A Randomized, Double-Blind, Placebo-Controlled, Cross-over Phase 2 Study of Continuous 8-Hour Intravenous Infusions of BMS-986231 in Patients With Heart Failure and Impaired Systolic Function Given a Standard Dose of Loop Diuretic
Phase: PHASE2
Conditions: Cardiac Failure, Myocardial Failure, Congestive Heart Failure, Heart Decompensation
Sponsor: Bristol-Myers Squibb

 
Page: 1 
Protocol Number: CV013-034 
 
EX-US Non-IND 
 
EUDRACT Number: 2018-000970-31 
Date, Version: 15-Apr-2019 
Revised Protocol, FINAL v4.0 
 
Clinical Protocol CV013-034 
A Randomized, Double-Blind, Placebo-Controlled, Cross-over Phase 2 Study of Continuous 
8-Hour Intravenous Infusions of BMS-986231 in Patients with Heart Failure and Impaired 
Systolic Function Given a Standard Dose of Loop Diuretic 
Study Director 
 
Maria Borentain, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is the confidential and proprietary information of Bristol-Myers Squibb Company 
and its global affiliates (BMS). By reviewing this document, you agree to keep it confidential and to 
use and disclose it solely for the purpose of assessing whether your organization will participate in 
and/or the performance of the proposed BMS sponsored study. Any permitted disclosures will be 
made only on a confidential "need to know" basis within your organization or to your independent 
ethics committee(s). Any other use, copying, disclosure or dissemination of this information is strictly 
prohibited unless expressly authorized in writing by BMS. Any supplemental information (eg, 
amendments) that may be added to this document is also confidential and proprietary to BMS and 
must be kept in confidence in the same manner as the contents of this document. Any person who 
receives this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply to 
partners to which BMS has transferred obligations, eg, a Contract Research Organization (CRO). 
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DOCUMENT HISTORY 
Document 
Date of Issue 
Approver(s) 
Summary of Change 
Original Protocol 
09-May-2018 
Not applicable 
Protocol v2.0 
11-Jan-2019 
Updates were made according to Protocol 
Amendment 1.0, which includes: 
 
Update of the address for BMS 
 
Update of the Medical Monitor 
 
Update of Appendix 3 to clarify 
the definition of adverse event to 
be used in the study 
 
Correction position vital signs in 
Table 1 
In addition, minor editorial corrections 
were included 
Protocol v3.0 
14-Mar-2019 
Updates were made according to Protocol 
Amendment 2.0, which include: 
 
Allowance of more flexibility to 
the investigators regarding 
withholding diuretics and fluid 
intake and emphasizing that the 
target population should be 
patients with stable chronic heart 
failure with reduced ejection 
fraction (HFrEF) without signs of 
decompensation. 
 
Clarification that if the end of 
infusion occurs prior to 8 hours 
after start of infusion (H8), the end 
of infusion should be considered 
an early discontinuation. 
 
Minor editorial and administrative 
changes. 
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Protocol v4.0 
15-Apr-2019 
 
 
Updates were made according to Protocol 
Amendment 3.0, which include: 
 Changes to Section 5.1 Inclusion Criteria, 
to allow patients with lower levels of 
baseline natriuretic peptides and higher 
baseline estimated glomerular filtration 
rate (eGFR). 
 Minor editorial or administrative changes 
or corrections of typographical errors. 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
DOCUMENT HISTORY .................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
1 
PROTOCOL SUMMARY ............................................................................................6 
1.1 
Synopsis ........................................................................................................................6 
1.2 
Schema ........................................................................................................................10 
1.3 
Schedule of Activities (SOA) .....................................................................................10 
2 
INTRODUCTION ......................................................................................................18 
 
 
 
 
3 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4 
STUDY DESIGN .......................................................................................................25 
4.1 
Overall Design ............................................................................................................25 
4.2 
Number of Participants ...............................................................................................27 
4.3 
End of Study Definition ..............................................................................................27 
 
 
 
 
5 
STUDY POPULATION .............................................................................................29 
5.1 
Inclusion Criteria ........................................................................................................29 
5.2 
Exclusion Criteria .......................................................................................................30 
5.3 
Lifestyle Restrictions ..................................................................................................31 
5.4 
Screen Failures ............................................................................................................31 
6 
TREATMENT ............................................................................................................32 
6.1 
Treatments Administered ............................................................................................34 
6.2 
Method of Treatment Assignment ..............................................................................34 
6.3 
Blinding ......................................................................................................................34 
6.4 
Dosage Modification ..................................................................................................35 
6.5 
Preparation/Handling/Storage/Accountability ............................................................37 
6.6 
Treatment Compliance ................................................................................................37 
 
 
6.8 
Treatment After the End of the Study .........................................................................38 
7 
DISCONTINUATION CRITERIA ............................................................................38 
7.1 
Discontinuation from Study Treatment ......................................................................38 
7.2 
Discontinuation from the Study ..................................................................................39 
7.3 
Lost to Follow-Up .......................................................................................................40 
8 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1 
Efficacy Assessments .................................................................................................41 
8.2 
Adverse Events ...........................................................................................................42 
8.3 
Overdose .....................................................................................................................44 
8.4 
Safety ..........................................................................................................................45 
8.5 
Pharmacokinetics ........................................................................................................48 
 
 
8.7 
Health Economics OR Medical Resource Utilization and Health Economics ...........54 
9 
STATISTICAL CONSIDERATIONS .......................................................................54 
9.1 
Sample Size Determination ........................................................................................54 
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9.2 
Populations for Analyses ............................................................................................55 
9.3 
Endpoints ....................................................................................................................55 
9.4 
Statistical Analyses .....................................................................................................56 
 
 
11 
APPENDICES ............................................................................................................60 
APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS .............................................61 
APPENDIX 2 
STUDY GOVERANCE CONSIDERATIONS .........................................64 
APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP AND REPORTING ...............................72 
APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS 
AND METHODS OF CONTRACEPTION ..............................................77 
 
