of aspirin and other antiplatelet drugs (ARISTOTLE33, APPRAISE-236, 
ATLAS-237, COMPASS24). Concern about bleeding is a major obstacle to use of anticoagulation, 
even when clinical trial data show that the absolute risk of bleeding is lower than the risk of 
thromboembolic events.38
A number of scores based on clinical factors (HEMORRHAGES39, ATRIA40, and HAS-BLED41) 
have been developed to predict the risk of major bleeding. However, none of the currently available 
scores are sufficiently accurate in predicting major bleeding in patients with non-valvular atrial 
fibrillation (NVAF) to be used as a rationale to withhold anticoagulation to reduce the risk of 
thromboembolic events, especially stroke.42 In addition, some clinical factors (hypertension, 
stroke, renal impairment) included in bleeding scores also increase the risk of thromboembolic 
events.
DOACs are a major advance in improving the safety of anticoagulation. The risk of intracranial 
hemorrhage, the most devastating kind of bleeding, is at least 50% lower with DOACs compared 
to warfarin in patients with NVAF.43
A recent publication describes uniform definitions of cardiovascular and stroke outcomes 
developed by the Standardized Data Collection for Cardiovascular Trials and Initiatives (SCTI) 
and the U.S. Food and Drug Administration (FDA).44 According to Hicks et al, “The aim is for 
clinical trials to apply the stroke definition to assess the clinically relevant consequences of 
vascular brain injury”.
In the context of the SCTI definition, a clinically meaningful benefit of treatment is not only to 
decrease the number of strokes but also to mitigate the clinical consequences of ischemic brain 
infarction. Since no single outcome measure can describe all the dimensions of brain infarction45, 
we plan to use multiple instruments to assess the clinical consequences of brain infarction: 
National Institute of Health Stroke Scale/Score (NIHSS), modified Rankin Scale (mRS), Montreal 
Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (DSST; subtest of WAIS-IV).
The available preclinical and clinical evidence suggest that direct inhibition of Factor XIa by 
BMS-986177 has the potential to reduce the risk of thromboembolic events with a lower risk of 
major bleeding than currently available DOACs, even in combination with aspirin + clopidogrel, 
thus providing a favorable benefit/risk.
Revised Protocol No.: 06
Date: 09-Oct-2020
51
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
While bleeding was not observed to any significant degree at high doses of BMS-986177 either in 
healthy participants or in patients with ESRD undergoing hemodialysis, there is a potential risk of 
bleeding with any antithrombotic agent. Therefore, participants will be closely monitored for 
bleeding with oversight of the study by an independent Data Monitoring Committee (DMC).
More detailed information about the known and expected benefits and risks, as well as reasonably 
anticipated adverse events (AEs) of BMS-986177, is provided in the Investigator’s Brochure.26
4
OBJECTIVES AND ENDPOINTS
Objectives and endpoints for CV010031 can be found in Table 4-1. Definition and details related 
to study endpoints can be found in the Study Events Assessment Manual.
Table 4-1:
Objectives and Endpoints for CV010031
Objective
Endpoints
Primary
To estimate the dose-response relationship of 
BMS-986177 in participants with ischemic stroke or 
TIA treated with aspirin and clopidogrel
Composite of new ischemic stroke during the treatment 
period and new covert brain infarction (FLAIR + DWI) 
detected by MRI at Day 90 (MRI assessed by central 
review)
Secondary
To assess the rate of major bleeding after treatment 
with BMS-986177 relative to placebo
Event rate based on bleeding according to Bleeding 
Academic Research Consortium (BARC) Type 3 and 5
To assess the rate of all bleeding after treatment with 
BMS-986177 relative to placebo
Event rate based on BARC, ISTH and PLATO-defined 
criteria
To compare the rate of the composite of new ischemic 
stroke and new covert brain infarction detected by 
MRI at 90 days on treatment with BMS-986177 
compared to placebo
Rate of the composite of new ischemic stroke during the 
treatment period and new covert brain infarction
(FLAIR + DWI) detected by MRI at 90 days
To assess the effect of BMS-986177 on characteristics 
of brain lesions on Day 90 MRI
Location, number, and volume of new FLAIR + DWI 
lesions
To compare the rate of the composite of new ischemic
stroke, myocardial infarction (MI) and all-cause 
mortality during treatment with BMS-986177 vs.
placebo
Event rates for new ischemic non-fatal stroke, non-fatal 
MI, and all-cause death during the treatment period
To assess stroke severity, neurological, and cognitive 
function following BMS-986177 treatment vs. 
placebo
National Institutes of Health Stroke Scale (NIHSS), 
Modified Rankin Scale (mRS), Montreal Cognitive 
Assessment (MoCA), and Digit Symbol Substitution 
Test (subtest of WAIS-IV) at baseline, on Days 21 and 
90, and at the time of a new stroke event.
To assess the safety and tolerability of BMS-986177
Adverse events, vital signs, physical exams, 
electrocardiogram (ECG), and clinical laboratory results
To assess the pharmacokinetics (PK) of BMS-986177 
and potential effects of covariates on exposure
Estimated clearance (CL) and volume of distribution 
(Vd) and effect of body weight, age, gender, race, renal 
function, liver function, concomitant medications
Revised Protocol No.: 06
Date: 09-Oct-2020
52
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 4-1:
Objectives and Endpoints for CV010031
Objective
Endpoints
To assess the dose-response of BMS-986177 on 
pharmacodynamic (PD) biomarkers
% change from baseline in aPTT and Factor XI clotting 
activity during treatment
Exploratory
To assess the effect of BMS-986177 on characteristics 
of cerebral microbleeds (CMBs), hemorrhagic 
transformation of ischemic stroke and asymptomatic 
intracranial bleeding on Day 90 MRI
Incidence and characteristics of CMBs, hemorrhagic 
transformation of ischemic stroke and asymptomatic 
intracranial bleeding on Day 90 MRI
To explore the exposure-response (E-R) relationship 
of BMS-986177 on efficacy endpoints
New ischemic non-fatal stroke, non-fatal MI, and all-
cause death during the treatment period
To explore the E-R relationship of BMS-986177 on 
major bleeding
Bleeding according to BARC Type 3 and 5 definitions
To assess the PK of clopidogrel (and metabolites), 
aspirin and salicylic acid
Clopidogrel (and metabolites), aspirin and salicylic acid 
plasma concentrations
To explore the E-R relationship of BMS-986177 on 
aPTT and Factor XI clotting activity
% change from baseline in aPTT and Factor XI clotting 
activity during treatment
To explore biomarkers related to FXI pathway, stroke, 
thrombosis/hemostasis, inflammation and 
cardiovascular diseases, and their relationship to 
BMS-986177 treatment and selected endpoints
These markers may include, but are not limited to: 
plasma D-dimer, PT, F1.2, and Factor XI antigen.
5
STUDY DESIGN
5.1
Overall Design
The study is a multi-center, Phase 2, randomized, double-blind, placebo-controlled, dose-ranging
trial. Eligible participants will be screened for potential inclusion into the study as soon as possible 
after presentation and randomized within 48 hours of the index event.
Following signing of informed consent, participants will receive aspirin 100 mg and a single 
loading dose of clopidogrel 300 mg. Participants will then be randomized to receive BMS-986177 
or placebo, plus open-label uncoated aspirin 100 mg in combination with clopidogrel 75 mg QD 
for the next 21 days. Participants will continue treatment from Day 22 through Day 90 with 
BMS-986177 or placebo, plus open-label 100 mg uncoated aspirin only.
An MRI of the brain will be performed on Day 90 ± 6 days (based on randomization on Day 1). 
All participants should remain on study treatment until the Day 90 MRI is performed up to Day 96. 
The enrollment period for this trial will last approximately 36 months.
Screening Period:

All study assessments should occur within the first 48 hours after the index event, following 
participant consent.
Revised Protocol No.: 06
Date: 09-Oct-2020
53
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

A baseline MRI should be acquired within 48 hours of the index event and prior to 
randomization on Day 1. If the baseline MRI cannot be performed within 48 hours of the index 
event and before randomization, it can be acquired after randomization but must be performed 
within 72 hours of the index event and up to 24 hours after randomization. In instances where 
the baseline MRI is completed after 48 hours from the onset of the index event, the first dose 
of study medication should still be taken immediately after randomization within 48 hours 
from the onset of the index event.

Within 48 hours of the index event, and prior to randomization, all participants will have a 
Doppler ultrasound, computed tomography angiogram (CTA), magnetic resonance angiogram 
(MRA), or catheter angiography to assess for the presence of intracranial or cervical arterial 
atherosclerotic plaque, ulceration, or thrombus that is proximal to the index lesion. Use of 
available vascular imaging showing a qualifying lesion prior to the stroke event is allowed for 
participants who cannot complete the vascular imaging within 48 hours of the index event.

At screening, the following will be obtained: physical examination, physical measurements,
local clinical laboratory tests (including pregnancy test for WOCBP), vital signs, ECG, and 
medical history.

The following functional/disease severity assessments are to be completed at screening for 
eligibility assessment: ABCD2, NIHSS, and mRS.
Double-blind Treatment Period:

The double-blind treatment period will be from Day 1 to Day 90.

During the initial phase of the study, a minimum of 800 participants will be randomized to one 
of the following 4 doses of BMS-986177: 25 mg daily (QD); 25 mg, 50 mg, or 100 mg twice 
daily (BID); or placebo. Twenty-five percent (25%) of the participants will be randomized to 
the placebo arm, and the rest of the participants will be randomized equally to the 4 doses of 
BMS-986177.

All participants will be treated with open-label uncoated aspirin, 100 mg QD, and clopidogrel, 
75 mg QD (after a single 300-mg clopidogrel loading dose + aspirin 100 mg one day prior), 
for 21 days, followed by aspirin alone from Day 22 to Day 90.

On Day 1, prior to the initial dose of study medication, the following will be obtained: central
clinical laboratory tests for safety, PD samples, exploratory biomarker samples, and optional 
pharmacogenomic samples.

Assessments of stroke severity, disability, impact of stroke on daily activities, and cognitive 
function will be collected at times specified in Table 2-1 and Table 2-2.

A Day 60 visit is required for central clinical safety laboratory sample within a 7-day visit 
window for approximately 450 participants, after which the DMC will determine if such safety 
laboratory assessment will be continued, reduced, or discontinued. The DMC will review 
safety data, including clinical laboratory and any available imaging results when 
approximately 450 participants have completed the Day 21 visit. The DMC will recommend
if further monitoring of Day 60 laboratory samples is needed. The DMC recommendation 
regarding the Day 60 clinical safety laboratory sample will be communicated to investigators
by the study Sponsor.

A telephone contact is required on Day 60 if all the respective assessments have not been 
completed onsite.
Revised Protocol No.: 06
Date: 09-Oct-2020
54
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Onsite visits will be required on Days 21 and 90 (end-of-treatment visit). At these visits, the 
following will be obtained: central laboratory tests for safety, PK, PD, and exploratory 
biomarkers.

In the event participants are unable or not permitted to attend an onsite visit due to the COVID-
19 pandemic, alternative measures can be considered to obtain required visit assessments as 
local regulatory requirements permit.

The randomization of participants to the 200-mg BID dose may occur in a staggered approach
after a minimum of 800 participants have been randomized. The decision to proceed with the 
200-mg BID dose group will depend on the evaluation of the population, the DMC review of 
efficacy and safety data, and an assessment of whether it is safe to randomize participants to 
that dose group.

When approximately 800 participants have been randomized, randomization for the placebo 
group will be used to achieve a 2:1 ratio relative to each treatment arm by the end of the study.
Once a decision to add the 200-mg BID dose group has been made, randomization will be 
revised to achieve a target 2:1:1:1:1:1 (placebo: 25 mg QD: 25 mg BID: 50 mg BID: 100 mg 
BID: 200 mg BID) by the end of this study.

All participants will also have an MRI of the brain performed on Day 90 ± 6 (based on 
randomization on Day 1) to accommodate scheduling and scanner availability. Sites are 
encouraged to schedule the Day 90 MRI at the time of the baseline visit. All participants should 
remain on study treatment until the Day 90 MRI is performed up to Day 96. In the event that 
participants are unable or not permitted to attend the Day 90 onsite visit due to the COVID-19 
pandemic, the Day 90 MRI may be performed at an external facility provided that the MRI 
protocol and scanner have been pre-approved by the central imaging vendor. In the event the 
Day 90 MRI cannot be performed within the ± 6-day window, the MRI can be acquired outside 
the + 6-day window using the study site or an external facility MRI scanner. For these 
participants, it is understood that they may not be taking study medication past Day 96.

Investigators will determine the management of participants who have a clinical event during 
the study and assess events, including those lacking an MRI.

A telephone contact to assess efficacy and safety events will be required for all participants.  
For participants completing treatment, this contact will be timed within 7 days after the end of 
the treatment period and after the Day 90 MRI. For participants not completing treatment, an 
MRI is to be scheduled at Day 90, with a telephone contact scheduled 7 days after the Day 90 
MRI; if for any reason a Day 90 MRI is not obtained, then a telephone contact is to be 
performed at Day 97 ± 2.

Any participant who discontinues study drug treatment for any reason during the trial will 
require a Day 90 MRI, followed by the study discharge telephone visit (Day 97 ± 2).

Participants who permanently discontinue study treatment early should complete the end-of-
treatment assessments, except MRI, at time of study drug discontinuation. For these 
participants, the Day 90 MRI as well as Day 97 visit must be completed at the planned visit 
days. Other Day 90 visit assessments do not need to be performed if they already were 
completed at the end-of-treatment visit. In addition, a follow-up telephone contact between
discontinuation and Day 90 MRI is encouraged for participants who permanently discontinue 
study treatment early.
Revised Protocol No.: 06
Date: 09-Oct-2020
55
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

For participants who withdraw consent for follow-up, there should be documentation of the 
reason for withdrawal. Study staff should explicitly seek information about the possible 
contribution of AEs to the participant’s desire to withdraw and document any AEs that are 
identified in the AE section of the CRF.

Early permanent discontinuation of study medication should be distinguished from withdrawal 
of consent for follow-up visits, telephone contacts, or medical records checks. Participants 
requesting withdrawal from the follow-up should be informed that withdrawal of consent for 
follow-up will result in loss of important information about the benefits and risks of 
BMS-986177.
Follow-up Period:

To be discharged from the study, a telephone contact to assess efficacy and safety events will 
be required for all participants. For participants completing treatment, this contact will be timed 
within 7 days after the end of the treatment period and after the Day 90 MRI. For participants 
not completing treatment, an MRI is to be scheduled at Day 90, with a telephone contact 
scheduled 7 days after the Day 90 MRI. If for any reason a Day 90 MRI is not obtained, then 
a telephone contact is to be performed at Day 97 ± 2.
The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical 
laboratory evaluations will be performed at selected times throughout the dosing interval. 
Participants will be closely monitored for AEs throughout the study. Blood samples will be 
collected for PK analysis for up to 24 hours after study drug administration. Approximately 
200 mL of blood will be drawn from each participant during the study.
Revised Protocol No.: 06
Date: 09-Oct-2020
56
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Rationale for Imaging Endpoints
Brain infarction detected by MRI frequently occurs without focal neurological signs or symptoms
associated with acute stroke. The difference between clinically diagnosed stroke and 
“covert/silent” brain infarctions detected by MRI is not pathogenesis, but rather size and location 
(sparing motor and speech areas of the brain) of the lesion. Covert, MRI-detected brain infarctions
can have clinically meaningful neurological consequences. Covert brain infarctions, by definition,
do not produce symptoms of TIA or stroke but they can be associated with neurologic dysfunction
such as cognitive impairment and gait abnormality.46,47,48 Furthermore, covert brain infarctions
are associated with an up to 5-fold increase in the risk of future stroke, even after adjustment for 
other risk factors, and with an increased risk of dementia (HR = 6.12, 95% CI: 1.82 to 20.54) 
independently of vascular risk factors and interim stroke.48,49,50 Clinicians consider covert brain 
infarctions clinically relevant, and this is now reflected in the recent American Heart Association 
Scientific Statement on preventing stroke in patients with apparently “silent” cerebrovascular 
disease, offering guidance for clinical evaluation and management of these participants.48
MRI-detected brain infarction has been included as an endpoint in stroke prevention trials of 
transfusion in sickle cell anemia51 and closure of patent foramen ovale52 and as an exclusive 
efficacy endpoint for a neuroprotectant during endovascular intracranial aneurysm repair53.
In summary, MRI-detected brain lesions are an accepted measure of brain ischemia and tissue 
necrosis that can be used to assess efficacy in a Phase 2 dose-finding study in participants with 
acute non-hemorrhagic stroke or TIA. The rate of new, covert, MRI-detected brain infarctions
(~12% at Day 90) is at least 2- to 3-fold times higher than the cumulative rate of acute stroke (~5%
with aspirin and clopidogrel at 90 days in the POINT trial13). Therefore, the rate (~15%) of the 
composite endpoint of covert, MRI-detected brain infarction and stroke should be sufficient to 
detect a treatment effect across doses in this dose-ranging study with a manageable sample size.
5.1.1
Data Monitoring and Other External Committees
Data Monitoring Committee (DMC)
An independent DMC, whose activities will be described in a charter, will monitor the study and 
be comprised of experienced clinicians, trialists, and statistical experts. The DMC will review
efficacy and safety data at designated times during the trial with the purpose of each review defined 
in the DMC charter. After approximately 450 participants have completed the Day 21 visit, the 
DMC will recommend if the Day 60 central laboratory samples are still needed. The DMC 
recommendation regarding the Day 60 clinical safety laboratory sample will be communicated to
the investigator by the study Sponsor.
The DMC will review efficacy and safety data after a minimum of 800 participants have been 
randomized, and assess whether it is safe to randomize participants to the 200-mg BID dose arm.
The DMC will use their clinical and statistical judgment to evaluate pertinent trial data and may 
recommend early termination of an individual study arm or the entire trial for important safety 
Revised Protocol No.: 06
Date: 09-Oct-2020
57
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
concerns that are felt to outweigh potential benefits. Details of the DMC activities will be described 
in a DMC charter.
Steering Committee (SC)
The SC will consist of the Lead Investigator, who will serve as SC Chair. Other members will 
include: national leaders from other countries, other experts, and Sponsor representatives. The SC 
will be responsible for scientific aspects of the study and will ensure that the study execution and 
management are of the highest quality. The SC will convene regularly to discuss and report on 
ongoing supervision of the study.
5.2
Participants
Approximately and up to 2350 participants from approximately 30 countries and approximately
380 clinical research sites will be randomized using a competitive enrollment approach (see 
Section 10.1).
5.3
End-of-Study Definition
The start of the study is defined as the date the first participant is screened. End-of-study is defined 
as the date the last participant completes the Day 97 discharge visit. Study completion is defined 
as the final date on which data for the primary endpoint was, or is expected to be, collected, if this 
is not the same as the end-of-study definition. The approximate duration of the study for each 
participant will be 99 days, which includes a maximum 48-hour screening period, a 90-day 
treatment period and 7-day health follow-up period.
5.4
Justification for Doses
5.4.1
Identification of Effective Doses of BMS-986177
Identification of effective doses of BMS-986177 was based on inhibition of thrombus formation 
in a rabbit model of electrically-induced thrombus in the carotid artery of rabbits (ECAT). The 
rabbit ECAT model has been calibrated against clinical results in venous thromboembolism 
prevention (VTEp) based on apixaban. In this model, targeting the concentration that led to 50%
reduction in thrombus weight was correlated with the steady-state trough concentration of the 
clinical dose of apixaban. In the rabbit ECAT model, BMS-986177 caused a dose-dependent 
decrease in both clot weight (Figure 5.4.1-1) and preservation of blood flow without a significant 
increase in bleeding time.  The dose of BMS-986177 in humans that is equivalent to the EC50 in 
the rabbit ECAT model is 55 nM. Free fraction and Ki against human vs rabbit factor XIa were 
used to estimate the human equivalent dose.
Revised Protocol No.: 06
Date: 09-Oct-2020
58
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Figure 5.4.1-1:
Exposure-dependent Reduction in Thrombus Weight and Human 
Equivalent Concentration Targets Based on BMS-986177
A Phase 2 study for VTE prophylaxis post total knee replacement provides the only published data
on the clinical safety and efficacy of reducing Factor XI activity. Patients were treated for 36 days 
prior to surgery with an antisense oligonucleotide (ASO) to reduce the level of Factor XI. The 
study showed a dose-dependent reduction in the risk of VTE events compared to enoxaparin. 
Doses that did not reduce FXI levels to 20% or less of normal did not reduce the risk of VTE
events compared to enoxaparin.14
Figure 5.4.1-2 shows the dose-dependent decrease in FXI levels and clot weight observed in the 
rabbit ECAT model with ASO-induced inhibition of FXI. Based on the dose-dependent reduction 
of FXI concentrations observed in the ASO VTEp study, a trough concentration of approximately 
150 ng/mL of BMS-986177 was necessary to achieve an antithrombotic effect equal to the 80% 
reduction in FXI level in the rabbit ECAT model.
Rabbit Plasma [ BMS-986177 ] nM
10
100
1000
10000
Thrombus Reduction (%)
0
20
40
60
80
100
Revised Protocol No.: 06
Date: 09-Oct-2020
59
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Figure 5.4.1-2:
Reduction in FXI Concentration Based on Factor XI Antisense 
Oligonucleotide (FXI ASO) Compound Used in Phase 2 VTE Study
Based on data obtained from healthy participants, population pharmacokinetic modeling indicates 
that doses likely to achieve the trough concentration targets based on apixaban and ASO for a 
VTEp study are between 50 - 200 mg QD and 25 - 100 mg BID. The data indicating coverage of 
the target concentrations in the rabbit ECAT model for both apixaban and the FXI inhibitor ASO, 
supports the potential for BMS-986177 to provide similar or greater efficacy in patients.
Finally, a lower risk of bleeding is anticipated with inhibition of Factor XIa than with inhibition 
of Factor Xa, based on the mechanistic rationale for targeting the intrinsic pathway via inhibition 
of Factor XIa and therefore testing high doses of Factor XIa inhibition is warranted for 
investigation of a maximized dose-response.
5.4.2
BMS-986177 with Aspirin + Clopidogrel
No clinical studies have assessed the effect of a combination of aspirin and Factor XIa inhibition 
or the combination of Factor XIa inhibition and aspirin and clopidogrel on efficacy or safety 
outcomes in any patient population. Results from a drug interaction study in healthy participants 
indicated that BMS-986177 and aspirin can be administered together without safety concerns. 
Similarly, a drug interaction study of dual antiplatelet therapy (aspirin + clopidogrel) and 
Revised Protocol No.: 06
Date: 09-Oct-2020
60
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
BMS-986177 demonstrated that BMS-986177 may be administered with each antiplatelet agent 
separately and in combination with low risk of serious bleeding.
The results of the COMPASS trial24 showed that, when combined with aspirin, a dose of 
rivaroxaban only 25% of that used for stroke prevention in participants with nonvalvular atrial 
fibrillation (NVAF) reduced the risk of ischemic stroke by 51% compared to aspirin alone. The 
doses of rivaroxaban used in combination with aspirin in COMPASS was half the dose of 
rivaroxaban used in VTEp. Assuming a similar synergistic effect as observed with rivaroxaban 
and aspirin, BMS-986177 combined with aspirin in addition to clopidogrel is expected to provide 
a favorable risk-to-benefit ratio for secondary stroke prevention. Based on the totality of this 
information, 50 - 150 mg QD or 25 - 50mg BID of BMS-986177 are the likely ranges of 
efficacious doses for secondary stroke prevention. However, investigating a wide dose range to 
establish a robust dose-response curve for BMS-986177 is critical to confirm these predictions.
Accordingly, a dose-response design will be used to investigate a range of doses of BMS-986177 
co-administered with aspirin and clopidogrel to identify the most favorable dose and dosing 
regimen for a secondary stroke prevention population for two reasons: (1) to evaluate the efficacy 
of BMS-986177 combined with aspirin and clopidogrel and (2) to establish an accurate and precise
dose-response relationship for BMS-986177.
Dose strengths selected for capsule development of BMS-986177 in Phase 2 are 25 and 100 mg.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met at randomization.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants ≥40 years of age (or legally acceptable representatives, as per country 
guidelines) from whom a signed and dated written consent for participation has been
obtained.
2) Type of Participant and Target Disease Characteristics
a) Ischemic stroke: a neurological deficit attributable to a non-lacunar acute brain infarction 
detected by neuroimaging (CT or MRI) and relevant to the clinical symptoms.
AND
National Institutes of Health Stroke Score (NIHSS) ≤7 at time of randomization.
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or 
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA 
or MRA or catheter angiography).
Note: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible.
Participants with complete occlusion of a cervical carotid or intracranial artery that 
is proximal to the index lesion should be excluded.
Revised Protocol No.: 06
Date: 09-Oct-2020
61
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
AND
Modified Rankin Score (mRS) 3 before the index event (pre-morbid).
b) TIA: acute onset neurological deficit attributable to focal ischemia of the brain by history 
or examination, with complete resolution of the deficit and no brain infarction on
neuroimaging (CT or MRI).
AND
ABCD2 Score ≥63 or presence of motor symptoms.
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or 
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA 
or MRA or catheter angiography).
Note: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible.
Participants with complete occlusion of a cervical carotid or intracranial artery that is 
proximal to the index lesion should be excluded.
AND
Modified Rankin Score (mRS) 3 before the index event (pre-morbid).
3) Two MRI scans are required for participation in this study (see Section 9.2.12). Therefore,
participants must have a body habitus suitable for MRI and cannot have any contraindications 
to the performance of the MRI (see Section 7.7.2.1).
4) No contraindication to clopidogrel or aspirin and suitable for treatment with aspirin 100 mg 
per day for at least 90 days.
5) Age and Reproductive Status
a) 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 treatment.
b) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with BMS-986177 plus 5 half-
lives of study treatment plus 30 days (duration of ovulatory cycle) for a total of 34 days 
post-treatment completion.
c) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study treatment 
BMS-986177, plus 5 half-lives of the study treatment, plus 90 days (duration of sperm 
turnover) for a total of 94 days post-treatment completion. In addition, male participants 
must be willing to refrain from sperm donation during this time. 
d) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active, or are not of childbearing potential, are also exempt 
from contraceptive requirements, and still must undergo pregnancy testing as described in 
this section.
Revised Protocol No.: 06
Date: 09-Oct-2020
62
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
e) Investigators shall counsel WOCBP, and male participants who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise on the use of highly effective methods of
contraception, (see Appendix 4). Highly effective methods of contraception have a failure 
rate of <1% when used consistently and correctly.
6) Enrollment of subjects who have received  thrombolytic therapy or mechanical thrombectomy
(without stenting) for the treatment of the index event is permitted if all of the following 
conditions are met:

At least 24 hours have elapsed between end of IV thrombolytic use/thrombectomy and 
first dose of study medication.

Neuroimaging (either clinical imaging or study MRI) after IV thrombolytic therapy/ 
post-thrombectomy excludes any hemorrhagic transformation.

NIHSS ≤ 7 at time of randomization.

Post-thrombolytic therapy/post-thrombectomy INR ≤ 1.5, aPTT ≤1.4 prior to study 
treatment administration.

No contraindications have been identified that in the opinion of the investigator would 
preclude start of study medication (e.g. large infarct volume, procedure-related 
bleeding).

All other study criteria are met.
In addition, we recommend following local practice and considering fibrinogen > 150 mg/dL 
before initiation of study treatment.
6.2
Exclusion Criteria
1) Medical Conditions
a) Predicted inability to swallow study medication.
b) Women who are pregnant or breastfeeding.
c) Any condition that, in the opinion of the investigator, contraindicates anticoagulant therapy 
or would have an unacceptable risk of bleeding such as a large infarct volume (per 
investigator discretion) or uncontrolled hypertension.
d) Hemorrhage, tumor, arteritis, large vessel dissection, arteriovenous malformation (AVM) 
or other pathology that could account for index symptoms must be excluded by CT or MRI 
interpreted locally.
e) Symptomatic carotid stenosis or intracranial artery stenosis for which endarterectomy or 
angioplasty is planned within 90 days.
f)
Not applicable per global protocol amendment 06.
g) Any condition for which chronic anticoagulation is indicated and expected to be initiated 
(eg, NVAF, DVT, PE).
h) Requirement for continued use of dual anti-platelet therapy (DAPT) for more than 21 days 
or non-aspirin antiplatelet therapy or anticoagulant for another medical condition 
(eg, prophylaxis for venous thromboembolism).
Note: Treatment with clopidogrel, aspirin, dipyridamole or another P2Y12 inhibitor prior 
to enrollment is allowed. Treatment with aspirin at a different dose before 
enrollment is also allowed. All participants must transition to the protocol-defined 
Revised Protocol No.: 06
Date: 09-Oct-2020
63
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
treatments and doses at randomization. No clopidogrel loading dose is needed for 
participants who received a clopidogrel loading dose prior to randomization. 
Participants who report taking chronic clopidogrel also require a 300 mg clopidogrel 
loading dose unless the investigator can verify that the participant has taken the daily 
dose for at least the preceding 3 days. Participants who have received dipyridamole 
or another P2Y12 inhibitor must receive the clopidogrel loading dose after 
discontinuing the non-clopidogrel P2Y12 inhibitor or dipyridamole/dipyridamole-
containing treatment.
i)
History of hemorrhage into the brain, subarachnoid hemorrhage, subdural hematoma or 
spinal cord hemorrhage except cerebral microbleeds (CMB) and minor hemorrhagic 
transformation of prior infarct manifesting as scattered petechiae (Hemorrhagic Infarction 
Type 1 [HI1] according to Heidelberg classification).54
Note: CMBs are defined as rounded foci of <10 mm in size that appear hypointense and 
distinct from vascular flow voids, leptomeningeal hemosiderosis, or non-
hemorrhagic subcortical mineralization on T2* weighted MRI.55
j)
History of clinically meaningful hepatic disease and/or clinically significant abnormal liver 
function.
k) Intracranial tumor (except meningioma, which is permitted) or aneurysm >5 mm (except 
treated aneurysm without history of intracranial bleed, which is permitted) or AVM.
l)
History of end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2, or requiring 
dialysis.
2) Prior/Concomitant Therapy
a) Any investigational drug or placebo exposure within 4 weeks of study drug administration.
b) Any prior exposure to BMS-986177.
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.
Note: Participants who received UFH or LMWH for DVT prophylaxis prior to enrollment 
can be randomized. The use of anticoagulants for post-stroke DVT prophylaxis after 
randomization is prohibited. For post-stroke DVT prophylaxis, non-pharmacological 
prophylaxis (ie, intermittent pneumatic compression) is recommended.
d) Planned concomitant use of omeprazole or esomeprazole after randomization for the 
duration of clopidogrel treatment (eg, H2 blockers [except cimetidine] and other PPIs are 
allowed).
e) Anticipated concomitant chronic (>14 days) use of systemic nonsteroidal anti-
inflammatory drugs (NSAIDs). NSAID (including COX-2 inhibitors) use prior to 
randomization is allowed.
f)
Use of combined P-gp and strong CYP3A4 inhibitors or combined P-gp and strong 
CYP3A4 inducers in the 7 days prior to randomization or the need for ongoing treatment 
with concomitant oral or intravenous therapy with combined P-gp and strong CYP3A4 
inhibitors or combined P-gp and strong CYP3A4 inducers during the study. A list of
Revised Protocol No.: 06
Date: 09-Oct-2020
64
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
combined P-gp and strong CYP3A4 inhibitors is attached as Appendix 11. A list of
combined P-gp and strong CYP3A4 inducers is attached as Appendix 12. 
g) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7.1.
3) Physical and Laboratory Test Findings
a) Any of the following laboratory results outside of the ranges specified below prior to study
treatment administration, confirmed by repeat:
- Hemoglobin <9 g/dL
- Platelet count <100,000 mm3
- aPTT >1.4x upper limit of normal (ULN)
- INR 1.5
- AST or ALT >3x ULN
b) History of or any of the following findings on 12-lead ECG prior to study drug 
administration.
- Atrial fibrillation or atrial flutter
- Complete heart block or Mobitz second-degree heart block
c) Known positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 
and HIV-2 antibody.
Note: Participants with a treated and completely resolved hepatitis C infection without any
sequelae are permitted.
4) Allergies and Adverse Drug Reactions
a) History of allergy to BMS-986177, clopidogrel, aspirin, or aspirin-containing compounds.
b) History of any significant drug allergy (such as anaphylaxis).
c) History of drug-induced hematologic or hepatic abnormalities.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. 
Note: Under certain specific circumstances a person who has been imprisoned may be included 
or permitted to continue as a participant. Strict conditions apply and Bristol-Myers 
Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
c) Participants in whom MRI procedures cannot be performed. Section 7.7.2.1 provides a list 
of some common conditions that may preclude the participants from having MRI. 
However, this should not be used as a substitute for local clinical standards of care. The 
ultimate decision to perform MRI in an individual participant rests with the site radiologist, 
the investigator and the standard set by the local practice.
6) Known SARS-CoV-2 infection within 4 weeks prior to screening.
Note: To be considered for enrollment, symptoms must have completely resolved and based 
on investigator assessment in consultation with the Medical Monitor/Clinical Trial 
Physician, there are no sequelae that would place the participant at a higher risk of 
receiving investigational treatment.
Revised Protocol No.: 06
Date: 09-Oct-2020
65
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants. Therefore, all participants must fully meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes date of consent, demography, screen failure 
details, eligibility criteria, and any serious AEs.
6.5
Retesting During Screening or Lead-In Period
This study does not permit the re-enrollment of a participant who has discontinued the study as a 
pre-treatment failure.
Retesting of laboratory parameters and/or other assessments during the screening period will not 
be permitted except for parameters that require a confirmatory result.
The most recent result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most recent clinical state.
7
TREATMENT
Study treatment (aka study drug) is defined as any investigational treatment(s), marketed 
product(s), placebo or medical device intended to be administered to a study participant according 
to the study randomization or treatment allocation.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. The 
investigational product should be stored in a secure area according to local regulations. The
investigator is responsible for ensuring that investigational product is only dispensed to study 
participants. The investigational product must be dispensed only from official study sites by
authorized personnel according to local regulations.
7.1
Treatments Administered
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.
Revised Protocol No.: 06
Date: 09-Oct-2020
66
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
In this protocol, all Sponsor-supplied treatments (Table 7.1-1) are considered investigational 
product. The Sponsor will be providing uncoated 100-mg aspirin tablets and clopidogrel 75-mg 
tablets.
Table 7.1-1:
Study Treatments for CV010031
Product Description/
Class and Dosage Form
Potency
IP/Non-IP
Blinded or 
Open Label
Packaging/
Appearance
Storage 
Conditions
(per label)
BMS-986177 Capsule 
25 mg
IP
Blinded
Blister
Refer to the 
label on 
container
BMS-986177 Capsule 
100 mg
Placebo For 
BMS-986177 Capsule
NA
IP
Blinded
Blister
Refer to the 
label on 
container
Clopidogrel Tablets
75 mg
IP
Open-Label
Bottle: North America 
& South America 
Blister: Rest of World
Refer to the 
label on 
container
Uncoated Aspirin Tablets
100 mg
IP
Open-Label
Blister
Refer to the 
label on 
container
7.2
Method of Treatment Assignment
This study will be using an Interactive Response Technology (IRT) to centrally enroll and 
randomize all participants. Before the study is initiated, each user will receive log in information 
and directions on how to access the IRT.
During the screening visit, the investigative site will obtain the participant’s unique 5-digit 
participant number from the IRT system. Enrolled participants, including those not dosed, will be 
assigned sequential participant numbers starting with 00001, (eg, 00001, 00002, 00003...00010). 
The participant identification number (PID) will ultimately be comprised of the site number and 
participant number. For example, the first participant screened (ie, enrolled) at Site Number 1, will 
have a PID of 0001 00001. Once it is determined that the participant meets the eligibility criteria 
following the screening visit, the investigative site will obtain the participant’s unique 5-digit 
participant number from the IRT system.
Study treatment will be dispensed at the study visits as listed in the Schedule of Activities (see 
Section 2).
This study initially started with placebo and 6 dose-schedule combination (3 doses x once daily 
[QD] and twice daily [BID] schedules), with 25% of the participants randomized to placebo. The 
randomization of participants to the 200-mg BID dose will be considered in a staggered approach
after a minimum of 800 participants have been randomized. The DMC will review efficacy and 
safety data and assess whether it is safe to randomize participants to the 200-mg BID dose group.
The target randomization ratio by the end of this study, assuming addition of 200 mg BID, will be 
2:1:1:1:1:1 (placebo: 25 mg QD: 25 mg BID: 50 mg BID: 100 mg BID: 200 mg BID). All 
participants will receive open-label aspirin 100 mg + open-label clopidogrel 300-mg single 
Revised Protocol No.: 06
Date: 09-Oct-2020
67
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
loading dose followed by clopidogrel 75 mg once daily (QD) and aspirin 100 mg for 21 days then
continue to receive open-label aspirin 100 mg for the duration of the study.
At all study visits when study drug is dispensed, each participant will be assigned a container
number by the IRT. 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 electronic Case Report Form (eCRF). The IRT will be available 24 hours per day, 
7 days a week.
7.3
Selection and Timing of Dose for Each Participant
Study drug may be administered in the clinical facility or self-administered by the participant 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 participant with their 
daily dosing.
Following signing of informed consent, participants will be randomized to receive BMS-986177 
or placebo, plus open-label uncoated aspirin 100 mg in combination with clopidogrel (a loading 
dose followed by maintenance doses) for the next 21 days. Participants will continue treatment 
from Day 22 through Day 90 with BMS-986177 or placebo, plus open-label 100 mg uncoated 
aspirin only. 
Aspirin and clopidogrel will be given open-label as a background therapy according to the 
following scenarios:
1) Prior to signing informed consent:

Participants who have received a single open-label clopidogrel loading dose of between 
300 mg and 600 mg as standard-of-care prior to obtaining informed consent can be enrolled 
in the study. No additional loading dose of clopidogrel is required for such participants 
after randomization. 