 
LIST OF TABLES 
Table 1: 
Screening Procedural Outline (CV013-034) ..............................................12 
Table 2: 
On Treatment Procedural Outline (CV013-034) .......................................13 
Table 3: 
Objectives and Endpoints ..........................................................................23 
Table 4: 
Study Treatments for CV013-034 ..............................................................33 
Table 5: 
Selection and Timing of Dose ....................................................................34 
Table 6: 
Potential Pharmacokinetic Parameters Calculated for Furosemide ...........49 
Table 7: 
Blood Sampling for Furosemide, BMS-986231 (and its 
metabolites) ................................................................................................50 
Table 8: 
Urine Collection Intervals for Urine Output and Assessment of 
Furosemide, BMS-986231, K, Na, P, Bicarbonate, Creatinine, and 
Cl ................................................................................................................51 
 
 
 
 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ............................................................................27 
 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Cross-over Phase 2 Study 
of Continuous 8-Hour Intravenous Infusions of BMS-986231 in Patients with Heart Failure 
and Impaired Systolic Function Given a Standard Dose of Loop Diuretic 
Study Phase: 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Population: 
Study participants will be stable chronic patients with HFrEF, left ventricular EF ≤ 45%, treated 
with chronic guideline-directed therapy for HF including chronic loop diuretics, 
angiotensin-converting-enzyme inhibitor (ACEi), angiotensin-receptor blockers (ARB), 
mineralocorticoid receptor antagonists (MRAs), angiotensin-receptor/neprilysin inhibitor (ARNI) 
or / and β-blockers as tolerated.  
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 Evaluate the effects of HNO donor 
BMS-986231 on 4-hour urine output in 
patients with HFrEF after 
administration of 40 mg of IV 
furosemide  
 4-hour urinary output following intravenous 
administration of 40 mg furosemide to 
HFrEF patients receiving BMS-986231 
infusion compared to placebo 
Secondary 
 Assess the effect of BMS-986231 on 
fractional excretion of Na (FeNa) 
 FeNa in patients with HFrEF while on 
BMS-986231 compared to placebo 
  Assess the effect of BMS-986231 on 
fractional excretion of K (FeK) 
 FeK in patients with HFrEF while on 
BMS-986231 compared to placebo 
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Objectives 
Endpoints 
 Assess the effects of BMS-986231 on 
furosemide urinary and plasma 
concentration and the ratio urinary 
sodium to urinary furosemide 
 Furosemide urinary and plasma concentration 
in patients with HFrEF while on BMS-986231 
compared to placebo 
 Ratio Urinary Na to Urinary furosemide after 
BMS-986231 compared to placebo 
Safety  
 
 Assess safety of BMS-986231 
 Clinically relevant hypotension during 
infusion, adverse events, clinical laboratory 
values, vital signs, ECGs, telemetry, physical 
examinations 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Design: 
This is a double blinded, randomized, two-way cross-over, placebo-controlled study to evaluate 
the effects of HNO donor BMS-986231 on 4-hour urine output in stable chronic HFrEF patients 
after administration of 40 mg of IV furosemide. The study consists of 2 one-day treatment periods 
(BMS-986231 or placebo) separated by a washout period of at least 7 days (Day 2 to at least 
Day 8), but no more than 4 weeks. Each period includes 8-hour infusion. A standard dose of 40 mg 
IV furosemide will be administered by IV bolus injection at the midpoint (4 hour, H4) of an 8-hour 
infusion. Screening for inclusion in the study will be performed up to 4 weeks before the first 
treatment day (Day 1 of the first period). Approximately 20 eligible subjects will be randomized. 
For each period, subjects must remain for at least 3.5 hours after the end of infusion. Patients may 
stay overnight or may be discharged the same day 3.5 hours after end of infusion if certain 
conditions are met (see Section 4.1 for details). The total duration of the study will be 
approximately 8 weeks. 
 
Number of Participants:  
This study will include approximately 20 participants. 
Treatment Arms and Duration: 
Study treatment: BMS-986231 or placebo will be administered in a blinded manner for 8 hours 
as continuous IV infusion. BMS-986231 will be administered at the dose of 12 µg/kg/min, 
corresponding to an infusion rate of 20 mL/H. Placebo will be an infusion of D5W that will be 
administered at the flow rate of 20 mL/H. 
At hour 4 after the start of the infusion, 40 mg IV bolus of furosemide will be administered through 
a separate IV line, given slowly over 1-2 minutes. 
In case of significant decrease in systolic blood pressure at any time during the infusion, an 
algorithm will be used to down-titrate / interrupt or discontinue the study drug infusion (see 
Section 6.4 in the protocol). 
 
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For safety and exploratory assessments, H0 (pre-dose, before start of infusion) assessments will 
be performed within 1 hour prior to dosing. Safety assessments and exploratory assessments 
postdose will be performed with time margins of ±15 minutes of the nominal time points. 
 
For urine sampling, pre-dose (before start of infusion) sampling will be started within 1 hour prior 
to dosing. Urine sample intervals postdose will be performed with time margins of ±15 minutes 
of the nominal time points. The 4.0 hours urine sample interval will be obtained within 15 minutes 
before furosemide bolus. The 8.0 hours urine sample interval will be obtained within 15 minutes 
before end of infusion. 
 
The actual time points of PK, exploratory and safety laboratory collection will be documented in 
the electronic case report form (eCRF). 
 
In the event assessments are planned for the same scheme time, the following sequence should 
be followed:  
(1) vital signs assessments including body temperature;  
(2) electrocardiogram (ECG) recording;  
(3) blood sampling.  
 