Following a standard-of-care clopidogrel loading dose, the standard-of-care clopidogrel 
daily dose of 75 mg will be taken the next day, and it can be taken prior to randomization. 

Participants who report taking chronic clopidogrel also require a 300-mg clopidogrel 
loading dose unless the investigator can verify that the participant has taken the daily dose 
for at least the preceding 3 days. 
2) Prior to randomization and after signing informed consent:

Following signing of informed consent, a 300-mg loading dose of clopidogrel and 100 mg 
aspirin may be assigned for immediate treatment upon consenting the participant and 
registering the participant in Interactive Response Technology (IRT), if considered 
clinically appropriate. Daily 75 mg clopidogrel and 100 mg daily aspirin will be started the 
next day.
3) After randomization:

A clopidogrel loading dose of 300 mg along with 100 mg aspirin will be administered after 
randomization on Day 1 for participants who have not received any clopidogrel loading 
dose. 
Revised Protocol No.: 06
Date: 09-Oct-2020
68
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

For participants who have received at least 75 mg aspirin as standard of care before 
randomization, and if this dose was taken on the same day as randomization, then no 
additional aspirin is required on Day 1. In this case, 100 mg daily aspirin should be started 
in the morning of Day 2.
The first dose of double-blind study medication (BMS-986177 or placebo) should be taken as soon 
as possible after the baseline MRI assessment, preferably within 2 hours, but no longer than 6 
hours. If outside of the 6-hour post-MRI window, the investigator should call the Medical Monitor 
for guidance. In instances where the baseline MRI is completed after 48 hours from the onset of 
the index event, the first dose of study medication should still be taken immediately after 
randomization and within 48 hours from the onset of the index event.
BMS-986177 or placebo will be taken twice daily (BID), once in the morning (between 
6AM - 9AM) and again in the evening (between 6PM - 9PM).
Open-label aspirin and clopidogrel should be taken QD in the morning (between 6AM - 9AM) 
with the dose of double-blind study medication.
Following the first dose of study medication, the interval between Dose 1 and Dose 2 on Day 1 is 
flexible to ensure a consistent AM-PM dosing schedule after Day 1 dosing. The second dose of 
study medication (if outside the window of 6AM - 9AM or 6PM – 9PM) can be administered at a 
minimum of 6 hours post-dose or maximum of 15 hours post last dose. Three examples are 
provided below:

Participant enters the study and is administered study medication at 2:30AM. The next dose 
of study medication would be administered between 8:30AM and 9AM (a 6- to 6.5-hour 
window) on the same day. The participant would then receive the next dose between 6PM and
9PM.

Participant enters the study and is administered study medication at 4AM. The next dose of 
study medication would be administered between 6PM and 7PM (a 14- to 15-hour window). 
Since the interval between 4AM and 9 AM is <6 hours, the participant must wait for the 
evening dose to be taken no more than 15 hours after Dose 1.

Participant enters the study and is administered study medication at 5PM. The next dose of 
study medication would be administered between 6AM and 8AM (a 13- to 15- hour window).
Since the interval between 5PM and 9PM is <6 hours, the participant would not receive the 
evening dose and must wait to administer the second dose as a morning dose.
The flexibility in the schedule between Dose 1 and Dose 2 allows the most ethical dosing of 
BMS-986177 to ensure the integrity of the study while providing appropriate exposure coverage 
during a high-risk period for a stroke.
Blinded study medication (BMS-986177 or placebo) will be provided by the Sponsor. Open-label 
aspirin will be provided by the Sponsor. Participants will take one tablet each day in the AM with 
their morning dose of blinded study medication. Open-label clopidogrel will be provided by the 
Sponsor. Participants will take one tablet each day in the AM with their morning dose of blinded 
study medication on Days 1 through Day 21.
Revised Protocol No.: 06
Date: 09-Oct-2020
69
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Study medication (double-blinded medication and aspirin + clopidogrel) will be provided as a 21
day supply at Day 1 and a 64-day re-supply of double-blind study medication at the Day 21 visit.
The treatment period will last 90 ± 6 days, with the last doses of study medication taken on Day 
90 or until the Day 90 MRI visit is completed, but no more than 96 days, while continuing 
treatment. Participants who cannot complete the Day 90 MRI due to the COVID-19 pandemic
should continue treatment with study drug until the MRI is completed and until all other study 
assessments are completed, if at a later time. For these participants, it is understood that they may 
not be taking study medication past Day 96 (see Section 9.2.12).
Study medication should be taken at approximately the same time each day once a consistent 
AM/-PM dosing schedule is achieved. If a participant misses a dose of study medication, the 
missed dose should be taken as soon as possible and no later than 6 hours after the regular dosing 
time. If it is greater than 6 hours from the regular dosing time, the missed dose should not be taken. 
Instead, the next dose should be taken at the regular time. Twice-daily dosing should then be
resumed.
7.4
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 participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, i.e., that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The principal investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the participant's study medication has been made.
For this study, the method of unblinding for emergency purposes is through the IRT system. In 
case of an emergency, the investigator has unrestricted access to randomization information via 
IRT and can break the blind through the IRT system without prior approval from the Sponsor. 
After the unblinding, the investigator shall notify the Medical Monitor or Clinical Scientist. The 
method of unblinding for emergency purposes is described in the IRT Manual. Participant and 
unblinded treatment information and the reason for the blind being broken must be recorded on 
the appropriate study status page of the eCRF.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. Any request to unblind a participant for non-emergency purposes should be 
discussed with the Medical Monitor.
Revised Protocol No.: 06
Date: 09-Oct-2020
70
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
A separate analysis team for the Sponsor, separate from the clinical team involved with the conduct 
of this study, will perform an administrative interim analysis (see Section 10.3.7), in order to 
facilitate subsequent program development.
Designated staff of Bristol-Myers Squibb Research & Development, not involved in the study, 
may be unblinded (obtain the randomization codes) prior to database lock to facilitate the 
bioanalytical analysis of pharmacokinetic samples. A bioanalytical scientist in the Bioanalytical 
Sciences department of Bristol-Myers Squibb Research & Development (or a designee in the 
external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples, as well 
as provide assistance for analyses needed for DMC in scope of the DMC charter.
The Data Monitoring Committee (DMC; see Section 5.1.1) will assess safety on an ongoing basis, 
and will have access to unblinded treatment codes for individual participants. 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.
Except as noted above, other members of Sponsor Research and Development personnel, as well 
as all vendors responsible for the conduct of the trial (protocol team) will remain blinded.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. The 
investigator is responsible for ensuring that investigational product is only dispensed to study 
participants. The investigational product must be dispensed only from official study sites by 
authorized personnel.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. Refer to 
Table 7.1-1 for storage requirements for study medication. If concerns regarding the quality or 
appearance of the study treatment arise, the study treatment should not be dispensed and contact 
BMS immediately.
Investigational product documentation (whether supplied by Sponsor or not) that includes all 
processes required to ensure drug is accurately administered must be maintained. This includes 
documentation of drug storage, administration and, storage temperatures.
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. Sites should discuss discrepancies with the participant at each on-treatment study 
visit.
Each time study medication (BMS-986177, placebo, clopidogrel, or aspirin) is dispensed, 
compliance will be reinforced. When study medication is returned, compliance will be assessed 
based upon the participant’s interview and a count of the tablets or capsules returned. Compliance 
should be between ≥80 and ≤120%.
Revised Protocol No.: 06
Date: 09-Oct-2020
71
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
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 participants should be re-educated regarding treatment 
compliance.
Information on overdose is provided in Section 9.2.8.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The treatments outlined in the exclusion criteria are prohibited as described below: 

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. 

Omeprazole or esomeprazole after randomization for the duration of clopidogrel treatment (eg, 
H2 blockers [except cimetidine] and other PPIs are allowed).

Chronic (>14 days) use of systemic nonsteroidal anti-inflammatory drugs (NSAIDs).
Combined P-gp and strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 
inducers. A list of combined P-gp and strong CYP3A4 inhibitors is attached as Appendix 11. 
A list of combined P-gp and strong CYP3A4 inducers is attached as Appendix 12.
Medications taken, including statins, anticoagulants and antiplatelet agents, within 7 days prior to 
randomization must be recorded on the CRF.
No new concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the eCRF.
7.7.2
Other Restrictions and Precautions
Participants are not permitted to consume any food or beverages containing grapefruit juice for the 
duration of the study.
7.7.2.1
Imaging Restriction and Precautions
Study participation does not require x-ray imaging (eg, computed tomography). Study MRIs may 
be performed with or without contrast administration as per investigator discretion and local 
clinical practice.
Imaging contraindications should be considered in this assessment. Participants with tattoos, 
metallic implants, pacemakers, etc., may be excluded from MRI.
MRI contraindications include, but are not limited to:
1) History of claustrophobia
2) Physical limitation related to fitting in the bore of the magnet (i.e., weight greater than that 
allowable by the MRI table)
Revised Protocol No.: 06
Date: 09-Oct-2020
72
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
3) MRI-incompatible implantable cardiac device, 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) MRI-incompatible cochlear implants
5) Spinal nerve stimulator
6) Infusion pump that cannot be discontinued temporarily for the scan
7) Tattoos or permanent makeup near the eye
8) Metallic fragments in the eyes/orbits or in the vicinity of the brain or major neurovascular 
structures of the body
9) Employment history, which involves exposure to welding; unless absence of metallic 
fragments is documented by X-ray examination as per institutional practice.
10) Shrapnel at any place in the body
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
7.8
Treatment After the End-of-Study
At the end of the study, the Sponsor will not continue to provide study treatment to 
participants/investigators unless the Sponsor chooses to extend the study. The investigator should 
ensure that the participant receives appropriate treatment for the condition under study.
8
DISCONTINUATION OR INTERRUPTION CRITERIA
During the course of the study, situations may occur in which the investigator considers a 
temporary interruption or permanent discontinuation of study drug necessary. For treatment 
interruptions ≥48 consecutive hours, the period of interruption should be noted and the investigator 
should document on the CRF the time and date of interruption and restart of therapy, as well as 
the reason for interruption and measures taken to correct the event. An adverse event (AE) should 
be reported, if applicable.
Guidance on dose interruptions or permanent discontinuations for selected events are described 
below. For an individual participant, dose interruptions may be more or less conservative than 
indicated below based on the clinical judgment of the investigator.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
Revised Protocol No.: 06
Date: 09-Oct-2020
73
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
8.1
Bleeding
All study treatment must be discontinued immediately in participants with a major bleeding event 
(BARC Types 3 and 5).  Please refer to the Study Events Assessment Manual for definitions/details 
related to BARC bleeding criteria.
Participants with other than major bleeding or suspected bleeding should be assessed for an 
underlying cause with appropriate laboratory testing (e.g., hematology, ultrasound, CT, MRI). The 
date and time of onset of the bleeding event should be recorded on the CRF. Refer to Section 9.2.1
for measures to consider for management of a bleeding event.
8.2
Elevated Liver Function Tests
All participants will discontinue treatment with blinded study treatment immediately if criteria for 
drug-induced liver injury (DILI) are met (see Section 9.2.11 for details).
In addition, stop treatment with blinded study treatment if:

ALT and/or AST >5x ULN for ≥7 consecutive days, confirmed by repeat.

ALT and/or AST ≥10x ULN, confirmed by repeat.
Interrupt treatment with blinded study treatment if:

ALT and/or AST >3x ULN, confirmed by repeat.
Participants with abnormal liver function tests should be followed until ALT/AST returns to <2x 
ULN or to baseline prior to considering re-start of treatment with blinded study treatment, but not 
later than 14 days post-interruption.
8.3
Elective Procedures or Surgery
The anticoagulant effects of BMS-986177 should dissipate in 48 - 72 hours after the last dose of 
the drug. Therefore, blinded study treatments must be stopped at least 48 hours prior to an invasive 
procedure to reduce the risk of bleeding. The participant will re-start blinded study medication 
once the investigator determines that hemostasis is secure and resuming treatment is safe, but no 
earlier than 24 hours after the procedure/surgery.
The interruption of aspirin or clopidogrel treatment for elective procedures or surgery should 
follow local practice.
8.4
Emergency Procedures
For participants receiving BMS-986177, the risk of bleeding with invasive procedures is unknown. 
At therapeutic doses, the anticoagulant effects of BMS-986177 will not be reflected by INR values,
but may be reflected by prolongation of aPTT. Currently, there is no reversal agent for 
BMS-986177. However, the anticoagulant effect of BMS-986177 dissipates in 48 - 72 hours.
Refer to Section 9.2.1 for measures to consider for management of a bleeding event.
For participant with a new stroke during the study period, the use of thrombolytic therapy, 
mechanical thrombectomy (without stenting), or other standard-of-care therapy, is to be 
implemented at the discretion of the investigator, to include possibility of unblinding (see Section 
Revised Protocol No.: 06
Date: 09-Oct-2020
74
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
7.4). If thrombolytic therapy and/or mechanical thrombectomy is used, study treatment with BMS-
986177 must be interrupted and restart of BMS-986177 is only permitted if all of the following 
conditions are met: 

At least 24 hours have elapsed between end of IV thrombolytic use/thrombectomy and first 
dose of study medication.

Clinical imaging has been performed to exclude any hemorrhagic transformation of the 
new infarct.

Post-thrombolytic therapy/post-thrombectomy INR ≤ 1.5, aPTT ≤ 1.4 at the time of 
BMS-986177 restart.

No contraindications have been identified that in the opinion of the investigator would 
preclude start of study medication (eg, large infarct volume, procedure-related bleeding).

All other study criteria are met.
In addition, we recommend following local practice and considering fibrinogen > 150 mg/dL 
before initiation of study treatment.
8.5
Other Reasons for Permanent Discontinuation from Study Treatment
Participants MUST discontinue BMS-986177 for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and should be encouraged to be followed for protocol-
specified follow-up procedures. The only exception to this is when a participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
participant to provide this information.

Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Termination of the study or program 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 (e.g., infectious disease) illness. 
Note: Under specific circumstances, a participant who has been imprisoned may be permitted
to continue as a participant. Strict conditions apply and Sponsor approval is required.

Severe non-compliance to protocol, as judged by the investigator and/or Sponsor.

Incorrect enrollment (i.e., the participant does not meet the required inclusion/exclusion 
criteria) for the study, as determined after consultation with the Sponsor.

Pregnancy: the investigator must immediately, within 24 hours of awareness of the pregnancy, 
notify the BMS Medical Monitor/designee of this event. See Section 9.2.7.
Discontinuation of open-label clopidogrel and/or aspirin are at the discretion of the investigator.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a female participant becomes pregnant during a 
clinical trial, the study treatment must be discontinued immediately. Please call the BMS Medical 
Monitor within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
Revised Protocol No.: 06
Date: 09-Oct-2020
75
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
favorable benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol-specified follow-
up procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.6
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and should be 
encouraged to continue to be followed for protocol specified follow-up procedures. For these 
participants, the following visits must be conducted:

End-of-treatment assessments, except MRI, at the time of study drug discontinuation.

MRI at Day 90 (± 6 days). In the event that participants are unable or not permitted to attend 
the Day 90 visit at the study site due to the COVID-19 pandemic, the Day 90 MRI may be 
performed at an external facility provided that the MRI protocol and scanner have been pre-
approved by the central imaging vendor. In the event the Day 90 MRI cannot be performed 
within the ± 6-day window, the MRI can be acquired at any time after Day 90 using the study 
site or an external facility MRI scanner. For these participants, it is understood that they may 
not be taking study medication past Day 96.

A phone call visit Day 97 ± 2 (7 days after Day 90 MRI)
In addition, a follow-up telephone contact between discontinuation and Day 90 MRI is encouraged 
for participants who permanently discontinue study treatment early. The only exception to this is 
when a participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information.
For participants who withdraw consent for follow-up, there should be documentation of the reason 
for withdrawal. Study staff should explicitly seek information about the possible contribution of 
AEs to the participant’s desire to withdraw and document any AEs that are identified in the AE
section of the CRF.
Withdrawal of consent for treatment with study medication should be distinguished from 
withdrawal of consent for follow-up visits, telephone contacts, or medical records checks. 
Participants requesting withdrawal from follow-up should be informed that withdrawal of consent 
for follow-up will result in loss of important information about the benefits and risks of 
BMS-986177.
Revised Protocol No.: 06
Date: 09-Oct-2020
76
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post-treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being collected, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.7
Post-Study Treatment Follow-up
Post-treatment follow-up is required to assess participant safety and to preserve the integrity of the 
study. Efficacy outcomes will also be collected during the follow-up period. If study treatment is 
discontinued early, the participant is expected to complete the end-of-treatment assessments at the 
time of discontinuation (Table 2-2) except MRI. For these participants, a Day 90 MRI, as well as 
Day 97 visit, must be completed at the planned visit dates. In the event that participants are unable 
or not permitted to attend the Day 90 visit at the study site due to the COVID-19 pandemic, the
Day 90 MRI may be performed at an external facility provided that the MRI protocol and scanner 
have been pre-approved by the central imaging vendor. In the event the Day 90 MRI cannot be 
performed within the ± 6-day window, the Day 90 MRI can be acquired at any time after Day 90 
using the study site or an external facility MRI scanner. For these participants, it is understood that 
they may not be taking study medication past Day 96.
8.8
Lost to Follow-Up
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
If at the participant has died, the site will use permissible local methods to obtain date and cause 
of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the participant’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining participant’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study.
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, to obtain updated contact information.
Revised Protocol No.: 06
Date: 09-Oct-2020
77
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities (see Section 2). Protocol 
waivers or exemptions are not allowed. All immediate safety concerns must be discussed with the 
Sponsor immediately upon occurrence or awareness to determine if the participant should continue 
or discontinue treatment.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. All screening evaluations must be completed 
and reviewed to confirm that potential participants meet all eligibility criteria before 
randomization. The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) 
and obtained before signing of informed consent may be utilized for screening or pre-treatment 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
All participants will have a study MRI scan at baseline (Day 1) and Day 90, as described in Table 
2-1 and Table 2-2. The baseline MRI should be acquired within 48 hours of the index event and 
prior to randomization on Day 1. If the baseline MRI cannot be performed within 48 hours of the 
index event and before randomization, it can be acquired after randomization but must be 
performed within 72 hours of the index event and up to 24 hours after randomization. If the study-
specific MRI cannot be acquired at baseline, a clinical (standard-of-care) MRI scan can be used 
provided that the clinical MRI protocol and scanner have been pre-approved by the central imaging 
vendor.
The first dose of study medication (BMS-986177 or placebo) should be taken as soon as possible 
after the baseline MRI assessment, preferably within 2 hours, but no longer than 6 hours. If outside 
of the 6-hour post-MRI window, the investigator should call the Medical Monitor for guidance. If 
the baseline MRI is completed after 48 hours from the onset of the index event, the first dose of 
study medication should still be taken immediately after randomization within 48 hours from the 
onset of the index event.
The baseline MRI and the Day 90 MRI will be submitted to a central imaging vendor for analysis.
Details regarding MRI acquisition, including required sequences, slice thickness, and qualifying 
phantom image(s) are presented in the CV010-031 Imaging Manual. Sites must be trained and 
qualified prior to scanning the first study participant.
9.1.1
Primary Efficacy Assessments
The primary efficacy endpoint assessment is the composite of a new ischemic stroke during the 
treatment period and new covert brain infarction (FLAIR + DWI) detected by MRI on Day 90.
Revised Protocol No.: 06
Date: 09-Oct-2020
78
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Please refer to the Study Events Assessment Manual for definitions/details concerning 
stroke/covert brain infarction endpoints.
9.1.2
Secondary Efficacy Assessments
The following are secondary efficacy assessments:

Composite of new ischemic non-fatal stroke, non-fatal myocardial infarction, or all-cause
death

Location, number, and volume of new FLAIR + DWI lesions

National Institutes of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Montreal 
Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (subtest of WAIS-IV) will 
be collected at baseline (at randomization for NIHSS), on Days 21 and 90, and at the time of a 
new stroke event. MoCA and DSST (subset of WAIS-IV) will be read by a third-party central 
laboratory blinded to treatment.
9.2
Safety Assessments
9.2.1
Bleeding
The main safety endpoint assessment is major bleeding (based on BARC Types 3 and 5
definitions). Participants with bleeding or suspected bleeding will be assessed and treated 
according to usual clinical practice at each site. Severity of bleeding will be classified according 
to BARC, ISTH and PLATO (Refer to the Study Events Assessment Manual for definitions and 
details for the bleeding endpoints).
Approach to a Participant with a Bleeding Event
If a participant has a bleeding event requiring intervention during the study, the following measures 
should be considered:

Discontinue the study drug (refer to Section 8.1, Discontinuation of Study Drug).