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Table 1: 
Screening Procedural Outline (CV013-034) 
Procedure 
Screening 
Visit 
Notes 
 
Eligibility Assessments 
 
 
Informed Consent 
X 
A participant is considered enrolled only when a protocol specific informed 
consent is signed. 
Inclusion/Exclusion Criteria 
X 
 
Medical History 
X 
 
 
 
 
Safety Assessments 
 
 
Physical Examination 
X 
If the screening physical examination is performed within 3 days prior to 
first dosing then a single exam may count as both the screening and pre- 
dose evaluation.  
Includes height, weight, and BMI. 
Vital Signs 
X 
Includes body temperature, respiratory rate, and supine blood pressure and 
heart rate. Blood pressure and heart rate should be measured after the 
participant has been resting quietly for at least 5 minutes. 
Adverse Events Assessment 
X 
SAEs must be collected from the date of the participant’s Informed 
consent. 
ECG 
X 
ECGs should be recorded after the participant has been supine for at least 5 
minutes. At screening, single ECGs will be recorded. 
Laboratory Tests 
X 
Includes blood (hematology, serum chemistry, NT-proBNP or BNP [details 
in the protocol section]) and urine samples. Participants are required to fast 
for at least 10 hours prior to the collection of specimens for clinical 
laboratory tests (details in the protocol Section 8.4.6). 
Pregnancy Test  
X 
For WOCBP only. 
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Table 2: 
On Treatment Procedural Outline (CV013-034) 
Procedure 
Treatment Period 
 
Notes 
 
Period 1 
Day 1  
Washout 
(7-28 days) 
Period 2 
Day 1  
Washout between periods should be at least 7 days 
and no more than 4 weeks. 
Safety Assessments 
 
 
 
 
Weight 
X 
 
X 
Weight within 15 minutes prior to and within 15 minutes after the end of the 
infusiona in each treatment period with bio-impedance scale. Weight should 
be measured after the void. 
Targeted physical examination 
X 
 
X 
To be done at H0 (before start of infusion). Based on subject’s report since 
the last visit. Includes temperature, signs and symptoms of congestion. If the 
screening physical examination is performed within 3 days prior to first 
dosing then a single physical exam may count as both the screening and at H0 
(before start of infusion) evaluation. 
Vital Signs  
(Blood pressure and heart rate) 
X 
 
X 
Prior to infusion, and 30 minutes for first hour then every 1 hour until 
discontinuation of infusion, then at H9, H10 and H11.5 (3.5 hour after end of 
infusiona) in each treatment period. 
Peripheral Oxygen Saturation 
X 
 
X 
Prior to the start of infusion and immediately prior to the end of the infusiona 
in each treatment period, measured with a pulse oximeter device. 
12-lead ECG 
X 
 
X 
Prior to the infusion and after end of infusiona (both with 15 minutes window) 
in each treatment period. Triplicate ECGs will be recorded. 
Telemetry 
X 
 
X 
From start of infusion to 3 hours after end of infusiona in each treatment 
period. 
Adverse Events Assessment 
X 
 
X 
Nonserious AEs will be collected from the start of the study drug infusion 
until 24 hours after end of infusiona in each treatment period of dosing. 
Serious adverse events must be collected from the date of Informed consent 
and will be assessed up to 30 days after end of infusiona of the last period. 
 
 
 
 
 
 
 
 
  
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Table 2: 
On Treatment Procedural Outline (CV013-034) 
Procedure 
Treatment Period 
 
Notes 
 
Period 1 
Day 1  
Washout 
(7-28 days) 
Period 2 
Day 1  
Washout between periods should be at least 7 days 
and no more than 4 weeks. 
Follow-up call/assessment 
X 
 
X 
To be done at Day 2 of each period. Will inquire about general status and 
occurrence of any AEs.  
For each period, subjects must remain for at least 3.5 hours after the end of 
infusiona. Patients may stay overnight or may be discharged the same day 3.5 
hours after end of infusiona if certain conditions are met (see Section 4.1 for 
details) 
Laboratory Tests 
 
 
 
 
Hematology and Serum 
Chemistry 
X 
 
X 
Laboratory tests will be performed in the morning of each treatment day (H0 
[before start of infusion], H4 [just before furosemide bolus], and H8). See 
protocol Section 8.4.6 for details. 
Pregnancy Test (WOCBP only) 
X 
 
X 
 
Blood sampling for PK 
(furosemide and BMS-986231 
[and its metabolites])  
X 
 
X 
Blood sampling for PK will be done at H0 (before start of infusion), H2 and 
at H4 hours (just before furosemide bolus), H5, H6, H8 (or end of infusiona) 
and H10 (2 hours after the end of the infusiona) in each treatment period. 
In addition, PK samples should be taken when the dose is lowered or 
discontinued (see protocol Section 8.5). 
Blood sampling for Na, K, 
bicarbonate, creatinine, and 
eGFR  
X 
 
X 
Blood sampling for Na, K, bicarbonate, creatinine, and eGFR will be done at 
H0 (before start of infusion), H4 (just before furosemide bolus), H5, H6, H7, 
H8 (or end of infusiona) in each treatment period. 
Urine sampling for furosemide 
and BMS-986231 (or its 
metabolites) 
X 
 
X 
Urine samples can be taken from the urine collection intervals done for the 
urinary output (see Table 8 in Section 8.5.1). An aliquot for both sets of 
metabolites and a back-up will be required for the analysis.  
Urine sampling for Na, K, P, 
Cl, creatinine and bicarbonate 
concentrations 
X 
 
X 
Urine samples can be taken from the urine collection intervals done for the 
urinary output (see Table 8 in Section 8.5.1).   
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Table 2: 
On Treatment Procedural Outline (CV013-034) 
Procedure 
Treatment Period 
 
Notes 
 
Period 1 
Day 1  
Washout 
(7-28 days) 
Period 2 
Day 1  
Washout between periods should be at least 7 days 
and no more than 4 weeks. 
Efficacy Assessments 
 
 
 
 
Urinary output 
X 
 
X 
Prior to start of infusion, patients will be asked to void and urine collected. A 
bladder scan (ultrasound) can be performed to ensure adequate bladder 
emptying. Patients will be asked to void at least every 2 hours during the first 
4 hours post-start infusion and before furosemide bolus, and at least hourly 
from 4 to 8 hours post-start infusion. A second bladder scan can be performed 
at H8 (8 hours after start of infusion and just after study drug discontinuation 
and after the void).  
A final void will be done at 2 hours after the study drug discontinuationa.  
The urine will be collected and volume recorded for each collection interval. 
Whole body bio-impedance 
 
 
 
Prior to start of study drug infusion, at H4 (4 hours after the start of infusion 
and prior to furosemide bolus), at H8 (8 hours after the start of infusion and 
prior to study drug discontinuation), H10 (2 hours after the end of the 
infusiona) in each treatment period. 
Echocardiography 
X 
 
X 
Prior to start of study drug infusion, at H4 (4 hours after the start of infusion 
and prior to before furosemide bolus), at H5, H6, H8, and H10 (2 hours after 
the end of the infusiona in each treatment period).  
Lung ultrasound 
X 
 
X 
Prior to start of study drug infusion, at H4 (4 hours after the start of infusion 
and before furosemide bolus) and at H8 (end of infusiona). 
Clinical Drug Supplies 
 
 
 
 
Randomize 
X 
 
 
Subjects will be randomized prior to start of infusion. Subjects will be 
randomized 1:1 to either BMS-986231 or Placebo in Period 1 and to either 
placebo or BMS-986231 in Period 2, such that within a sequence each patient 
will receive in random order one infusion of placebo. 
Administration of Study Drug 
X 
 
X 
 
Administration of furosemide 
bolus 
X 
 
X 
Furosemide bolus administration at H4 (4 hours after start of infusion of 
BMS-986231 or Placebo). 
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Table 2: 
On Treatment Procedural Outline (CV013-034) 
Procedure 
Treatment Period 
 
Notes 
 
Period 1 
Day 1  
Washout 
(7-28 days) 
Period 2 
Day 1  
Washout between periods should be at least 7 days 
and no more than 4 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a If end of infusion occurs prior to 8 hours after start of infusion (H8), the end of infusion should be considered early discontinuation. In case of an early 
discontinuation, the timing for the assessments will be adapted accordingly, ie, H8 will be immediately after end of infusion, H9 will be 1 hour after end of infusion, 
H10 will be 2 hours after end of infusion, H11 will be 3 hours after end of infusion, and H11.5 will be 3.5 hours after end of infusion, as applicable.  
 
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STUDY ACKNOWLEDGMENT/DISCLOSURE 
I understand that this protocol contains information that is confidential and proprietary to Bristol-Myers Squibb 
Company (BMS). Any supplemental information that may be added to this document is also confidential and 
proprietary to BMS and must be kept in confidence in the same manner as the contents of this protocol. 
I have read the original protocol and agree that it contains all necessary details for carrying out the study as described. 
I will conduct this protocol as outlined therein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide copies of the protocol and access to all information furnished by BMS to study personnel under my 
supervision. I will discuss this material with them to ensure that they are fully informed about the investigational 
product and the study. 
I will provide protocol information to my Institutional Review Board(s) [IRB(s)] or Independent Ethics Committee(s) 
[IEC(s)]. I understand that original protocol/revised protocols must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given favorable opinion by all 
necessary Health Authorities before implementation unless to eliminate an immediate hazard to subjects. 
I agree that the contents of the protocol may not be disclosed to any other person or entity or used for any other purpose 
without the prior written consent of BMS. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, I will give prompt notice to BMS of any such disclosure. 
I agree that the study data derived from this protocol may only be used and disclosed in furtherance of the protocol, 
for the medical treatment of a study subject or for publication of study results in accordance with the terms of the 
clinical trial agreement or as otherwise permitted by the terms of the clinical trial agreement. 
I agree not to collect or use samples (e.g., tissue, blood, serum, urine) or collect data (other than for diagnostic or 
treatment purposes) from the study subjects while enrolled in the study, except as expressly permitted by the protocol 
or the terms of the clinical trial agreement. 
I understand that I may terminate or suspend enrollment of the study at any time if it becomes necessary to protect the 
best interests of the study subjects. Unless otherwise provided in the clinical trial agreement, the study may be 
terminated at any time by BMS, with or without cause. 
Original Protocol: 
 
 
Revised Protocol: 
 
Protocol Number: CV013-034 
 
Site Number:  
Date 
of 
Protocol 
or 
Revised 
Protocol: 
15-Apr-2019 
 
 
IND Number: NA 
 
EUDRACT Number: 2018-000970-31 
 
 
 
Investigator:  
 
Date:  
(signature) 
 
 
(printed name) 
 
 
 