Usual treatment measures for bleeding events, including local pressure, fluid replacement and 
hemodynamic support, and blood transfusion, if indicated

Other causes besides antithrombotic medication can contribute to the seriousness of the 
bleeding event (e.g., rule out thrombocytopenia, disseminated intravascular coagulation, and 
other coagulopathies, kidney and liver dysfunction, concomitant medications, etc.) and should 
be assessed and treated accordingly

Consultation with a coagulation/hematology expert

Possibility of unblinding at the discretion of the investigator (see Section 7.4)
Currently, there is no specific reversal agent for BMS-986177. Before considering the use of any 
pro-hemostatic agent, the benefit and risk for each individual participant should be assessed, and 
consultation with a hematologist should be considered. Replacement therapy with Factor XI 
concentrates is not recommended because the participants are not Factor XI deficient. 
BMS-986177 does not bind Factor XI but rather only binds to activated Factor XI. Therefore, 
increasing circulating Factor XI is not likely to have a significant impact on BMS-986177 
pharmacology. In vitro studies in human plasma demonstrated that addition of 4-factor activated 
Revised Protocol No.: 06
Date: 09-Oct-2020
79
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
prothrombin concentrate complex (FEIBA, aPCC) or recombinant Factor VIIa (NovoSeven) 
reduced the BMS-986177-induced prolongation of the aPTT. In FXI-deficient participants, 
recombinant Factor VIIa has been used successfully to prevent surgical bleeding without 
complication. Therefore, if severe bleeding occurs that cannot be controlled by the above 
measures, or emergent surgery/invasive procedure is required, pro-hemostatic agents may be 
considered according to their package insert. 
At therapeutic doses, the anticoagulant effects of BMS-986177 will not be reflected by 
international normalized ratio (INR) values but may be reflected by prolongation of aPTT. The 
anticoagulant effect of BMS-986177 dissipates in 48 to 72 hours after the last dose.
Clopidogrel and aspirin inhibit platelet function and may also contribute to bleeding. Participants 
receiving clopidogrel and aspirin should be managed according to the local standard-of-care and 
the drug product label.
9.2.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported to the investigator by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study.
Contacts for SAE reporting are specified in Appendix 3.
9.2.3
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE (NSAE) information should begin at randomization until the 
time points specified in the Schedule of Activities (Section 2). NSAE 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 participants.
Section 6 in the Investigator’s Brochure26 (IB) represents the Reference Safety Information (RSI) 
to determine expectedness of SAEs for expedited reporting. Following the participant’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 protocol-specified procedures.
All SAEs that occur during the screening period through the follow-up period must be collected.
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:

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section. Labs performed 
locally for assessment of SAEs should have reports faxed or scanned and emailed to 
 
.
Revised Protocol No.: 06
Date: 09-Oct-2020
80
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3.

The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek NSAEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating, and assessing causality of NSAEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.4
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting NSAE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement 
in the context of known AEs, when appropriate for the program or protocol.
9.2.5
Follow-up of AEs and SAEs

Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for NSAEs that cause interruption or discontinuation of study 
treatment and for those present at the end of study treatment as appropriate.

All identified non-serious AEs must be recorded and described on the NSAE 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.

Investigators should collect a Medical Release Form from all study participants to allow access 
to SAE information occurring at off-site medical facilities.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.8).
Further information on follow-up procedures is given in Appendix 3.
9.2.6
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential to meet legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Revised Protocol No.: 06
Date: 09-Oct-2020
81
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.7
Pregnancy
If, following initiation of the study treatment it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 
half-lives (4 days) after product administration, the investigator must immediately notify the 
Sponsor Medical Monitor/designee of this event and complete and forward a Pregnancy 
Surveillance Form to Sponsor Designee within 24 hours of awareness of the event and in 
accordance with SAE reporting procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy 
has ended), 
following approvals of 
participant/Sponsor /IRB/EC, as applicable.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.8
Overdose
For this study, the accidental or intentional administration of any dose of BMS-986177 that is 
considered both excessive and medically important by the investigator will be considered an 
overdose and should be reported as a SAE (medically important event).
The sponsor does not recommend specific intervention for an overdose. There is no known antidote 
for overdose with BMS-986177 and no studies have been performed to assess methods of reversing 
BMS-986177 absorption effects; however, in theory, activated charcoal may reduce the absorption 
of BMS-986177 if given early after administration of BMS-986177.
See Section 9.2.1 for management of serious bleeding.
Overdose of aspirin or clopidogrel may increase the risk of bleeding. Follow the local product 
label for management of aspirin or clopidogrel overdose.
Revised Protocol No.: 06
Date: 09-Oct-2020
82
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
In the event of an overdose, the investigator or treating physician should contact the Medical 
Monitor immediately and:

Obtain a plasma sample for PK analysis as soon as possible after the last dose of study 
treatment, if requested, by the Medical Monitor (determined on a case-by-case basis).

Document the quantity of the excess dose as well as the duration of the overdosing on the CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
Planned time points for all safety assessments are listed in the Schedule of Activities (see 
Section 2).
9.2.9
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any abnormal laboratory test result that required the participant to have study treatment 
discontinued or interrupted

Any abnormal laboratory test result that required the participant to receive specific corrective 
therapy
The clinical rather than laboratory term (e.g., anemia vs. low hemoglobin value) should be used 
wherever possible by the reporting investigator.
9.2.10
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, X-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a NSAE or SAE, as appropriate, and reported accordingly.
9.2.11
Potential Drug Induced Liver Injury (DILI)
Participants meeting the criteria for DILI must have blinded study treatment discontinued 
immediately.
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 Appendix 3 for reporting details).
Potential drug-induced liver injury is defined as:
ALT or AST elevation >3x ULN
AND
Total bilirubin >2x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
Revised Protocol No.: 06
Date: 09-Oct-2020
83
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
AND
No other immediately apparent possible causes of transaminase
elevation and 
hyperbilirubinemia, including, but not limited to: viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.
9.2.12
Magnetic Resonance Imaging
A baseline and Day 90 MRI of the brain are required for all participants randomized in the trial 
per study guidelines. All scans should be acquired in compliance with the study-specific MRI 
protocol as outlined in the imaging manual provided by the central imaging vendor.
The baseline MRI should be acquired within 48 hours of the index event and prior to randomization 
on Day 1. If the baseline MRI cannot be performed within 48 hours of the index event and before 
randomization, it can be acquired after randomization but must be performed within 72 hours of 
the index event and up to 24 hours after randomization. If the study-specific MRI cannot be 
acquired at baseline, a clinical (standard-of-care) MRI scan can be used provided that the clinical 
MRI protocol and scanner have been pre-approved by the central imaging vendor.
A second MRI of the brain will be performed on Day 90 ± 6 days (based on randomization on 
Day 1) to accommodate scheduling and scanner availability. Sites are encouraged to schedule the 
Day 90 MRI at the time of the baseline visit. All participants should remain on study treatment 
until the Day 90 MRI is performed up to Day 96. 
In case of early study drug discontinuation prior to Day 90, a Day 90 MRI will still be required.
In the event that participants are unable or not permitted to attend the Day 90 visit at the study site 
due to the COVID-19 pandemic, the Day 90 MRI may be performed at an external facility provided 
that the MRI protocol and scanner have been pre-approved by the central imaging vendor. In the 
event the Day 90 MRI cannot be performed within the ± 6-day window, the Day 90 MRI can be 
acquired outside of the + 6-day window after Day 90 using the study site or an external facility 
MRI scanner. For these participants, it is understood that they may not be taking study medication 
past Day 96.
All MRI scans must be performed at qualified MRI facilities. More than one imaging facility can 
be utilized during conduct of the study with preference to perform baseline and Day 90 scans on 
the same scanner or of the same manufacturer, or minimally with the same magnet strength as the 
baseline scan.
An Imaging Manual and Quick Reference Guide (QRG) will be provided detailing site 
qualification process, required MRI sequences, and participant scanning.
9.2.13
Physical Examinations
A complete physical examination should include general appearance, head, eyes, ears, nose, throat, 
neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, and 
musculoskeletal. Full physical exams will be conducted at screening and on Day 90.
Revised Protocol No.: 06
Date: 09-Oct-2020
84
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
A brief physical assessment (including organ systems pertinent to the participant’s signs, 
symptoms, or adverse events, e.g., assessment of signs of thromboembolism and bleeding) will be 
conducted on the Day 21 visit.
Physical measurement of height and weight will also be collected at screening and weight will be 
collected again on Day 90.
The individual performing the physical examinations must be licensed by state law and must be 
delegated to conduct this study-specific assessment after randomization.
9.2.14
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.
9.2.15
Electrocardiograms
A 12-lead ECG will be recorded at screening, on Day 21, and at the end-of-treatment visit
(Day 90).
9.2.16
Clinical Safety Laboratory Assessments
All screening laboratory tests will be performed locally to assess eligibility per inclusion/exclusion 
criteria. Laboratory samples collected as standard-of-care prior to signing informed consent can 
be used to assess eligibility if meeting protocol-specified requirements. Investigators must 
document their review of each laboratory safety report.
The central laboratory will perform the study-specific analyses and will provide reference ranges 
for these tests. A central laboratory sample will be collected on Day 1 prior to the first dose of 
blinded study medication, and at Day 21, Day 60, and Day 90 visits. In the event that the Day 1 
lab results are not available, local screening labs will be used for analysis.
Table 9.2.16-1:
Clinical Laboratory Assessments
Hematology:
Hemoglobin
Hematocrit
Red blood cell count (RBC)
Total leukocyte count, including differential
Absolute platelet count
Chemistry:
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin (TB)
Direct bilirubin (done as reflex if TB is >2x ULN)
Alkaline phosphatase
Bicarbonate
Lactate dehydrogenase (LDH)
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Revised Protocol No.: 06
Date: 09-Oct-2020
85
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 9.2.16-1:
Clinical Laboratory Assessments
Hematology:
Creatinine
eGFR
Blood Urea Nitrogen (BUN)
Uric acid
Phosphorus
Magnesium
WOCBP Only:
Pregnancy test (at screening and every 30 days).
Follicle stimulating hormone (FSH) (screening only for women only) use as applicable
Note: PT and aPTT are collected as PD markers and will be sent to the central laboratory for analysis (See Section 9.3).
9.3
PK, PD, Biomarkers and PK/PD Assessments
Table 9.3.1.1-1 and Table 9.3.2.1-1 show collection times for PK and PD in participants who are 
being treated. Samples for BMS-986177 PK are considered mandatory and the planned times allow 
a window to accommodate site staff and scheduling.  PK and PD data will be used for exploratory 
exposure-response (E-R) analyses for efficacy, safety, and PD endpoints. These samples will be 
analyzed at central laboratories: PT aPTT and FXI clotting activity assay, and the results will be 
blinded to investigator, study staff and Sponsor.
9.3.1
PK Assessments
Pharmacokinetics of BMS-986177, clopidogrel (and metabolites), aspirin (acetylsalicylic acid) 
and its major metabolite (salicylic acid) will be assessed. A population PK model (PPK) will be 
developed to understand the PK of BMS-986177 (See Section 10.3.4).
9.3.1.1
PK Sample Analyses
The plasma samples will be analyzed for BMS-986177 by a validated liquid chromatography-mass 
spectrometry/mass spectrometry (LC-MS/MS) assay. The plasma samples for acetylsalicylic acid, 
salicylic acid, clopidogrel, and clopidogrel metabolite will be analyzed by validated high-
performance liquid chromatography mass spectrometry/mass spectrometry assays. (HPLC-
MS/MS). PK samples collected from a participant who received placebo will not be analyzed for 
BMS-986177, but may be analyzed for clopidogrel (and metabolites), aspirin and salicylic acid. 
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will 
be provided to the site in the central laboratory procedure manual.
In addition, after the scheduled PK 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 central laboratory procedure 
manual.
Table 9.3.1.1-1 lists the sampling schedule to be followed for the assessment of PK in treated 
participants. Further details of blood collection and processing will be provided to the site in the 
central laboratory procedure manual. In addition to the times listed in the table below, a sample 
Revised Protocol No.: 06
Date: 09-Oct-2020
86
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
for measurement of BMS-986177 plasma concentration, PT, aPTT and FXI clotting activity should 
be collected as close as possible to the time of major bleeding or a new stroke.
Table 9.3.1.1-1:
Pharmacokinetic Sampling Schedule
Study Day of Sample 
Collection
Time of Sample 
Collection Relative to 
BMS-986177 Dose 
(Hour:Min)a
BMS-986177 
Blood Sample 
for Plasma
Clopidogrel,
Acetylsalicylic Acid 
and Salicylic Acid Blood    Sam
ple for Plasma
Day 1- Day 4 (Relative to 1st
or 2nd dose)b
00:30 - 6:00
X
6:00 - 12:00
X
12:00 - 72:00c
X
Day 21
Any time
X
X
Day 90 
Any time
X
Xd
Outcome Event 
Up to 48 hours after 
stroke event or major 
bleeding event
X
X
a It is critical to record ingestion time of each dose prior to each PK sample and sample collection time. Ensure that 
there is at least a one-hour gap between samples collected, as windows are continuous. 
b All PK samples on Day 1 - Day 4 should be collected relative to the same dose. Select either the first dose or second 
dose and collect Day 1 - Day 4 samples relative to dose selected.
c For participants discharged prior to this sampling window, collect one PK sample prior to discharge.  
d Sample for acetylsalicylic acid and salicylic acid PK only.
9.3.2
PD and Biomarker Assessments
Effects of BMS-986177 on PD markers including aPTT, FXI clotting activity, and PT will be 
assessed. Blood samples for these PD markers will be collected and sent to central laboratories for 
analysis. A dose-response assessment will be performed for aPTT and FXI clotting activity as PD 
biomarkers for BMS-986177 according to the sample collection schedule detailed in Table 
9.3.2.1-1.
9.3.2.1
Exploratory Biomarker Assessments
Blood will be drawn at the times indicated in Table 9.3.1.1-1 for exploratory biomarker 
assessments. The goal of these assessment is to explore the effect of BMS-986177 on the body, 
explore markers related to the FXI pathway and associated pathways, markers of stroke, 
thrombosis, cardiovascular disease and related pathophysiological conditions (such as 
inflammation, endothelial function, metabolic, neurological, and extracellular matrix turnover).
The assessments may include, but are not limited to, those listed below and in Table 9.3.2.1-1 and
Table 2-2.

Thrombosis, hemostasis, and cardiovascular diseases related exploratory biomarkers such as 
PT, FXI antigen, D-dimer, and F1.2.

Exploratory serum and plasma biomarkers associated with FXI pathway or pathways impacted 
by target, stroke, cardiovascular disease, metabolic and neurological disorder, brain injury, 
Revised Protocol No.: 06
Date: 09-Oct-2020
87
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
endothelial dysfunction, inflammation, and severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection status or related pathophysiological pathways. Biomarkers may 
include but are not limited to kallikrein, bradykinin, IL-6, NT-proBNP, fibrinogen, chemerin,
soluble von Willebrand factor (vWF) and or related multi-biomarker panels. Exploratory
serum and plasma samples to develop new or improved assays for pathway markers associated 
with either BMS-986177, FXI, stroke, or cardiovascular diseases.

A PK/PD sample should be drawn at the time of stroke or major bleed.

A blood sample for future genotyping may include, but not be limited to specifically FXI, 
genes related to FXI pathway, stroke, cardiovascular disease, and disposition of BMS-986177
and other co-medication (drug absorption, distribution, metabolism, and excretion related 
genes such as CYP3A4/CYP3A5, 2C9/2C19, P-gp, MDR1, BCRP, OATP1B1, CES1 and 
CES2) as well as Whole Genome Sequencing. These samples will be collected only in 
participants in countries and sites where genetic testing is allowed and who opt in to genetic 
testing as captured on an Informed Consent Form (ICF).

Further details of sample collection and processing will be provided to the site in the central
laboratory procedure manual. Results of exploratory biomarkers may be reported separately 
from the CSR.
Table 9.3.2.1-1:
Biomarker Sampling Schedule
Study Day of Sample 
Collection 
Time of Sample 
Collection 
Relative to BMS-
986177 Dose 
(Hour:Min)a
PT, aPTT
and FXI C
lotting
Activityb   
FXI Antigen
Exploratory
Plasma and
Serum 
Biomarkers
F1.2
and
DDimer
Day 1- Day 4 (Relative 
to 1st or 2nd dose)c
00:00 (pre-dose)d
X
X
X
X
00:30 - 6:00
X
6:00 - 12:00
X
12:00 - 72:00e
X
X
X
Day 21
Any time
X
X
X
Day 90
Any time
X
X
X
Outcome Event
(Up to 48 hours after 
stroke event or major 
bleeding event)
X
X
a It is critical to record ingestion time of each dose prior to each PD sample and sample collection time. Ensure that 
there is at least a one-hour gap between samples collected, as windows are continuous. 
b PD samples (PT, aPTT and FXI clotting activity) must be collected at same time as the matched PK time points, 
where applicable, and at the time of a new major bleeding or stroke event.
c All PD samples on Day 1 - Day 4 should be collected relative to the same dose. Select either the first dose or second 
dose and collect Day 1 - Day 4 samples relative to dose selected.
d The pre-dose sample can be collected up to 2 hours before first dose.
e For participants discharged prior to this sampling window, collect one PD sample prior to discharge.  
Revised Protocol No.: 06
Date: 09-Oct-2020
88
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
9.3.3
Additional Research Collection
This protocol will include residual sample storage for additional research (AR). All samples, 
including all residual samples, may be stored and the research with these samples as described in 
the protocol may continue for 15 years post end-of-study. The scope of work involves using serum, 
plasma, DNA from whole blood to assess markers of stroke, cardiovascular and associated diseases 
and pathways (such as inflammation, endothelial function, metabolic, neurological, brain injury, 
and extracellular matrix turnover). Work may also include studies on the FXI pathway and 
mechanism of action as well as any pathways impacted by BMS-986177, as well as development 
of new or improved assays for pathway and markers associated with either BMS-986177, FXI, 
stroke, or cardiovascular diseases. The goal is to better understand stroke, cardiovascular and
associated diseases/syndromes and any effects of the drug, BMS-986177.
Sites in the United States
Consent to additional research is required for all study participants, except where prohibited by 
IRB/ECs or academic/institutional requirements. Where one or more of these exceptions occurs, 
participation in the additional research should be encouraged but will not be a condition of overall 
study participation.