 
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2 
INTRODUCTION 
Heart failure (HF) is a leading cause of morbidity and mortality. Acute decompensated heart 
failure (ADHF) is the number one cause of hospitalization in the elderly, and is associated with 
considerable morbidity, mortality and economic cost.1,8,9,10,11 Although advances in drug and 
device treatment of chronic HF over the past 40 years have led to improvements in outcome of 
these patients, the morbidity and mortality of HF remains high. In contrast, there have been few 
advances in the approach to treat episodes of ADHF over the same time period, and no 
therapies have been demonstrated to improve long- term clinical outcomes.12 
Standard of care therapies for ADHF are based on the use of intravenous (IV) diuretics to 
promote fluid removal to reduce dyspnea, and in some patients, oral or IV vasodilators, to reduce 
the load on the heart and improve cardiac performance. Collectively, these treatments may 
reduce dyspnea but do not target the primary cause of HF, impaired cardiac contractility. Drugs 
that specifically enhance diminished cardiac contractility, called inotropic agents, may have an 
important role to help rapidly improve hemodynamics leading to rapid symptom relief. However 
the use of currently available cardiac inotropic drugs is associated with increased heart rate and 
myocardial oxygen consumption, induction of atrial and ventricular arrhythmias, concerns about 
provocation of ischemia, and adverse long-term outcomes, limiting the use of these inotropic 
agents to low cardiac output state with signs of end-organ hypoperfusion.13,14,15 
An agent that increases contractility, while avoiding the adverse safety profile of an inotropic 
agent and retaining the capacity to unload the heart, could address a significant unmet medical 
need and be used in a broader patient population. 
In this context, BMS-986231, a second generation HNO donor, is being developed in ADHF. It 
has demonstrated vasodilation, enhanced inotropy and improved relaxation in animal models and 
improved hemodynamics consistent with vasodilation and inotropic effect in early studies in 
humans. 
Heart failure continues to be a leading cause of morbidity and mortality in the developed world. 
In the United States alone, an estimated 5.7 million people have HF, contributing to approximately 
1 million hospital admissions and 280,000 deaths annually. In patients with ADHF, standard 
therapies are targeted at fluid removal (via diuretics) and reduction of cardiac preload and afterload 
(via vasodilators). In addition to diuretics and vasodilators, the use of parenteral inotropes to 
improve cardiac contractility more directly is warranted in a subset of patients. Administration of 
conventional inotropic agents requires close monitoring in the hospital’s intensive care unit setting 
due to potential safety risks such as tachyarrhythmia and hypotension, and is also associated with 
increased myocardial oxygen consumption and longer-term adverse outcomes. Therefore, there is 
a need for a safe and effective therapy that would reduce cardiac loads in the clinical setting of 
ADHF, while safely enhancing cardiac output through improvement of diastolic and systolic 
function. 
HNO (nitroxyl, nitrosyl hydride, or hydrogen oxonitrate) is a compound closely related to NO 
(nitric oxide). However, their physiological effects and biological mechanisms of action are 
distinct. The biological effects of HNO are reversible and thought to be mediated by direct reaction 
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with thiolates in myocardial and vascular target proteins in an O2-independent manner.1,2,3,4 In 
animal models of HF, HNO reduces both preload and afterload and enhances the relaxation and 
contractility of the failing heart.5,6 Vasodilation by HNO appears to be mediated at least in part by 
soluble guanylate cyclase. In cardiomyocytes, HNO modifies both the ryanodine receptor and the 
cardiac sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA)/phospholamban to 
increase the efficiency of calcium cycling without a concomitant increase in overall cellular 
calcium levels. In addition, HNO donors do not increase heart rate (HR) or myocardial oxygen 
consumption (MVO2).7 HNO cannot be administered directly and must be delivered as a prodrug 
(ie, an HNO donor). Suitable bioanalytical methods for measuring concentrations of HNO in 
biologic samples do not exist; therefore, characterization of the prodrug and metabolites serves as 
the primary means of understanding HNO disposition. 
BMS-986231 is a pH-sensitive prodrug of HNO that is being developed for IV administration for 
the treatment of ADHF. Following IV administration, BMS-986231 nonenzymatically releases the 
active pharmacophore, HNO, and an inactive sulfinic acid byproduct that is designated 
BMT 284730.  
Preclinical in vivo studies show that infusion of BMS-986231 produces consistent cardiovascular 
(CV) effects in several models, with a minimum effective dose of 0.7 μg/kg/min. These effects 
include peripheral vasodilation, increased inotropy, and improved lusitropy; they persist for the 
duration of infusion and partially resolve within 60 minutes after the end of infusion. The CV 
effects are evident in both normal and failing myocardium and occur without evidence of direct 
chronotropy or increased myocardial oxygen demand. BMS-986231 has demonstrated favorable 
hemodynamic effects in patients with advanced HF, including reductions in right and left 
ventricular filling pressures and increase in cardiac index. The salient features of the compound 
are further described below. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of BMS-986231 is 
provided in the Investigator’s Brochure (IB).16  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 Evaluate the effects of HNO donor 
BMS-986231 on 4-hour urine output in 
patients with HFrEF after 
administration of 40 mg of IV 
furosemide  
 4-hour urinary output following intravenous 
administration of 40 mg furosemide to 
HFrEF patients receiving BMS-986231 
infusion compared to placebo 
Secondary 
 Assess the effect of BMS-986231 on 
fractional excretion of Na (FeNa) 
 FeNa in patients with HFrEF while on 
BMS-986231 compared to placebo 
 Assess the effect of BMS-986231 on 
fractional excretion of K (FeK) 
 FeK in patients with HFrEF while on 
BMS-986231 compared to placebo 
 Assess the effects of BMS-986231 on 
furosemide urinary and plasma 
concentration and the ratio urinary 
sodium to urinary furosemide 
 Furosemide urinary and plasma concentration 
in patients with HFrEF while on BMS-986231 
compared to placebo 
 Ratio Urinary Na to Urinary furosemide after 
BMS-986231 compared to placebo 
Safety  
 
 Assess safety of BMS-986231 
 Clinically relevant hypotension during 
infusion, AEs, clinical laboratory values, 
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Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
vital signs, ECGs, telemetry, physical 
examinations 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
 
 
 
 
 
  
 
 
4 
STUDY DESIGN 
4.1 
Overall Design 
This is a double blinded, randomized, two-way cross-over, placebo-controlled study to evaluate 
the effects of HNO donor BMS-986231 on 4-hour urine output in stable chronic HFrEF patients 
after administration of 40 mg of IV furosemide. The study consists of 2 one-day treatment periods 
(BMS-986231 or placebo) separated by a washout period of at least 7 days (Day 2 to at least 
Day 8), but no more than 4 weeks. Each period includes 8-hour infusion. A standard dose of 40 mg 
IV furosemide will be administered by IV bolus injection at the midpoint (4 hour, H4) of an 8-hour 
infusion. Screening for inclusion in the study will be performed up to 4 weeks before the first 
treatment day (Day 1 of the first period). Approximately 20 eligible subjects will be randomized. 
For each period, subjects must remain for at least 3.5 hours after the end of infusion. Patients may 
stay overnight or may be discharged the same day 3.5 hours after end of infusion if certain 
conditions are met (see Section 4.1). The total duration of the study will be approximately 8 weeks. 
 
Study Drug 
BMS-986231 or placebo will be administered in a blinded manner for 8 hours as continuous IV 
infusion. BMS-986231 will be administered at the dose of 12 µg/kg/min, corresponding to an 
infusion rate of 20 mL/H. Placebo will be an infusion of D5W that will be administered at the flow 
rate of 20 mL/H. 
At hour 4 after the start of the infusion, 40 mg IV bolus of furosemide will be administered through 
a separate IV line, given slowly over 1 to 2 minutes.  
In case of significant decrease in SBP at any time during the infusion, an algorithm will be used to 
down-titrate / interrupt or discontinue the study drug infusion (see Section 6.4 in the protocol). 
Screening 
Screening for inclusion in the study will be performed up to 4 weeks before the first treatment day. 
Screening will assess the eligibility criteria. After screening, study participants will be enrolled in 
the study according to their eligibility as per the inclusion and exclusion criteria, and will be 
randomized to 1 of the 2 sequences that will be conducted in parallel. 
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Treatment Day (Day 1 of Each Period) 
Study participants will be admitted to the study facility the day before or on the treatment day, 
according to local practice and patient preferences. Assessment of symptoms and signs of HF, 
including body weight, vital signs and laboratory tests will be performed pre-dose (before start of 
infusion). On each treatment day, blood pressure and HR should be within the inclusion / exclusion 
criteria limits prior to study drug administration. The study drug infusion could start without 
waiting for the results of the laboratory assessments done in the morning of the treatment day at 
the study facility if the following criteria are met: 
 The results of the laboratory assessment at screening / previous period are within ranges 
compatible with inclusion criteria,  
 The study participant was medically stable with no signs of overt HF decompensation or 
deteriorating signs and symptoms of congestion and without change in medication since 
the screening visit / previous period.  
If the laboratory tests (e.g. electrolytes, serum creatinine, estimated glomerular filtration rate 
(eGFR), hemoglobin, transaminases) on the morning prior to infusion, are not within inclusion and 
exclusion criteria limits, the study drug could be interrupted / discontinued after consultation with 
the Medical Monitor. The abnormalities should be corrected before the next treatment period.  
Physical examinations, vital sign measurements, 12-lead ECG and urinary output will be 
performed at selected times throughout the dosing interval. Participants will be closely monitored 
for AEs throughout the study. Blood samples will also be collected at selected intervals after start 
of study drug administration for PK analysis and biomarkers. 
Prior to start of the infusion, study participants will be asked to void and urine collected. A bladder 
scan can be performed to ensure adequate bladder emptying. Patients will be asked to void at least 
every 2 hours during the first 4 hours post-start infusion and before furosemide bolus, and at least 
hourly from 4 to 8 hours post-start infusion. At 8 hours after start of study drug infusion, just before 
study drug discontinuation, a void will be done, collected and recorded and a second bladder 
ultrasound can be performed to ensure adequate bladder emptying. Urine will be collected until 2 
hours after the study drug discontinuation. 
Discharge 
Study participants may remain overnight at the study facility. There is the possibility to discharge 
the patients the same day if the following conditions are met: 
 Study participants have been under medical supervision for approximately 3.5 hours 
post-dose  
 In the opinion of the investigator an overnight stay is not warranted  
 There is no hypotension or other events of concern after mobilization  
 None of the following events occurred during the study drug infusion: prolonged 
hypotension, symptoms of hypotension, new onset of sustained arrhythmia requiring 
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5 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
 