If the IRB/ECs and site agree to the mandatory additional research retention and/or collection, 
then the study participant must agree to the mandatory additional research as a requirement for 
inclusion in the study

If optional participation is permitted and approved, then the study participants may opt in or 
opt out of the additional research retention and/or collection
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
of such samples is prohibited by local laws or regulations, ECs, or institutional requirements. 
Participants (or legally authorized representatives, as applicable) will be required to provide 
separate informed consent to participate. Participants must also provide separate informed consent 
to participate in collection of additional blood samples for future genotyping, including, but not 
limited to FXI. Samples for genotyping will only be collected at sites where allowed by local laws 
and regulations.
Sample Collection and Storage
All serum, plasma, and blood DNA samples from PK, PD and exploratory biomarker collections 
(as defined in Table 9.3.1.1-1, Table 9.3.2.1-1 and Table 2-2) may be retained for additional 
research purposes as described above. Samples kept for future research will be stored at the 
Sponsor biorepository or an independent, Sponsor-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than 15 years after 
the end of the study or the maximum allowed by applicable law
Revised Protocol No.: 06
Date: 09-Oct-2020
89
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Transfers of samples by Sponsor to third parties will be participant to the recipient’s agreement to 
establish similar storage procedures
All requests for access to samples or data for additional research will be vetted by the Sponsor to 
ensure the research supports appropriate research activities.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the investigator at the clinical site, so there is no direct ability for a researcher
to connect a sample to a specific individual.
Further details of sample collection, processing, submission and storage are provided in the Study 
Laboratory Manual.
9.4
Other Assessments
9.4.1
Assessment of Index Stroke and New Strokes
The National Institutes of Health Stroke Score (NIHSS) will be used to assess the index stroke as 
a qualifying criteria (must be ) at randomization on Day 1. The NIHSS will also be evaluated
on Days 21 and 90, and at the time of a new stroke (see Appendix 5).
9.4.2
Assessment of Risk for Subsequent Stroke Associated with Index TIA
The ABCD2 Score3 or presence of motor symptoms will be used as one of the qualifying criteria 
for TIA (must be 6) (see Appendix 6).
9.4.3
Assessment of Clinical Severity of Stroke
In participants who have had a prior stroke, the Modified Rankin Scale (mRS) will be used to 
assess the clinical severity of the prior stroke or TIA at screening as a qualifying criteria (must be 
3) to be randomized. mRS will also be assessed on Days 21 and 90, and at the time of a new 
stroke (see Appendix 7).
9.4.4
Assessment of Cognitive Function
Cognitive function will be assessed at baseline on Day 1, on Days 21 and 90, and at the time of a 
new stroke event by the clinical site and evaluated by a third-party laboratory blinded to study 
treatment:

The Montreal Cognitive Assessment (MoCA) (see Appendix 8)

The Digit Symbol Substitution Test (DSST; subtest of WAIS-IV) (see Appendix 9)
9.4.5
Assessment of Bleeding Severity
Severity of bleeding will be based on definitions contained in the Study Events Assessment 
Manual for:

Bleeding Academic Research Consortium (BARC)

International Society of Thrombosis and Hemostasis (ISTH)

Platelet Inhibition and Patient Outcomes (PLATO)
Revised Protocol No.: 06
Date: 09-Oct-2020
90
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The primary endpoint for this study is the incidence of events within a composite of new ischemic 
stroke during the treatment period and new covert brain infarction (FLAIR + DWI) detected by 
MRI at 90 days. Sample size calculations were performed for detecting a dose-response effect with 
the MCP-MOD methodology using simulations with the Dose-Finding package in R statistical 
analysis software. Simulations of 2500 clinical trials were performed, assuming a true incidence 
for placebo of 15%, a plateau shaped dose response relationship with maximum relative risk 
reduction of 32% for BMS-986177 100 or 200 mg BID relative to placebo and reductions of 10%, 
17.5%, and 27% for the 25-mg QD, 25-mg BID, and 50-mg BID doses, respectively. Candidate 
models included an Emax model, a logistic model, and an exponential model.
Using these assumptions, a total of 2100 participants allocated in a 2:1:1:1:1:1 ratio to placebo and 
BMS-986177, 25 mg QD, 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID groups would
provide approximately 80% power to demonstrate a dose-response relationship, with a 1-sided 
type I error of 0.049 (See Section 10.3.7). Without the 200-mg group, a total of 1800 participants 
allocated in a 2:1:1:1:1 ratio to placebo and BMS-986177, 25-mg QD, 25-mg BID, 50-mg BID, 
and 100-mg BID groups would provide approximately 79% power to demonstrate a dose-response 
relationship with similar pattern, but risk reduction of 32% for BMS-986177 50 or 100 mg BID 
relative to placebo and reductions of 17.5%, and 27% for the 25-mg QD and 25-mg BID doses, 
respectively. Allowing up to 10% of participants who do not have a clinical event and also do not 
have a Day 90 imaging assessment, approximately and up to 2350 participants may be randomized. 
The frequency and reasons for missing data will be evaluated in blinded fashion during the course 
of the study.
10.2
Populations for Analyses
The analyses will use several populations as defined below:
1) All Enrolled Participants: Includes all participants who signed informed consent.
2) All Randomized Participants /Intent-to-Treat (ITT) Population: Includes all participants 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 Participants: Includes All Randomized Participants, as above, excluding those 
participants’ visits where relevant protocol deviations occurred. The relevant protocol 
deviations will be pre-specified in the SAP prior to database lock.
4) All Treated Participants: Includes all participants 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 participant received the same incorrect treatment throughout the study (until either Day 
90 or discontinuation of the study drug), then the participant will be analyzed based on the 
treatment received.
Revised Protocol No.: 06
Date: 09-Oct-2020
91
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

If a participant received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
participant will be analyzed based on the first treatment received.
5) Pharmacodynamics (PD) Population: A subset of the ITT Population that includes participants 
with at least one PD endpoint assessed following the first dose of BMS-986177.
6) Pharmacokinetic (PK) Population for BMS-986177, clopidogrel, and aspirin: Includes all 
participants treated with BMS-986177, clopidogrel, and aspirin, respectively, who also have 
at least one post-dose PK sample.
The primary efficacy data set will be the ITT population. For the primary efficacy endpoint 
analysis, the population will include all Randomized Participants who:

have a primary endpoint event (a new ischemic stroke during the study period or a new covert 
brain infarction detected by MRI on Day 90)
OR

have an evaluable MRI image on Day 90.
For the primary endpoint, analysis will be performed using the Evaluable Participant data set as 
well as the Primary Efficacy data set.
10.3
Statistical Analyses
The Statistical Analysis Plan (SAP) will be developed and finalized before the final database lock 
and will describe the selection of participants to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. Below is a summary of planned statistical 
analyses of the primary and secondary endpoints.
Except as otherwise noted, descriptive summaries will use data from all randomized groups, while 
dose-response analyses of primary and secondary endpoints will use data from participants 
randomized to placebo, 25 mg QD and 25 mg, 50 mg, 100 mg, and 200 mg BID groups.
A description of the participant population will be included in the statistical output reported, 
including subgroups of age, gender, and race.
10.3.1
Demographics and Baseline Characteristics
Frequency distribution and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all participants combined. Key demographic and baseline 
variables to be summarized include geographic region, age, gender, race, height, weight, body 
mass index, vital signs (systolic blood pressure, diastolic blood pressure, and heart rate) and 
medical history (hypertension, diabetes, heart failure).
10.3.2
Efficacy Analyses
Clinical definitions and details related to the study endpoints can be found in the Study Events 
Assessment Manual.  Table 10.3.2-1 provides details about efficacy endpoints and analysis 
methods to be used.
Revised Protocol No.: 06
Date: 09-Oct-2020
92
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 10.3.2-1:
Efficacy Endpoints and Analysis Methods
Endpoint
Statistical Analysis Methods
Primary

Estimation of dose-response using 
composite of new ischemic stroke 
during the treatment period and new 
covert 
brain 
infarction 
(FLAIR + DWI) detected by MRI 
at 90 days using central review
Dose-response relationship will be analyzed based on a generalized 
Multiple Comparisons and Modeling (gMCP-Mod) analysis56,57 for the 
BMS-986177 dose regimens, with placebo and 25 mg QD as the 
lowest dose added to the ordered BID dose regimens. 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. An Emax model, a logistic 
model, and an exponential model will be used as the candidate models 
for the gMCP-Mod analysis. 
Secondary

Comparison of rates of the 
composite of new ischemic stroke 
during the treatment period and 
new covert brain infarction 
(FLAIR + DWI) detected by MRI 
at 90 days

Event rates for new ischemic non-
fatal stroke, non-fatal MI, and all-
cause death during the treatment 
period

Location, number, and volume of 
new FLAIR + DWI lesions

National Institutes of Health Stroke 
Scale (NIHSS), Modified Rankin 
Scale (mRS), Montreal Cognitive 
Assessment (MoCA), and Digit 
Symbol Substitution Test (subtest 
of WAIS-IV) at baseline, on Days 
21 and 90, and at the time of a new 
stroke event.
Point estimates with 95% confidence intervals for the following event 
rates will be summarized by treatment group.

Composite of new ischemic stroke during the treatment period and 
new covert brain infarction detected by MRI at 90 days

New covert brain infarction detected by MRI at Day 90

Composite of new ischemic non-fatal stroke, non-fatal MI and all-
cause death during the treatment period

New ischemic stroke during the treatment period

Non-fatal myocardial infarction (MI)

All-cause death
Dose-response analysis for new ischemic non-fatal stroke and the 
composite of new non-fatal stroke, non-fatal MI, and all-cause death 
will be assessed similar to the primary endpoint analysis.
Location, number, and volume of new FLAIR + DWI lesions will be 
summarized descriptively by treatment group.
Functional/disability status assessed by the National Institutes of 
Health Stroke Score (NIHSS), modified Rankin Scale (mRS), Montreal 
Cognitive Assessment (MoCA) and Digit Symbol Substitution Test 
(subtest of WAIS-IV) will be summarized by treatment group. 
10.3.3
Safety Analysis
Table 10.3.3-1 provides details about safety endpoints and analysis methods to be used.
Table 10.3.3-1:
Safety Endpoints and Analysis Methods
Endpoint
Statistical Analysis Methods

Major bleeding event rate based on 
bleeding according to Bleeding 
Academic Research Consortium 
(BARC) Type 3 and 5
The event rates of major bleeding (based on BARC Types 3 and 5 
definitions) will be summarized by treatment groups and point 
estimates with 95% confidence intervals will be presented for each 
treatment group.
If a sufficient number of major bleeding events occurs, then dose-
response for the BMS-986177 will be assessed.  
Revised Protocol No.: 06
Date: 09-Oct-2020
93
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Table 10.3.3-1:
Safety Endpoints and Analysis Methods
Endpoint
Statistical Analysis Methods

Event rate for all bleeding events, 
based 
on 
BARC, 
ISTH 
and 
PLATO-defined criteria
The event rates for all bleeding will be summarized by treatment 
group, including point estimates with 95% confidence intervals within 
group. Additionally, bleeding events will be summarized by BARC 
category, ISTH (major and CRNM bleeding), and PLATO criteria 
(major, including life-threatening and other; minor, and minimal).

Incidence and characteristics of 
CMBs, hemorrhagic transformation 
of 
ischemic 
stroke 
and 
asymptomatic intracranial bleeding 
on Day 90 MRI
Incidence and characteristics of CMBs, hemorrhagic transformation of 
ischemic stroke and asymptomatic intracranial bleeding on Day 90 
MRI will be summarized by treatment group

Adverse 
events,
vital 
signs, 
physical exams, electrocardiogram 
(ECG), and clinical laboratory 
results

Incidence of adverse events, related adverse events, serious adverse 
events, adverse events leading to discontinuation, and deaths will 
be summarized by treatment group
Additionally, changes from baseline in vital signs, ECG and clinical 
laboratory results will be summarized by treatment group.
10.3.4
Pharmacokinetic Analysis
The PK of BMS-986177, clopidogrel (and metabolites), aspirin (acetylsalicylic acid) and its major 
metabolite, salicylic acid, will be assessed. A population PK model (PPK) will be developed to 
understand the PK (CL and Vd) of BMS-986177 and the potential effect of covariates (e.g., body 
weight, age, gender, race, renal function, liver function, concomitant medicine) on the PK of 
BMS-986177. These results will be reported separately.
10.3.5
Pharmacodynamic and Biomarker Analysis
Percent (%) change from baseline for aPTT, PT and Factor XI clotting activity, as well D-dimer, 
PT, F1.2, and Factor XI antigen may be summarized by treatment group.  In addition, exploratory 
analyses may be conducted to explore the relationship of BMS-986177 to:

Percent (%) change from baseline in aPTT and Factor XI clotting activity via exposure-
response

Biomarkers related to FXI pathway, stroke, thrombosis/hemostasis, inflammation and 
cardiovascular diseases, include, but are not limited to: plasma D-dimer, PT, F1.2, and Factor 
XI antigen.

PD and biomarker results and analysis may be reported separately.
10.3.6
Exposure-Response Analyses
Exposure-response analyses will be conducted to explore the relationship of BMS-986177 
exposure to the following using data collected from all randomized participants:

Composite of new ischemic stroke during the treatment period and new covert brain infarction
detected by MRI at 90 days

New ischemic stroke non-fatal MI, and all-cause death during the treatment period
Revised Protocol No.: 06
Date: 09-Oct-2020
94
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Major bleeding according to BARC Type 3 and 5 definitions