5.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Subjects will be required to provide a written informed consent.  
2) Type of Participant and Target Disease Characteristics 
a) Males and Females, ages 18 or age of majority or older. 
b) Left ventricular EF <45%, as assessed by echocardiography, a multigated acquisition 
(MUGA) scan or magnetic resonance imaging (MRI) scan within 18 months.  
c) On stable chronic guideline-directed therapy for HF including chronic loop diuretics, 
ACEi, ARBs, MRAs, ARNI or / and β-blockers as tolerated, with no changes of these 
medications in the past 2 weeks. 
d) Not applicable per Protocol Amendment 3.0. 
e) Not applicable per Protocol Amendment 3.0.  
f) Not applicable per Protocol Amendment 3.0. 
g) Elevated natriuretic peptides (N terminal-pro BNP [NT-proBNP] ≥ 200 pg/mL or brain 
natriuretic peptide [BNP] ≥ 60 pg/mL). For subjects with atrial fibrillation, NT-pro BNP 
≥ 400 pg/mL or BNP ≥ 120 pg/mL. 
h) eGFR between 30 and 80 mL/min/1.73m2. 
3) 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 human chorionic 
gonadotropin [HCG]) within 24 hours prior to the start of each study treatment. 
b) Women must not be breastfeeding. 
c) WOCBP must agree to follow instructions for methods of highly effective contraception 
(APPENDIX 4) for 31 days after discontinuation (duration of study drug exposure plus 
30 days duration of one ovulatory cycle). 
d) Males who are sexually active with WOCBP must require these partners to follow 
instructions for highly effective methods of contraception (APPENDIX 4) for 91 days after 
discontinuation (duration of study drug plus 90 days (duration of sperm turnover). 
e) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
but still must undergo pregnancy testing as described in this section. 
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. 
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Investigators shall advise on the use of highly effective methods of contraception (APPENDIX 4) 
which have a failure rate of < 1% when used consistently and correctly. 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1) Target Disease Exceptions 
a) SBP < 115 mm Hg or > 180 mm Hg at screening or pre-randomization.  
b) Heart rate < 50 beats per minute (bpm) or > 120 bpm at screening or pre-randomization. 
c) Primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, 
idiopathic hypertrophic or uncorrected severe valvular disease as defined by American 
Heart Association (AHA)/American College of Cardiology (ACC)/European Society of 
Cardiology (ESC) criteria. 
d) Patients with urinary/prostate disorders with urinary retention/significant bladder 
dysfunction or urinary incontinence. 
e) Inability to comply with the serial urine collection procedures. 
f) Pericardial tamponade or constrictive pericarditis. 
g) Left ventricular (LV) assist device or prior heart transplant. 
h) Hospitalized for acute decompensated HF in the previous month. 
i) New York Heart Association (NYHA) Class IV symptoms of HF. 
j) Hospitalized with acute coronary syndrome, coronary revascularization or acute 
myocardial infarction during the previous 90 days prior to screening. 
k) Have a history of a cerebral vascular accident (cerebrovascular accident [CVA] or stroke) 
or of a transient ischemic attack (TIA) during the previous 90 days prior to screening. 
l) Considered clinically unstable for any condition. 
m) Serious comorbid non-cardiovascular disease in which the life expectancy of the subject is 
< 3 months. 
n) Liver disease defined as history of cirrhosis with evidence of portal hypertension such as 
varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 34.2 μmol/L) or significant 
elevation of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase 
[ALT] > 3 times the upper limit of normal). 
o) Prior solid organ transplant. 
2) Prior/Concomitant Therapy 
a) Patients taking thiazides / metolazone or potassium-sparing diuretics (with the exception 
of spironolactone or eplerenone at doses ≤ 50 mg/day which are allowed). 
3) Physical and Laboratory Test Findings 
a) Have persistent abnormal serum electrolytes not resolved between screening and start 
of the study drug infusion, as defined by any of the following: 
i) A sodium (Na+) concentration < 130 or > 145 mEq/L (mmol/L). 
ii) A potassium (K+) concentration < 3.2 or > 5.5 mEq/L (mmol/L). 
b) Have severe anemia, as documented by a hemoglobin < 9 g/dL (< 5.59 mmol/L). 
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4) Allergies and Adverse Drug Reaction 
a) Any history of allergic reaction to components of BMS-986231, Captisol® or potassium 
acetate. 
b) Any history of allergic reactions to furosemide. 
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’s approval is required). 
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness. 
c) Participation in an investigational clinical drug study within 30 days or 5 elimination half-
lives, (whichever is longer) prior to randomization. 
d) Prior participation and treatment in a study using BMS-986231.  
e) Alcohol beverage consumption within 6 hours prior to randomization. 
f) Body weight < 45 kg or ≥ 140 kg. 
g) Site personel and their families. 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 
5.3 
Lifestyle Restrictions 
5.3.1 
Meals and Dietary Restrictions 
Study participants will be asked to eat their usual diet, but it should remain similar for the 3 days 
prior to the infusion. Patients should keep a 3-day diet diary to record what they consume. During 
the infusion, study participants will be given up to 200 mL / hour as fluid intake, as tolerated. 
Urinary output will be collected every 2 hours in the first 4 hours and then hourly from 4 hours to 
8 hours after start of infusion.  
On each treatment day standardized meals and snacks will be served. No fasting is required the 
evening prior to each treatment day. 
5.3.2 
Caffeine, Alcohol and Tobacco 
Study participants will avoid alcohol in the 6 hours prior to infusion start and caffeine in the 
12 hours prior to infusion start and during the stay in the clinic. Smoking is not allowed during the 
stay in the clinic. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. 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 
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authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs. 
5.4.1 
Retesting During Screening or Lead-In Period 
Participant Re-enrollment: This study permits the re-enrollment of a participant that did not 
initially meet Inclusion/Exclusion criteria (i.e., participant has not been randomized). If re-
enrolled, the participant must be re-consented. 
Laboratory parameters and/or assessments that are included in Table 1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter could allow for the patient to be randomized. 
6 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation. 
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following: 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
In this study the investigational products are BMS-986231 for injection and placebo. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
In this study, the required potassium acetate used as a buffer for BMS-986231 infusions and 
furosemide are considered non-investigational products. 
Study medication will be prepared by an unblinded pharmacist (or appropriate designee) on Day 1 
of each period (treatment day), at time of randomization in the first period and before start of the 
infusion for the second period. Detailed instructions for preparing, reconstituting, and handling of 
BMS-986231 and placebo, as well as infusion setups, instructions for labeling individual infusion 
bags after they are prepared, and information on dosing solution stability are provided in the Study 
Pharmacy Manual. 
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Table 4: 
Study Treatments for CV013-034 
Product Description / 
Class and Dosage 
Form 
Potency 
IP/Non-IMP 
Blinded or Open 
Label 
Packaging / Appearance 
Storage Conditions 
(per label) 
BMS-986231 For 
Injectiona 
240 mg/vial 
IP 
Blinded 
Vial(s) in a carton 
Refer to the label 
on container and/or 
pharmacy 
manual 
Furosemide 
10 mg/mL 
Non-IMP 
Open Label 
TBD 
Refer to the label 
on container and/or 
pharmacy 
manual 
Placebo 
Not Applicable 
IP 
Blinded 
TBD 
Refer to the label 
on container and/or 
pharmacy 
manual 
Potassium Acetate 
Injection, USPb 
2 mEq/mL 
Non-IMP 
Open Label 
Vial(s) in a 
carton. 
Refer to the label 
on container or 
package insert / 
summary of 
product 
characteristics 
a BMS-986231 for infusion contains active pharmaceutical ingredient BMS-986231 240 mg/vial formulated with Captisol® 3405 mg/vial 
b Potassium Acetate Injection may be supplied by BMS centrally (ex-US sites) or through site sourcing procedures. It is used as a buffer for BMS-986231 
infusion (1 mEq potassium per 100 mL of reconstituted BMS-986231 further diluted for infusion). 
 