Percent (%) change from baseline in aPTT and Factor XI clotting activity

Biomarkers related to FXI pathway, stroke, thrombosis/hemostasis, inflammation and 
cardiovascular diseases, including, but not limited to: include, but are not limited to: plasma 
D-dimer, PT, F1.2, and Factor XI antigen.
10.3.7
Interim Analyses
In order to facilitate subsequent program development, an administrative interim analysis will be 
conducted after approximately 70% of participants have had a 90 day follow-up. The 
administrative analysis may include the primary efficacy endpoint, selected secondary efficacy 
and safety endpoints. An adjustment to the type I error of 0.001 for the final analyses will be done.  
No changes will be taken with regard to the conduct or analysis of primary or secondary endpoint 
for this study as a result of this analysis. An analysis team for the Sponsor separate from the clinical 
team involved with the conduct of this study will conduct the analysis, and unblind data will not 
be shared outside the analysis group. A Data Monitoring Committee will assess safety throughout 
the course of this trial (see Section 5.1).
Revised Protocol No.: 06
Date: 09-Oct-2020
95
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
11
REFERENCES
1
Feigin VL, Forouzanfar MH, Krishnamurthi R, et al on behalf of the Global Burden of Diseases 
Stroke Experts Group. Lancet 2014: 383: 245-55.
2
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients 
with stroke and transient ischemic attack. Stroke 2014; 45(7):2160-23.
3
Amarenco P, Lavallee PC, Labreuche J et al. for the TIAregistry.org Investigators. One-year 
Risk of Stroke After Transient Ischemic Attack or Minor Stroke. N Engl J Med 2016; 374: 
1533-42.
4
Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke 
after transient ischemic attack: A systematic review and meta-analysis. Archives of internal 
medicine. 2007;167:2417-2422.
5
Johnston SC, Amarenco P, Albers GW et al. for the SOCRATES Steering Committee and 
Investigators. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J 
Med 2016; 375(14):1395.
6
Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic 
review and meta-analysis. Lancet Neurol 2007; 6: 1063-72.
7
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, et.al. Definition and evaluation 
of transient ischemic attack: A scientific statement for healthcare professionals from the 
American Heart Association/American Stroke Association Stroke Council; Council on 
Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and 
Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on 
Peripheral Vascular Disease. Stroke. 2009;40:2276-2293.
8
Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient 
ischaemic attack or minor stroke: Implications for public education and organisation of 
services. BMJ. 2004;328:326.
9
Lin HJ, Yeh PS, Tsai TC, Cheng TJ, Ke D, Lin KC, Ho JG, Chang CY. Differential risks of 
subsequent vascular events for transient ischaemic attack and minor ischaemic stroke. J Clin 
Neurosci. 2007;14:17-21.
10 Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB. Dual 
Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis 
Evaluated Using Doppler Embolic Signal Detection The Clopidogrel and Aspirin for 
Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial. Circulation. 
2005;111:2233-2240.
11 Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, Han Z, Tan KS, Ratanakorn 
D, Chollate P, Zhao Y, Koh A, Hao Q, Markus HS;. Clopidogrel plus aspirin versus aspirin 
alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery 
stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010 
May;9(5):489-97.
Revised Protocol No.: 06
Date: 09-Oct-2020
96
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
12 Wang Y, Wang Y, Zhao X, Liu L, Wang D, et. al, for the CHANCE Investigators. Clopidogrel 
with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. N Engl J Med 2013; 369:11-
19.
13 Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, 
Palesch YY for the Clinical Research Collaboration, Neurological Emergencies Treatment 
Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic
Stroke and High-Risk TIA. NEJM 2018; doi: 10.1056/NEJMoa1800410:1-11.
14 Buller HR, Bethune C, Bhanot S, et al. Factor XI Antisense Oligonucleotide for Prevention of 
Venous Thrombosis. NEJM 2015;372:232-240.
15 Yang DT, Flanders MM, Kim H, et al. Elevated factor XI activity levels are associated with 
an increased odds ratio for cerebrovascular events. Am J Clin Pathol. 2006 Sep;126(3):411-5.
16 Suri MF, Yamagishi K, Aleksic N, et al. Novel hemostatic factor levels and risk of ischemic 
stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Cerebrovasc Dis 
2010;29:497–502.
17 Siegerink B, Govers-Riemslag JW, Rosendaal FR, et al. Intrinsic coagulation activation and 
the risk of arterial thrombosis in young women: results from the Risk of Arterial Thrombosis 
in relation to Oral contraceptives (RATIO) case–control study. Circulation 2010;122:1854–61.
18 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008;14(6):1183-1189.
19 Preis M, Hirsch J, Kotler A, Zoabi A, Stein N, Rennert G, Saliba W. Factor XI deficiency is 
associated with lower risk for cardiovascular and venous thromboembolism events. Blood. 
2017;129(9):1210-1215.
20 Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, and Seligsohn U. Patients with  
severe factor XI deficiency have a reduced  incidence of deep-vein thrombosis. Thromb 
Haemost 2011;105:269-73.
21 Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost 2009;1 7 suppl:84-87.
22 CV010010 Clinical Study Report. A Study to Assess Safety and Tolerability of Single Oral 
Doses of BMS-986177 in Patients with ESRD Treated with Chronic Hemodialysis. Bristol 
Myers Squibb Company, 2018. Document Control No. 930125554.
23 Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Hill MD, Jonasson J, 
Kasner SE, Ladenvall P, Minematsu K, Molina CA, Wang Y, Wong KSL, and Claiborne 
Johnston S for the SOCRATES Steering Committee and Investigators. Efficacy and safety of 
ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: 
a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet 2017;
16(4): 301–310.
24 Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovsaka O, et al. on 
behalf of the COMPASS investigators. Rivaroxaban with and without aspirin in stable 
cardiovascular disease. N Engl J Med 2017; 377: 1319-30.
Revised Protocol No.: 06
Date: 09-Oct-2020
97
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
25 Sharma M, Eikelboom J, Connolly SJ, et al. ISC Abstract LB7: The effect of rivaroxaban with 
aspirin on stroke outcomes in the Cardiovascular Outcomes for People Using Anticoagulation 
Strategies (COMPASS) trial. 2018.
26 BMS-986177 JNJ-70033093 Investigators Brochure, Version 6.0., LLC 2020. EDMS-ERI-
176637744, Document Control No. 930095007.
27 CV010027 Protocol. A Double-blind, Randomized, Placebo-controlled, Parallel Group Study 
to Evaluate the Effect of Co-administration of Multiple Doses of BMS-986177 on Aspirin in 
Healthy Participants. Bristol-Myers Squibb Company, 2017. Document Control No. 
930119159.
28 Final Safety Report Synopsis for Study CV010034. A Randomized, Cross-Over Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics oBms-986177 
(An Oral Antithrombotic) With Single and Dual Antiplatelet Therapy (Aspirin and 
Clopidogrel) In Healthy Participants. Bristol Myers Squibb Company. 2019. Document 
Control No. 930139416.
29 The Stroke Prevention  In Reversible Ischemia Trial (SPIRIT) Study Group. A randomized 
trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The 
Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol. 1997 
Dec;42(6):857-65.
30 Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, et. al. A 
Comparison of Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke. N Engl 
J Med 2001;345:1444-51.
31 Chimowitz MI, Lynn NJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, 
et. al. Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis 
(WASID). N Engl J Med 2005;352:1305-16.
32 The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral 
ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665–
73.
33 Clinical Study Report for CV185030 (ARISTOTLE): A Phase 3, Active (Warfarin) Controlled, 
Randomized, Double-Blind, Parallel-Arm Study to Evaluate Efficacy and Safety of Apixaban 
In Preventing Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation. 
Bristol-Myers Squibb Company, 2011. Document Control No. 930050122.
34 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, et. al. Dabigatran versus 
Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-1151.
35 Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et. al. Rivaroxaban versus 
Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365:883-91.
36 Alexander JH, Lopes RD, James S, Kilaru R, He Y, et.al. Apixaban with Antiplatelet Therapy 
after Acute Coronary Syndrome. N Engl J Med 2011; 365:699-708.
37 Mega JL. Braunwald E, Wiviott SD, Bassand J-P, Bhatt DL, et. al.. Rivaroxaban in Patients 
with a Recent Acute Coronary Syndrome. N Engl J Med 2012; 366:9-19.
Revised Protocol No.: 06
Date: 09-Oct-2020
98
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
38 Patti, G, et al. Thromboembolic Risk, Bleeding Outcomes and Effect of Different 
Antithrombotic Strategies in Very Elderly Patients With Atrial Fibrillation: A Sub-Analysis 
From the PREFER in AF (PREvention oF Thromboembolic Events–European Registry in 
Atrial Fibrillation). J Am Heart Assoc. 2017;6:e005657.
39 Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: 
results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713–
9.
40 Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated 
hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am 
Coll Cardiol 2011;58:395–401.
41 Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-
year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 
2010;138:1093–100.
42 Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et. al. 2016 ESC Guidelines 
for the Management of Atrial Fibrillation Developed in Collaboration with EACTS. European 
Heart Journal (2016) 37, 2893–2962.
43 Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm
AJ, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in 
patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet. 
2014;383(9921):955-962.
44 Hicks KA, Mahaffey KW, Mehran R, Nissen SE. Consensus Report: 2017 Cardiovascular and 
Stroke Endpoint Definitions for Clinical Trials. Circulation. 2018;137:961–972.
45 Kasner SE. Clinical Interpretation and Use of Stroke Scales. Lancet Neurol. 2006 Jul;5(7):603-
12.
46 Engelter ST, Provenzale JM, Petrella JR, Alberts MJ. Diffusion MRI Imaging and Transient 
Ischemic Attacks. Stroke; A Journal of Cerebral Circulation. 1999;30:2762-2763.
47 Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP,
et al. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events 
in Clinical Trials: A Report of the American College of Cardiology/American Heart 
Association Task Force on Clinical Data Standards. J Am Coll Cardiol. 2015 Jul 28;66(4):403-
69.
48 Smith, EE. Prevention of Stroke in Patients With Silent Cerebrovascular Disease A Scientific 
Statement for Healthcare Professionals From the American Heart Association/American 
Stroke Association. Stroke. 2017;48:e44-e71.
49 Vermeer SE, Prins ND, den Heijer T et al. Silent Brain Infarcts and the Risk of Dementia and 
Cognitive Decline. N Engl J Med 2003; 348: 1215-22.
50 Vermeer SE, Longstreth  WT , Koudstaal PJ. Silent Brain Infarcts: A Systematic Review. 
Lancet Neurol 2007; 6: 611–19.
Revised Protocol No.: 06
Date: 09-Oct-2020
99
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
51 DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, et al. Controlled 
Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia.  N Eng J Med 
2014;371(8):699-710.
52 Sondergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, et al. 
Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Eng J Med. 
2017;377(11):1033-42.
53 Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, et al. Safety and Efficacy 
of NA-1 in Patients with Iatrogenic Stroke After Endovascular Aneurysm Repair (ENACT): a 
Phase 2, Randomised, Double-blind, Placebo-controlled Trial. Lancet neurology. 
2012;11(11):942-50.
54 von Kummer R, Broderick JP, Campbell BCV, Demchuk A, Goyal M, Hill MD, et.al. The 
Heidelberg Bleeding Classification: Classification of Bleeding Events After Ischemic Stroke 
and Reperfusion Therapy. Stroke. 2015; 46:2981-2986.
55 Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, 
Launer LJ, Van Buchem MA, Breteler MM. Cerebral Microbleeds: A Guide to Detection and 
Interpretation. 2009, Lancet Neurol; 8(2):165–174.
56 Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics 2005; 61:738–748.
57 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.
Revised Protocol No.: 06
Date: 09-Oct-2020
100
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
12
APPENDICES
Revised Protocol No.: 06
Date: 09-Oct-2020
101
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ABCD2
neurological assessment scores (age, blood pressure, clinical features, 
d
i b
ACC
American College of Cardiology
ADRC
adaptive design review committee
AE
adverse event
AF
atrial fibrillation
AHA
American Heart Association
ALT
alanine aminotransferase
Am, AM
morning
aPTT
activated partial thromboplastin time
ASA
acetylsalicylic acid
ASO
anti-sense oligonucleotide
AST
aspartate aminotransferase
ALT
amino transaminases
AUC
area under the concentration-time curve
AUC(0-24)
area under the concentration-time curve (time zero to 24 hours post dose)
AVM
arteriovenous malformation
BARC
Bleeding Academic Research Consortium
BID
twice-a-day
BMI
body mass index
BMS
Bristol Myers Squibb
BMS-986177
BMS Factor XIa (FXIa) inhibitor investigational anticoagulant compound
BP
blood pressure
BT
bleeding time
BUN
blood urea nitrogen
C
Celsius
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CL
estimated clearance
Revised Protocol No.: 06
Date: 09-Oct-2020
102
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
COMPASS
Cardiovascular Outcomes for People Using Anticoagulation Strategies
cm
centimeter
Cmax, CMAX
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COX-2
cyclooxygenase -2, enzyme responsible for inflammation and pain
CRF
case report form (paper or electronic)
CRNM
clinically relevant non-major
CSR
clinical study report
CT
computerized tomography
CTA
computed tomography angiography
CAT
computerized tomography angiography
CV
cardiovascular
CYP
cytochrome P450
CYP3A4
member of the cytochrome P450 family of oxidizing enzymes
DDI
drug-drug interaction
D-Dimer
protein fragment present in the blood after a clot is degraded by fibrinolysis
DILI
drug-induced liver injury
dL
deciliter
DNA
deoxyribonucleic acid
DOAC
direct oral anticoagulants
DSMB
data safety monitoring board
DSST
Digital Symbol Substitution Test
DWI
diffusion-weighted imaging MRI
ECAT
electronically induced thrombus in the carotid artery
EC
ethics committee
EC20
20% of maximal effect is observed
EC50
half maximal effective concentration
EC80
80% of maximal effect is observed
ECG
electrocardiogram
eCRF
electronic case report form
Revised Protocol No.: 06
Date: 09-Oct-2020
103
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
EDC
electronic data capture
ED90
minimum effective dose in 90% of patients
Emax
asymptotic maximum change from placebo effect
EOT
end of treatment
ESC
European Society of Cardiology
ESRD
end stage renal disease
F1.2
F1.2 fragment of prothrombin
FXa
Factor Xa, one of the enzymes in the coagulation cascade.
FXI (FXI)
Factor XI, one of the enzymes of the coagulation cascade
Factor XIa
Activated plasma Factor XI
FDA
Food and Drug Administration
FIH
first in human
FLAIR
fluid-attenuated inversion recovery
FSH
follicle stimulating hormone
g, gm
gram
GCP
good clinical practice
GPIIb/IIIa
glycoprotein IIb/IIIa
GRE
gradient echo sequences
h
hour
Hb
hemoglobin
HBsAg
hepatitis B surface antigen
HBV, HepB
hepatitis B virus
HCG
human chorionic gonadotropin
HepC
hepatitis C virus
HepB
hepatitis B virus
HepA
hepatitis A virus
HI
hemorrhagic infarction
HIV
human immunodeficiency virus
hr, hrs
hour, hours
HPLC-MS/MS
high-performance liquid chromatography-mass spectrometry/mass 
Revised Protocol No.: 06
Date: 09-Oct-2020
104
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
HR
heart rate
IAC
Imaging Adjudication Committee
IB
Investigator Brochure
ICD
International Classification of Diseases
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IL-6
interleukin 6
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational Product
IRT
Interactive Response Technology
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
IXRS
interactive web/voice response system
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
kg
kilogram
z
terminal disposition rate constant
L
liter
LC-MS/MS
liquid chromatography-mass spectrometry/mass spectrometry
LDH
lactate dehydrogenase
LFT
liver function test
LMWH
low-molecular-weight heparin
Lp-PLA(2)
lipoprotein-associated phospholipase A2
Revised Protocol No.: 06
Date: 09-Oct-2020
105
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
MACE
major adverse cardiovascular events
MAD
multiple-ascending dose
MCP-Mod
multiple comparison procedures and modeling
MDR1
multidrug resistance protein 1
MED
minimum effective dose
mg
milligram
MI
myocardial infarction
min
minute
mL
milliliter
mmHg
millimeters of mercury
MoCA
Montreal Cognitive Assessment
MRA
magnetic resonance angiography
mRNA
messenger ribonucleic acid
MRI
magnetic resonance imaging (or image)
mRS
modified Rankin Score
g
microgram
L
microliter
N
number of participants or observations
N/A
not applicable
ng
nanogram
NIHSS
National Institutes of Health Stroke Score/Scale
nm
nanomolar
NOAEL
no observed adverse effect level
Non-IMP
Non-Investigational Medicinal Product
NSAE
non-serious adverse event
NSAID
nonsteroidal anti-inflammatory drug
NT-proBNP
n-terminal prohormone of brain natriuretic peptide
NVAF
non-valvular atrial fibrillation
NYHA
New York Heart Association
PCR
polymerase chain reaction
Revised Protocol No.: 06
Date: 09-Oct-2020
106
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
PD
pharmacodynamics
PID
patient identification
PK
pharmacokinetics
PLATO
Platelet Inhibition and Patient Outcomes
pm, PM
evening
PO
by mouth 
PPI
proton pump inhibitor
PPK
population PK(pharmacokinetics)
PT
prothrombin time
PTT
partial thromboplastin time
P2Y12 
group of g protein-coupled (gpcr) purinergic receptors
OATP1B1
organic-anion-transporting polypeptide
QC
quality control
QD, qd
once daily
RAR
response adaptive rRandomization
R2
coefficient of determination
RBC
red blood cell
RNA
ribonucleic acid
RRR
relative risk reduction
RSI
reference safety information
SAD
single ascending dose
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus-2
SC
Steering Committee
SOP
standard operating procedures
SCTI
Standardized Data Collection for Cardiovascular Trials and Initiatives
SUSAR
suspected, unexpected serious adverse reaction
SWI
susceptibility weighted imaging
TB
total bilirubin
Revised Protocol No.: 06
Date: 09-Oct-2020
107
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Term
Definition
T-HALF
Half-life
TIA
transient ischemic attacks
ULN
upper limit of normal
Vd
volume of distribution
VTE
venous thromboembolism
VTEp
venous thromboembolism prevention
WOCBP
women of childbearing potential
wt
weight
Revised Protocol No.: 06
Date: 09-Oct-2020
108
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:

Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 

as defined by the International Council on Harmonization (ICH)

in accordance with the ethical principles underlying European Union Directive 2001/20/EC

United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 

Applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant 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, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
Revised Protocol No.: 06
Date: 09-Oct-2020
109
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
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 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
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 participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Revised Protocol No.: 06
Date: 09-Oct-2020
110
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the participant'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 participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant 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.
Revised Protocol No.: 06
Date: 09-Oct-2020
111
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
Revised Protocol No.: 06
Date: 09-Oct-2020
112
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant 
identifiers

amount transferred to another area/site for 
dispensing or storage

non-study disposition (e.g., 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)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
Revised Protocol No.: 06
Date: 09-Oct-2020
113
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
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. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. Electronic CRF review and approval/signature is completed electronically through the 
electronic data capture tool. The investigator must retain a copy of the CRFs including records of 
the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site or through other means of remote monitoring approved by 
the Sponsor and as local regulatory requirements permit, they will review study records and 
directly compare them with source documents, discuss the conduct of the study with the 
investigator, and verify that the facilities remain acceptable. Certain CRF pages and/or electronic 
files may serve as the source documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
Revised Protocol No.: 06
Date: 09-Oct-2020
114
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the Investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.
Revised Protocol No.: 06
Date: 09-Oct-2020
115
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the Investigator 
or designee.
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:

National Coordinating Investigator 

Study Steering Committee Chair 

Participant recruitment (e.g., among the top quartile of enrollers)

Involvement in trial design

Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Revised Protocol No.: 06
Date: 09-Oct-2020
116
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
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 treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication.
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Revised Protocol No.: 06
Date: 09-Oct-2020
117
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department <24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Revised Protocol No.: 06
Date: 09-Oct-2020
118
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.11 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.7 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Revised Protocol No.: 06
Date: 09-Oct-2020
119
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form.

The required method for SAE data reporting is through the eCRF.

The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
When paper forms are used, the original paper forms are to remain on site

Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
Revised Protocol No.: 06
Date: 09-Oct-2020
120
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over the age 
of 45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
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.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING
POTENTIAL
Any one of the approved methods of contraception (highly effective and/or less than highly
effective) listed below is required during study duration plus 5 half-lives of study treatment
BMS-986177 (4 days) plus 30 days (duration of ovulatory cycle) for a total of 34 days 
Revised Protocol No.: 06
Date: 09-Oct-2020
121
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
post-treatment completion or after treatment has been discontinued. Local laws and regulations 
may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
Revised Protocol No.: 06
Date: 09-Oct-2020
122
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until the end of relevant 
systemic exposure defined as 4 days after the end of treatment plus an additional 90 days for a 
total of 94 days.

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 4 days after the end of 
treatment with BMS-986177 in the male participant plus an additional 90 days for a total of 94
days.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 4 days after the end of treatment with BMS-986177 plus an 
additional 90 days for a total of 94 days. 
Revised Protocol No.: 06
Date: 09-Oct-2020
123
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor

Refrain from donating sperm for the duration of the study treatment and for 4 days after the 
end of treatment with BMS-986177 plus an additional 90 days for a total of 94 days.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.7 and the Appendix 3 for Adverse Events and Serious 
Adverse Events Definitions and Procedures for Evaluating, Follow-up and Reporting
Revised Protocol No.: 06
Date: 09-Oct-2020
124
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 5
NATIONAL INSTITUTES OF HEALTH STROKE SCALE (NIHSS)
Revised Protocol No.: 06
Date: 09-Oct-2020
125
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
126
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
127
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
128
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
  
Revised Protocol No.: 06
Date: 09-Oct-2020
129
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
130
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
131
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 6
ABCD2 SCORE ASSESSMENT TOOL
http://www.stroke.org/sites/default/files/resources/tia-abcd2-tool.pdf
Revised Protocol No.: 06
Date: 09-Oct-2020
132
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 7
MODIFIED RANKIN SCORE
http://www.strokecenter.org/wp-content/uploads/2011/08/modified_rankin.pdf
Revised Protocol No.: 06
Date: 09-Oct-2020
133
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 8
MONTREAL COGNITIVE ASSESSMENT (MOCA)
Revised Protocol No.: 06
Date: 09-Oct-2020
134
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 9
WAIS-IV DSST CODING SUBTEST
Revised Protocol No.: 06
Date: 09-Oct-2020
135
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
136
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
137
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
138
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
139
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Revised Protocol No.: 06
Date: 09-Oct-2020
140
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 10
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 05, 24-Aug-2019
The purpose of revised protocol 05 is to simplify the study design while maintaining scientific 
rigor to attain trial objectives, minimize the number of study participants being exposed to the new 
investigational drug, reduce the burden on participants and study centers, and streamline study 
procedures. Specifically, randomization to the once-daily (QD) arms of 50-, 100- and 200-mg dose 
arms will be closed for the study while maintaining the 25-mg QD arm and twice-daily (BID) dose 
arms (25, 50, 100, and 200 mg). Assessment of dose response remains the primary objective. The 
methodology to achieve this will result from analysis of  data from placebo, 25 mg QD arms, and 
BID dose arms (25, 50, 100, and 200 mg) using MCP-MOD to assess dose response, which allows 
assessment of multiple different dose-response patterns. With fewer study arms primarily focused 
on one schedule, the selected randomization is more closely oriented to assessment of the overall 
dose-response relationship with some improved power for detection of a dose-response (from ~77-
78% to 80%). The modification of the randomization to a non response-adaptive randomization 
will be completed while the study is still in the initial “burn-in” period, ie, prior to addition of the 
200-mg doses and prior to when the response-adaptive randomization was to be initiated. 
Participants who have received 50-mg and 100-mg QD doses will continue treatment until they 
complete the study period. Data acquired in these subjects will be used for descriptive analyses, 
population PK/PD modeling, and exposure-response analysis.
Maintaining the 25-mg QD dose is of importance in this secondary stroke prevention (SSP) trial 
for several reasons: 25 mg QD represents the lowest total daily dose included in the study and thus 
presents unique information in the context of dose-response compared to 50, 100, or 200 mg QD; 
also, PK/PD modeling with assumptions around combination dual antiplatelet therapy and existing 
data from direct oral anticoagulants (DOACs) suggests there is potential for this dose of 
BMS-986177 to be efficacious in secondary stroke prevention with a potential for lower risk of 
bleeding. The dose change will not allow a separate dose-response assessment for QD; however, 
it is possible a QD dose can still be an option for Phase III based on modeling and simulation. The 
25 mg QD dose plus the four BID doses will still be utilized in the exposure-response assessment. 
Population PK/PD analysis and exposure-response outcome modeling will be performed using 
data from all randomized participants, including those who received 50 or 100 mg QD, to support 
the modeling.
The changes made to the protocol have no adverse impact on the safety or the benefit-risk of the 
trial participants. Due to the reduction in sample size, fewer patients will be exposed to the new 
investigational medicine. The safety surveillance performed by the DMC and the Sponsor remains 
unchanged. The staggered approach for adding the highest 200-mg BID dose remains, ie, the DMC 
will review the efficacy and safety data including lab-testing data and MRI data from 
approximately 450 patients who complete 21-day treatment, and will assess benefit and risk of 
BMS-986177 and make recommendations as to whether or not the 200-mg BID dose can be added.
The table below highlights the key changes made to the protocol.
Sections in the synopsis have been updated to align with the protocol section changes listed below.
Revised Protocol No.: 06
Date: 09-Oct-2020
141
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 05
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
A Global, Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, 
Response-Adaptive Dose-Ranging 
Study of BMS-986177, an Oral Factor 
XIa Inhibitor, for the Prevention of 
New Ischemic Stroke or New Covert 
Brain Infarction in Patients Receiving 
Aspirin and Clopidogrel Following 
Acute Ischemic Stroke or Transient 
Ischemic Attack (TIA)
Title Changed to:
A Global, Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, 
Dose-Ranging Study of BMS-986177, 
an Oral Factor XIa Inhibitor, for the 
Prevention of New Ischemic Stroke or 
New Covert Brain Infarction in Patients 
Receiving Aspirin and Clopidogrel 
Following Acute Ischemic Stroke or 
Transient Ischemic Attack (TIA)
The title was changed to 
reflect changes in the 
randomization schema.
Section 2 (Schedule 
of Activities), Table 
2-1 (Screening Period 
Procedural Outline),
Section 
9.4.1(Assessment of 
Index Stroke and 
New Strokes)
National Institute of Health Stroke 
Scale (NIHSS) score assessment is 
removed from screening table and 
clarified in Section 9.4.1. 
Added text to Clinical Laboratory Tests 
Row: “Results from the screening labs 
should be faxed or scanned to 
 
.”
Neurological impairment 
will be assessed prior to 
randomization but not at 
screening.
Clarification for sites.
Revised Protocol No.: 06
Date: 09-Oct-2020
142
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 05
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.2.1 (Phase 
1 and 2a Studies with 
BMS-986177) Table 
3.2.1-1 (Highlights of 
Clinical 
Pharmacology after 
Oral Administration 
of Single and 
Multiple Doses of 
BMS-986177 to 
Healthy Participants 
and Subjects with 
Renal or Hepatic 
Impairment), Section 
5.4.2 (BMS-986177 
with Aspirin + 
Clopidogrel)
Added Hepatic Impairment PK 
properties to the table.
Added study results for drug interaction 
study with BMS-986177 with and 
without clopidogrel and aspirin.
Provide new preliminary 
data from recently 
completed studies.
Section 4 (Objectives 
and Endpoints), 
10.3.2 (Efficacy 
Analysis)
Kept estimation of dose response but 
removed specific mention of MED and 
ED90 in the primary objective. Primary 
analysis will be based on an MCP-
MOD method.  
Also clarified MRI assessment of 
endpoint.
MED and ED90 are specific 
parts of a dose-response 
relationship. With scientific 
interest in the overall dose-
response relationship, the 
objective was made more 
general. Primary analysis to 
be made consistent with 
study design, including 
powering of study.
Revised Protocol No.: 06
Date: 09-Oct-2020
143
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 05
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1 (Overall 
Design), 5.4 
(Scientific Rationale 
for Adaptive Study 
Design), 7.2 (Method 
of Treatment 
Assignment), 7.4 
(Blinding), 10.1 
(Sample Size), 10.2 
(Randomization), 
10.3 (Statistical 
Analyses), 10.3.6 
(Exposure-Response 
Analyses),10.3.7 
(Interim RAR 
Analyses)
Removed reference to response 
adaptive randomization (RAR), 
including interim analyses, including 
removal of Early Stopping Rules in 
Section 5.1 (Overall Design, Follow-up 
Period), removal of Section 5.4 
(Scientific Rationale for Adaptive 
Study Design), removal of Section 10.2 
(Randomization). Updated the study 
schematic to reflect the new dose arms.
Removed references to dose arms for 
50 mg QD, 100 mg QD, and 200 mg 
QD BMS-986177, except to note how 
participants randomized to these arms 
are included in analyses.
Added administrative interim analysis.
To simplify the study design 
while maintaining scientific 
rigor to attain trial 
objectives, minimizing the 
number of study participants 
being exposed to the new 
investigational drug, 
reducing the burden on 
participants and 
streamlining study 
procedures. 
Section 5.2 
(Participants), 10.1 
(Sample Size)
Sample size was adjusted to indicate 
2100 participants will be needed for 
assessment of dose response, and 
allowing approximately and up to 2350 
participants to be randomized, with 
consideration of missing data.
Power was raised from 
approximately 80% (77%-
78%) to 80%.  Sample size 
also reflects changes in 
treatment arms used for 
dose response (removal of 
50-, 100-, and 200-mg QD 
arms, and keeping 25 mg 
QD as the lowest dose in the 
dose-response assessment), 
as well as modification to a 
non-RAR design using 
MCP-MOD analysis 
method.
Section 5.4.1 
(Identification of 
Effective Doses of 
BMS-986177)
Doses to achieve trough concentration 
targets were updated to 50-200 mg QD 
and 25-100 mg BID.
Review of new 
pharmacokinetic modeling 
and simulation data 
indicated the doses should 
be revised. Because of the 
potential effectiveness of 
25 mg BID, the 25-mg QD 
dose was included as the 
lowest dose in the dose-
response assessment.
Revised Protocol No.: 06
Date: 09-Oct-2020
144
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 05
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.3 (Selection 
and Timing of Dose 
for Each Participant)
Added another example to demonstrate 
flexible interval to ensure consistent 
AM-PM dosing schedule.
To ensure consistent AM-
PM dosing schedule if 
outside the specified 
window.
Section 9.2.8 
Overdose, Appendix 
3 Appendix 3 
Adverse Events and 
Serious Adverse 
Events: Definitions 
and Procedures for 
Recording, 
Evaluating, Follow 
UP and Reporting
Text was revised for reporting overdose 
as an AE to align with Janssen process.
To provide consistency 
across protocols with a 
more conservative approach 
to capturing AEs. To align 
with Janssen as they hold 
the database for the study. 
Section 9.3.2.1 
(Exploratory 
Biomarker 
Assessments), Table 
9.3.2.1-1 (Biomarker 
Sampling Schedule), 
Section 9.3.3 
(Additional Research 
Collection)
Removed RNA and miRNA sample 
collection and testing.
These markers are removed 
to reduce burdens for the 
participants and the study 
sites. They are exploratory
and are not critical data for 
the assessment of efficacy 
and safety of BMS-986177.
Revised Protocol No.: 06
Date: 09-Oct-2020
145
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Overall Rationale for Revised Protocol 04, 03-May-2019
 
 The only change implemented in this revised protocol is to exclude participants with 
arteriovenous malformation (AVM).
No objectives or endpoints have been changed from the original protocol. The table below 
highlights the changes made to the protocol.
Summary of Key Changes for Revised Protocol 04
Section Number & Title
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities,
Table 2-1
Included AVM as 
exclusionary pathology that 
could account for index 
symptoms.
To restrict enrollment of 
patients with the incidental 
imaging finding of AVM 
 
Section 6.2: Exclusion 
Criteria 1d and 1k
and
Synopsis: Key Exclusion 
Criteria 4 and 12
Revised Protocol No.: 06
Date: 09-Oct-2020
146
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Overall Rationale for Revised Protocol 03, 05-Apr-2019
The purpose of this amendment is to update the protocol in consideration of feedback from the 
study sites, Steering Committee, and regulatory agencies. Key changes include: allowance of 
clopidogrel loading doses of 300 mg to 600 mg prior to signing of informed consent; removal of 
aortic arch atheroma >4 mm in thickness from vascular imaging criteria; clarifying that MRI is not 
required to determine study eligibility; clarifying Day 1, pre-dose assessments to be completed, 
adding instructions for missed doses; providing guidance for the management of bleeding events; 
modification of the PK and PD sample collection window for the 12-hour post-first dose time point 
and the requirement of a 12- and 24-hour PK/PD sample collection for TIA subjects on Day 1; and 
change in the SAE collection duration after discontinuation of study medication. Additionally, new 
appendices were added for strong CYP3A inhibitors and inducers. An exploratory objective was 
added to assess the incidence and characteristics of cerebral microbleeds (CMBs), hemorrhagic 
transformation of ischemic stroke and asymptomatic intracranial bleeding on Day 90 MRI.
No primary or secondary objectives or endpoints have been changed from the original protocol. 
Other changes are administrative changes that do not impact the integrity of the study, such as 
typographical errors or clarifications and changes in terminology. The changes made in the body 
of the protocol were also implemented in the Synopsis, where applicable. The table below 
highlights the key changes made to the body of the protocol starting at Section 2.
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 2: Schedule 
of Activities,
Table 2-1
and 
Section 5.1
Changed the clopidogrel loading 
dose from 300 mg to 300 mg to 
600 mg when administered as 
standard-of-care prior to the 
signing of informed consent
To allow for regional or 
institutional practices for 
clopidogrel loading dose
Removed AVM as exclusionary 
pathology
To allow for enrollment of patients 
with the incidental imaging finding 
from an asymptomatic AVM. 
Removed aortic arch atheroma >4 
mm as vascular imaging criteria
To simplify the criteria used for 
the required evidence of large 
vessel atherosclerosis on vascular 
imaging, as an isolated aortic arch 
atheroma is a rare imaging finding 
and therefore not routinely 
assessed with CTA/MRA or other 
modalities after TIA/stroke
Added clarification that pre-
morbid mRS should be 3 prior 
to index event
To align eligibility criteria for TIA 
and stroke patients
Revised Protocol No.: 06
Date: 09-Oct-2020
147
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Clarified timing of sample 
collection for clinical laboratory 
tests prior to treatment
To provide clear instructions on 
the collection of pre-treatment 
safety laboratory blood samples 
for safety monitoring
Removed T1 and T2 sequences
from Study-specific MRI 
requirements
To clarify that the T1 and T2 
sequences are not part of the 
study-specific MRI protocol. 
Section 2: Schedule 
of Activities,
Table 2-2
Changed the clopidogrel loading 
dose from 300 mg to 300 mg to 
600 mg when administered as 
standard-of-care prior to the 
signing of informed consent
To allow for regional or 
institutional practices for 
clopidogrel loading dose.
Clarified that NIHSS must be 5 
at time of randomization
To ensure the safety of study 
subjects in case of potential 
fluctuations in the NIHSS between 
screening and randomization.
Clarified footnote for required 
assessment for subjects who have 
study drug discontinued
To provide further guidance to 
sites regarding required study 
related activities in the case of 
early treatment discontinuation.
Changed Day 97 visit description 
from Study Discharge to End-of 
Study 
To align with text
Added window (6 days) to Day 
90 Visit in header
Added for consistency with text
Modified required duration of 
SAE collection from 30 days to 
7 days
Modified to coincide with 
BMS-986177 half-life
Section 3.2.1: Phase 
1 and 2a Studies 
with BMS-986177,
Table 3.2.1-1
Updated table to include renal 
clearance and effect of renal 
impairment on BMS-986177 PK
Updated PK characteristics to 
provide results from renal 
impairment study
Section 4:
Table 4-1: 
Objectives and 
Endpoints for 
CV010031
Added new exploratory objective 
to assess effect of BMS-986177 
on characteristics of cerebral 
microbleeds (CMBs), 
hemorrhagic transformation of 
ischemic stroke and 
To increase understanding of 
BMS-986177 safety profile 
Revised Protocol No.: 06
Date: 09-Oct-2020
148
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
asymptomatic intracranial 
bleeding on Day 90 MRI 
Section 5.1: Overall 
Design, Screening 
Period
Added assessments to be done at 
screening
Added to align with Schedule of 
Activities (Table 2-1)
Section 5.1: Overall 
Design, Double-
Blind Treatment 
Period
Removed vital signs, ECG, PK 
sample collection and medical 
history from Day 1, pre-dose 
assessments
Removed to align with Schedule 
of Activities (Table 2-2)
Clarified assessments for 
participants who permanently 
discontinue study treatment early
To clarify that this is to be for 
subjects who permanently 
discontinue study treatment and 
not for dose interruptions
Added clarification that early 
discontinuation of study 
medication should be 
distinguished from withdrawal of 
informed consent for follow-up 
To clarify that participants who 
discontinue study treatment should 
continue study assessments unless 
they also withdraw informed 
consent
Section 5.1: Overall 
Design, Early 
Stopping Rules
Modified probability 
(RRR> 0.20) from <0.05 to <0.10 
for stopping the study early for 
futility
Corrected to align with RAR 
report
Section 5.2: 
Participants
Updated to reflect additional 
countries and sites
Updated to current operational 
status
Section 6.1: 
Inclusion Criteria
and 
Synopsis
Clarify that MRI is not required 
to determine study eligibility
To also allow subjects to be 
enrolled in the study based on CT 
imaging (consistent with accepted 
alternate modalities to detect 
ischemic stroke) to reduce the site 
and subject burden within the 
randomization window. 
Clarified that NIHSS must be 5 
at time of randomization
To ensure the safety of study 
participants in case of potential 
fluctuations in the NIHSS between 
screening and randomization.
Revised Protocol No.: 06
Date: 09-Oct-2020
149
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Removed aortic arch atheroma 
>4 mm as vascular imaging 
criteria and added criteria related 
to severity of atherosclerotic 
plaque
To simplify the criteria used for 
the required evidence of large 
vessel atherosclerosis on vascular 
imaging, as an isolated aortic arch 
atheroma is a rare imaging finding 
and therefore not routinely 
assessed with CTA/MRA or other 
modalities after TIA/stroke
Added requirement that pre-
morbid mRS must be 3 before 
the index event for TIA patients
To align the eligibility criteria for 
TIA and stroke patients
Revised total duration of 
contraceptive use for males who 
are sexually active with WOCBP
Corrected to reflect total duration 
of required contraceptive use
Section 6.2: 
Exclusion Criteria
and 
Synopsis
Added specifics regarding 
petechiae on brain imaging
To ensure participant safety, the 
definition of petechiae was clarify 
to include only hemorrhagic 
infarction type 1 (HI1) defined 
petechiae on brain imaging
Added “other PPIs” to acceptable 
concomitant medications and
disallowed cimetidine as an H2 
blocker
To allow for regional differences 
in PPI use and to minimize any 
impact on the PK of clopidogrel by 
disallowing cimetidine as it 
inhibits CYP2C19
Added reference to appendices 
including strong CYP3A 
inhibitors and inducers
To support sites in the quick 
identification of strong CYP3A4 
inhibitors and inducers.
Section 7.1: 
Treatments 
Administered
Table 7.1-1
Revised description of 
Investigational Products (IPs) in 
table
To avoid confusion and allow 
flexibility for future revisions to 
supplied IP.
Changed the clopidogrel loading 
dose from 300 mg to 300 mg to 
600 mg when administered as 
standard-of-care prior to the 
signing of informed consent
To allow for regional or 
institutional practices for 
clopidogrel loading dose.
Section 7.3: 
Selection and 
Added dosing instructions for 
missed doses
To provide detailed guidance for 
the handling of missed doses of 
blinded study medication
Revised Protocol No.: 06
Date: 09-Oct-2020
150
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Timing of Dose for 
Each Participant
Section 7.4: 
Blinding
Added scenarios where the DMC 
and the RAR vendor will receive 
unblinded data for safety 
assessment
Updated for consistency with 
DMC role and study design
Section 7.7.1: 
Prohibited and/or 
Restricted 
Treatments
Shortened the time for collection 
of medications taken prior to 
study drug administration from 30 
days to 7 days 
Added reference to appendices 
including strong CYP3A 
inhibitors and inducers
Revised to remove burden from 
sites and participants
To support sites in the quick 
identification of strong CYP3A4 
inhibitors and inducers
Section 8.1: 
Bleeding
Removed measures that may be 
considered for management of 
bleeding events and referred to 
Section 9.2.1
To update the guidance for the 
handling of bleeding based on 
newly available information
Section 8.4: 
Emergency 
Procedures
Added guidance for use of 
thrombolytic therapy for the 
treatment of new stroke, 
including possibility of 
unblinding
Based on Investigator feedback, 
added further guidance on the 
handling of the blinded study 
medication if a subject qualifies 
for tPA treatment after a new 
stroke event.
Section 8.7: Post-
Study Treatment 
Follow-up
Clarified required assessment for 
subjects who have study drug 
discontinued
To provide further guidance to 
sites regarding required study 
related activities in the case of 
early treatment discontinuation.
Section 9.2.1:
Bleeding
Added measures to consider for 
management of bleeding events 
requiring intervention
To update the guidance for the 
handling of bleeding events that 
require intervention based on 
newly available information.
Section 9.2.3:
Time Period and 
Frequency for 
Collecting AE and 
SAE Information
Modified required duration of 
SAE collection from 30 days to 
7 days
Modified to coincide with 
BMS-986177 half-life
Revised Protocol No.: 06
Date: 09-Oct-2020
151
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.2.7: 
Pregnancy
Updated language for scenario 
where study treatment may be re-
initiated following pregnancy 
Update to align with BMS 
protocol model document
Section 9.2.8: 
Overdose
Updated definition of overdose to 
match Appendix 3
To align the definition of overdose 
throughout the protocol
Section 9.2.13
Added details for brief physical 
exam
To clarify assessments that 
constitute protocol-required brief 
physical exam
Section 9.2.16: 
Clinical Safety 
Laboratory 
Assessments
Clarified collection schedule for 
clinical laboratory samples; added 
Day 60 sample
Day 60 central clinical laboratory 
assessment added 
 
.
Section 9.3.1: PK 
Assessments
and
Section 9.3.2.1: 
Biomarker Sampling 
Schedule
Changed the collection window 
for the 12-hour post first dose 
PK/PD sample on Day 1 from 
4 hours to - 6/+4 hours.
Clarified the expectation for the 
protocol-specified 12- and 24-
hour sample collection for 
participants with TIA and 
explained that the blood sample 
should be collected prior to 
hospital discharge if the 
participant is released <24 hours 
after the index event. 
Broadened the sampling window 
from + 4 hours to -6/+4 hours to 
ensure that the 12-hour post dose 
sample does not overlap with the 
2nd dose of blinded study 
medication
To allow for regional or 
institutional practice variation 
regarding hospitalization durations 
of TIA patients 
Section 9.4.2: 
Assessment of Risk 
for Subsequent 
Stroke Associated 
with Index TIA
Modified text to reflect that the 
presence of motor symptoms can 
also be used as one of the 
qualifying criteria for TIA
To allow for enrollment of TIA 
patients with an ABCD2 score of 
6 in the presence of motor 
symptoms
Section 10.1: 
Sample Size 
Determination
and
Synopsis
Clarified the composite event rate 
that is being used for sample size 
determination
Revised assumption for sample 
size determination for subjects 
who discontinue early without 
usable endpoint data from 5% to 
10%
Added for clarity of composite 
event rate being used to determine 
sample size
Revised to align with RAR report
Revised Protocol No.: 06
Date: 09-Oct-2020
152
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of key changes for Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.4.2:
Efficacy Analyses
Modified section to tabular form 
matching endpoints and statistical 
method
To align with preferred 
presentation of endpoints and 
methods
Section 10.4.3: 
Safety Analyses
Modified section to tabular form 
matching endpoints and statistical 
method
Added new exploratory objective 
endpoint
To align with preferred 
presentation of endpoints and 
methods
Section 10.4.7: 
Interim RAR 
Analyses
Added scenarios where interim 
RAR will be used to stop the trial 
early for futility or expected 
success
To clearly define early stopping 
criteria for the study based on the 
event rate of clinical stroke and 
covert brain infarction
Appendix 4
Revised total duration of 
contraceptive use for WOCBP 
from 32 days to 34 days
Corrected inconsistency for total 
duration of required contraceptive 
use
Appendix 11
Added new appendix for strong 
CYP3A inhibitors
Added to inform sites of 
commonly administered 
medications that may qualify
Appendix 12
Added new appendix for strong 
CYP3A inducers
Added to inform sites of 
commonly administered 
medications that may qualify
Revised Protocol No.: 06
Date: 09-Oct-2020
153
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Overall Rationale for Revised Protocol 02, 31-Oct-2018
 
Key changes include the addition of a Day 60 central clinical 
laboratory sample and review by the DMC after the first 450 subjects complete the Day 21 visit.  
The PK sampling schedule was changed for Days 21 and 90; PD sample collection changed to be 
consistent with the revised PK sample times and sample collection window. The BMS-supplied 
aspirin and clopidogrel designation was changed from non-Investigational Product (Non-IP) to IP. 
INR was added to the blinded analytes on Days 21 and 90. Additionally, Appendix 3 (Adverse 
Events) was updated as part of standardization of AE collection procedures and details by the 
Sponsor.
No objectives or endpoints have been changed from the original protocol, except for the removal 
of Barthel Index. Other changes are administrative changes that do not impact the scientific 
integrity of the study, such as typographical errors or clarifications and changes in terminology. 
The changes made in the body of the protocol were also implemented in the Synopsis where 
applicable. The table below highlights the key changes made to the body of the protocol starting 
at Section 2.
Summary of Key Changes for Revised Protocol 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 2:
Table 2-2
Updated table to reflect addition 
of central clinical laboratory 
sample collection at Day 60 site 
visit with expanded visit window.
Added evaluation of MoCA and 
subset of WAIS-IV by central 
laboratory
Day 60 central clinical laboratory 
assessment added 
 
.
The accuracy and reliability of 
cognitive impairment instruments used 
in clinical trials is thought to be 
improved by central laboratory 
evaluation.
Section 5.1: 
Study Design 
and Synopsis
Added DMC review after the first 
450 subjects to make 
recommendation regarding 
central clinical laboratory 
sampling.
Update study schematic and 
approximate blood volume.
 the data 
from first 450 subjects who complete 
the Day 21 visit will be reviewed by 
the DMC to make a recommendation 
about continuing central laboratory 
sampling on Day 60.
Section 5.1.1:
Data 
Monitoring and 
Other External 
Committees
Added key responsibilities of the 
DMC to make recommendation 
for continued central clinical 
laboratory testing.
See above for rationale.
The RAR is being managed by the 
Revised Protocol No.: 06
Date: 09-Oct-2020
154
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Removed details about ADC.
leading world experts for RAR design 
and they will be checking the model 
simulation results and the algorithm 
outputs. The probability of having an 
erroneous algorithm is very low. In 
addition, the DMC will review the 
RAR results every 2 months. The DMC 
statistician has sufficient experience to 
assess whether the algorithm and 
randomization allocation are 
reasonable.
Section 7.1, 
Table 7.1-1:
Study 
Treatments for 
CV010031
Updated description of placebo 
for BMS-986177 treatments and 
changed designation of aspirin 
and clopidogrel from non-
investigational product (IP) to IP
Because BMS is providing the aspirin 
and clopidogrel, the designation was 
updated to reflect standard process.
Section 7.2: 
Method of 
Treatment 
Assignment
Clarified details related to the use 
of the IRT system
Updated to reflect proper terminology 
for use of the IRT system
Section 9.2.8: 
Overdose
Updated overdose text to reflect 
new definitions in the updated 
Appendix 3 
Updated to reflect updated Appendix 3 
which describes AE collection, 
definition and reporting requirements
Section 9.2.16:
Clinical Safety 
Laboratory 
Assessments
INR added to the blinded analytes 
on Days 21 and 90
Inconsistency corrected for blinding of 
coagulation factors
Section 9.3.1.1, 
Table 9.3.1.1-1
Modified PK collection times 
relative to dose to 2 Hours (-2/+4) 
for BMS-986177, aspirin and 
clopidogrel on Days 21 and 90 
The earlier timepoint for aspirin and 
clopidogrel sampling will allow for 
more quantifiable concentrations. PK 
sample collection times for 
BMS-986177 changed to align to ease 
site burden for Day 21 and 90 visits
Section 9.3.2.1, 
Table 9.3.2.1-1
Aligned biomarker collection 
schedule with PK sample 
collection schedule by modifying 
Day 21 and 90 sample collection 
time relative to dose.
Changed to ease site burden for sample 
collection.
Revised Protocol No.: 06
Date: 09-Oct-2020
155
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 9.3.3: 
Additional 
Research 
Collection
Removed text indicating that end-
of-study is defined as 2 years 
after the final study report is 
completed.
Modified to align with standards.
Section 9.4.4
Added evaluation of MoCA and 
subset of WAIS-IV by central 
laboratory
The accuracy and reliability of 
cognitive impairment instruments used 
in clinical trials is thought to be 
improved by central laboratory 
evaluation.
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
Appendices
Replaced Appendix 3 to reflect 
updated AE reporting definitions 
and details.
Appendix updated as part of 
standardization of AE collection 
procedure and details by Sponsor.
Revised Protocol No.: 06
Date: 09-Oct-2020
156
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Overall Rationale for Revised Protocol 01, 20-Sept-2018
The purpose of this amendment is to update the protocol in consideration of 
 
 further engagement with the Steering Committee (SC) and 
Key Opinion Leaders (KOLs) which provided new insights into the target population and 
operational feasibility of the protocol as initially written. Key changes include the scenarios for 
clopidogrel use prior to randomization and modification of clopidogrel loading dose from 600 mg 
to 300 mg. Some inclusion/exclusion criteria were modified to better define the target population. 
The collection of Barthel Index, to assess the impact of stoke on daily living, was removed from 
the protocol. The introduction of the high-dose BMS 986177 groups was modified and will now 
be considered in a staggered fashion after completion of up to 600 subjects and after DMC 
recommendation. The Day 90 MRI window was modified to reduce the probability of having 
missing Day 90 endpoint data due to scheduling conflict for the MRI assessment. The PK sampling 
schedule was revised to minimize site-level impact on Day 1 and to remove PK assessments for 
clopidogrel and aspirin at most study visits.
No objectives or endpoints have been changed from the original protocol, except for the removal 
of Barthel Index. Other changes are administrative changes that do not impact the scientific 
integrity of the study, such as typographical errors or clarifications and changes in terminology for 
“non-hemorrhagic stroke” to “ischemic stroke” and “silent” brain infarction to “covert” brain 
infarction. The changes made in the body of the protocol were also implemented in the Synopsis 
where applicable. The table below highlights the key changes made to the body of the protocol 
starting at Section 2.
Summary of Key Changes for Revised Protocol 01
Section
Number & 
Title
Description of Change
Brief Rationale
Section 2:
Tables 2-1 
and 2-2
Updated tables to reflect change 
to: NIHSS score for qualifying 
event from 7 to 5, scenarios 
where a clopidogrel loading dose 
is needed, and revisions to the 
Day 90 MRI window.
Based on feedback from the SC, the 
clopidogrel loading dose and scenarios 
related to use of clopidogrel prior to 
randomization were reconsidered, as 
was the qualifying NIHSS score.
Day 90 MRI window was modified to 
minimize the risk of lost endpoint data.
Section 4: 
Objectives and 
Endpoints 
Table 4-1
Updated objectives and 
endpoints table to reflect 
removal of Barthel Index and 
change in terminology for “non-
hemorrhagic stroke” to 
“ischemic stroke” and “silent” 
brain infarction to “covert” brain 
infarction
Barthel Index was removed as it was 
thought to offer minimal additional 
information compared to other 
assessments being collected, and the 
collection would be outweighed by the 
additional operational complexity to 
collect multiple assessments.
Terminology was modified to better 
align with more generally used terms.
Revised Protocol No.: 06
Date: 09-Oct-2020
157
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 01
Section
Number & 
Title
Description of Change
Brief Rationale
Section 5.1: 
Study Design 
and Synopsis
Revised clopidogrel loading 
dose from 600 mg to 300 mg 
and clarified scenarios under 
which clopidogrel or other 
antiplatelet agents can be used 
prior to randomization.
Updated study schematic (Figure 
5.1-1) and clarified the Day 90 
MRI window.
The enrollment of participant to 
the 200 mg QD or BID 
BMS-986177 doses was also 
changed to be implemented in a 
staggered manner
Clopidogrel loading dose was reduced 
from 600 mg to 300 mg due to similar 
clinical outcomes between these two 
loading doses (ie, CHANCE vs. POINT) 
and concerns about site/country 
acceptability since the study is planned 
for global recruitment.
The Day 90 MRI window was clarified 
to allow flexibility in an attempt to 
minimize Day 90 MRI data loss.
As BMS-986177 has not been studied in 
this acute stroke population in 
combination with DAPT therapy, it is 
prudent for the Sponsor to take a 
staggered approach to ensure patient 
safety. Therefore, the high doses of 
BMS-986177 will not be started until 
some safety data are obtained and 
reviewed by the DMC.
Section 6:
Study 
Population
Various inclusion and exclusion 
criteria were modified to reflect 
feedback from SC.
Other changes were made to 
align with allowance for pre-
randomization treatment with 
clopidogrel or other antiplatelet 
agents vis a vis clopidogrel 
loading dose scenarios.
Concomitant pantoprazole use 
was allowed.
Scenarios where UFH or 
LMWH were allowed for post-
stroke DVT prophylaxis prior to 
randomization.
NIHSS score for qualifying event was 
changed from 7 to 5 based on 
feedback from SC. 
Additional risk factors for participants 
between 40-54 years of age were 
removed because these factors have no 
added value in identifying the study 
population but will increase site burden.
Use of additional antiplatelet agents 
prior to randomization were allowed and 
details were provided where needed to 
limit exclusion of otherwise eligible 
patients.
Pantoprazole use was allowed as this 
PPI was thought to have the least impact 
on clopidogrel PK and remove a barrier 
to enrollment for participants who need 
treatment with acid-reducing agents
Revised Protocol No.: 06
Date: 09-Oct-2020
158
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 01
Section
Number & 
Title
Description of Change
Brief Rationale
Section 7.2:
Treatment 
Assignment
Section updated to reflect 
staggered approach for the 200-
mg QD and/or BID dose groups
Randomization (previously equally 
allotted to 8 doses) needed to be revised 
to 6 doses due to the staggered approach 
being employed for the introduction of 
200 mg BMS-986177 QD and/or BID 
doses.
Section 7.3:
Selection and 
Timing of Dose 
for Each 
Participant
Timing of BMS-986177 dose to 
meals was removed
The dependence on meals for 
BMS-986177 dosing was removed as it 
was thought to pose additional 
operational difficulty with limited 
benefit given the anticipated small effect 
of food in the dose range being 
investigated for BMS-986177
Section 9.2.12:
Magnetic 
Resonance 
Imaging (MRI)
Clarified details for Day 90 MRI 
window.
Expanded to Day 90 MRI window to 
+10 days and reinforced the need for 
continued treatment if participants 
utilize the window. MRI window 
intended to allow site and machine 
scheduling flexibility to avoid loss of 
data for the Day 90 MRI endpoint.
Section 9.2.16:
Clinical Safety 
Laboratory 
Assessments
PT added to Clinical laboratory 
Assessments table for Days 21 
and 90
PT added to clinical laboratory 
assessments as biomarker to confirm 
target selectivity. Results noted as 
“blinded to Investigator, site staff and 
Sponsor”
Section 9.3.1.1, 
Table 9.3.1.1-1
Modified PK sample collection 
times for BMS-986177 and 
removed Day 1 sampling for 
aspirin and clopidogrel PK. 
Added collection of PK samples 
at time of new stroke or major 
bleeding event
PK sample collection schedule revised 
to minimize site burden for sample 
collection during evening hours.
Removed sample collection for aspirin 
and clopidogrel due to low benefit vs 
additional operational complexity.
Sample collection at time of outcome 
event added to help characterize study 
drug exposure for participant having an 
outcome event
Section 9.3.2.1, 
Table 9.3.2.1-1
Aligned Biomarker collection 
schedule with PK sample 
collection schedule.
Alignment of sampling schedules to 
increase site compliance and pair data 
Revised Protocol No.: 06
Date: 09-Oct-2020
159
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
Summary of Key Changes for Revised Protocol 01
Section
Number & 
Title
Description of Change
Brief Rationale
Removed CRP from biomarker 
assessment and added PT to 
sample collection schedule
collection timepoint for future PK-PD 
analyses.
CRP removed due to low value vs 
operational complexity/blood volume 
considerations. 
PT added to assess target selectivity.
Section 9.4:
Other 
Assessments
NIHSS score for qualifying 
event was changed from 7 to 
5.
Added collection of NIHSS, 
mRS, MoCA and DSST at the 
time of new stroke or major 
bleeding event.
Removed Bathel Index from 
Section 9.4.4
NIHSS score for qualifying event was 
changed from 7 to 5 based on 
feedback from SC. 
Added/clarified which assessments are 
to be collected at the time of a new 
stroke or major bleeding event to 
provide information about cognitive 
function and stroke severity close to the 
time of a new outcome event.
Barthel Index was removed as it was 
thought to offer minimal additional 
information compared to other 
assessments being collected, and the 
collection would be outweighed by the 
additional operational complexity to 
collect multiple assessments.
Section 10.2:
Randomization
Section updated to reflect 
staggered approach for 200 mg 
QD and/or BID BMS-986177 
doses 
Section aligned to changes in Study 
Design for introduction of high-dose 
BMS-986177 doses.
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
Appendices
Appendices for Barthel Index, 
NYHA Functional 
Classification, and ISTH, 
PLATO and BARC Bleeding 
Criteria removed. Other re-
numbered accordingly.
Barthel Index removed from study 
assessments.
Additional risk criteria (including 
NYHA Score) for participants from 40 
to 54 years of age removed.
Bleeding definitions to be provided 
separately in the study endpoints 
manual.
Revised Protocol No.: 06
Date: 09-Oct-2020
160
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 11
COMBINED P-GP AND STRONG CYP3A INHIBITOR LIST
1) If the participant is taking or has taken one of the combined P-gp and strong CYP3A inhibitors 
listed below in the 7 days prior to randomization, do NOT randomize into the AXIOMATIC 
(CV010031) trial (as per Protocol, Section 6.2, Exclusion Criteria 2f).
2) The participant must discontinue the study drug (BMS-986177) if they require treatment with 
one of the strong CYP3A inhibitors listed below (as per Section 8.5, Other Reasons for 
Permanent Discontinuation from Study Treatment).
3) For questions, please submit questions to the 
 system at 
. If the 
 system is unavailable at the time of your question, please call the 
 Medical Monitor 
at 
.
Therapeutic Class
Agent
Antibiotics
clarithromycin
telithromycin
troleandomycin
Antifungals
itraconazole
ketoconazole
posaconazole
voriconazole
Antivirals
boceprevir
danoprevir /ritonavir combination
ombitasvir/paritaprevir/ritonavir combination
ombitasvir/partiaprevir/ritonavir/dasabuvir 
combination
telaprevir
Calcium Channel Blockers
mibefradil
Antidepressants
nefazodone
Cancer Treatments
idelalisib
Diuretics
conivaptan
Food Products
grapefruit juice double strength*
Kinase Inhibitors
idelalisib
Treatments of HIV
atazanavir
Revised Protocol No.: 06
Date: 09-Oct-2020
161
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
cobicistat (GS-9350)
darunavir
elvitegravir /ritonavir combination
indinavir
indinavir /ritonavir combination
lopinavir /ritonavir combination
nelfinavir
ritonavir
saquinavir
saquinavir /ritonavir combination
tipranavir /ritonavir combination
* made from frozen concentrate and reconstituted with half the normal amount of water
Listing provided by BMS
Source: UW Drug Interaction Database, FDA Database®, Lexicomp Database®
Version 0.1
Revised Protocol No.: 06
Date: 09-Oct-2020
162
Approved
8.0
v
Approved
1.0
v

Clinical Protocol
CV010031
BMS-986177/JNJ-70033093
Factor XIa Inhibitor
APPENDIX 12
COMBINED P-GP AND STRONG CYP3A4 INDUCER LIST
1) If the participant is taking or has taken one of the combined P-gp and strong CYP3A inducers 
listed below in the 7 days prior to randomization, do NOT randomize into the AXIOMATIC 
(CV010031) trial (as per Protocol, Section 6.2, Exclusion Criteria 2f).
2) The participant must discontinue the study drug (BMS-986177) if they require treatment with 
one of the strong CYP3A4 inducers listed below (as per Section 8.5, Other Reasons for 
Permanent Discontinuation from Study Treatment).
3) For questions, please submit questions to the 
 system at 
. If the 
 system is unavailable at the time of your question, please call the 
 Medical Monitor 
at 
.
Therapeutic Class
Agent
Antiandrogens
apalutamide
enzalutamide
Antibiotics
rifabutin
rifampin
Anticonvulsants
carbamazepine
fosphenytoin
phenobarbital
phenytoin
primidone
Herbal Medications
St John's Wort extract
Other Antilipemics
avasimibe
Other Antineoplastics
mitotane
Listing provided by BMS
Source: UW Drug Interaction Database, FDA database®, Lexicomp®
Database Version 1.0
Revised Protocol No.: 06
Date: 09-Oct-2020
163
Approved
8.0
v
Approved
1.0
v