 
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6.1 
Treatments Administered 
The selection and timing of dose for each participant is as follows: 
Table 5: 
Selection and Timing of Dose 
Study Treatment 
Unit dose 
strength(s)/Dosage 
level(s) 
Dosage formulation 
Frequency of 
Administration 
Route of Administration 
BMS-986231 
12 µg/kg/min for 8 hours 
(20 mL/H) 
Single infusion 
IV 
Placebo* 
20 mL/H for 8 hours 
Single infusion 
IV 
Furosemide 
40 mg 
Single IV bolus 
IV 
* Placebo will be a solution of 5% dextrose (D5W) that will be locally supplied by the site. 
Restrictions related to food and fluid intake are described in Section 5.3. 
6.2 
Method of Treatment Assignment 
All subjects who sign informed consent and are enrolled (including those not subsequently 
randomized or treated) will be assigned sequential subject numbers. Eligible subjects will be 
randomized according to a computer-generated randomization scheme.  
If a potential subject is rescreened, a new identification number will be used. 
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001, (e.g., 00001, 00002, 00003.... 00020). Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be randomized. Randomization numbers will be 
assigned prior to dosing. Subjects who are re-enrolled (See Section 5.4) will be assigned a new 
participant number. 
Participants will not be replaced if they are discontinued from the study. 
6.3 
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, ie, that it will alter the participant's immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the participant is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment be 
discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding AFTER 
the decision to discontinue the participant has been made. 
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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. 
In case of an emergency, the investigator may open the emergency unblinding envelope to reveal the 
identity of the study drug for that participant. If such unblinding occurs, the investigator shall notify 
the Medical Monitor immediately. This information, including the reason for the blind being broken, 
must be recorded on the appropriate study status page of the Case Report Form (CRF). In addition, 
the information that is requested on the emergency unblinding envelope must be completed. 
Randomization schedules will be shipped directly to a pharmacist or other individual(s) who will be 
responsible for the dispensing of blinded study drug. This (these) individual(s) will be unblinded to 
study drug identification but will not be involved in any other aspect of study conduct. The 
randomization schedules will be maintained in a secure location with access limited to authorized 
personnel. 
6.3.1 
Other Blinding and Unblinding 
The Bioanalytical Sciences section or its designate may be unblinded to the randomized treatment 
assignments, in order to minimize unnecessary assays of samples from subjects during the placebo 
treatment period. Likewise, the Metabolism and Pharmacokinetics section or its designate may be 
unblinded, if metabolite profiling work is conducted. 
In certain circumstances, a pharmacokineticist or designate(s) in Clinical Pharmacology and 
Pharmacometrics, biostatistician(s) and programmer(s) at BMS, or designee, may be unblinded in 
order to prepare preliminary summaries of PK and safety data, as needed. These summaries will not 
reveal individual subjects’ treatment sequence assignments. 
6.4 
Dosage Modification 
BMS-986231 or placebo 
The administration of the study drugs will be done through an infusion pump connected to a single 
peripheral IV line. After priming the infusion set tubing and connecting the lines to the IV catheter, 
the pump should be set to deliver the rates of infusion indicated on the infusion bag label. 
The pump infusion volume display should be re-set to 0 after priming the infusion line and just prior 
to the start of the infusion, and the total volume infused at the conclusion of the infusion after 8 hours, 
or at the time of any early discontinuation, should be recorded in the clinic source documents. 
At any time during the administration of study drug, the study drug infusion must be discontinued if 
an AE or any other safety issue suggests it is not in the patient’s best interest to continue to receive 
study drug. 
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The investigator has the option to adjust the study drug dosage level downward by 50%, interrupt or 
discontinue the study drug infusion in patients that develop hypotension, or if the patient experiences 
symptomatic hypotension that is not easily tolerated, as follows (and shown in Figure 2): 
 
Study drug reduction: Study drug is decreased by 50% if SBP decreases to levels <90 mmHg 
but ≥80 mmHg. The dose cannot be subsequently increased. 
 
Study drug interruption: Study drug is interrupted for 1 hour if SBP <80 mmHg or symptoms 
of low blood pressure occur. If the SBP is ≥ 105 mmHg after one hour interruption, the study 
drug could be resumed at 50 % of the dose.  
 
Study drug discontinuation: Study drug will be permanently discontinued if SBP remains 
< 105 mmHg after 1 hour interruption or if SBP decreases to levels <80 mmHg or symptoms 
of low blood pressure occur.  
After a dose reduction, the dose cannot be increased again. Study drug will be permanently 
discontinued after it has been down titrated once, and criteria for dose reduction or interruption has 
been met again. 
If an infusion in a given period is discontinued, patients remain eligible to complete the subsequent 
period. 
Any decision to lower the dosage level of study drug or discontinue study drug should be based on 
the investigator’s assessment of the patient’s overall clinical stability, in the context of appropriate 
ongoing monitoring of the patient’s condition. 
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A 50% dosage adjustment downward will be achieved by decreasing the rate of study drug infusion 
from 20 mL/H to 10 mL/H. 
Furosemide will be administered through an IV bolus injection at H4 of study drug infusion. In the 
event the study drug has been reduced, furosemide injection is administered at H4 as planned. If the 
study drug has been temporarily interrupted, then restarted, furosemide will be administered after at 
least 4 hours of effective study drug infusion. 
6.5 
Preparation/Handling/Storage/Accountability 
The investigational product should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only dispensed to study 
participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study treatment arise, the study treatment should not be 
dispensed and contact BMS immediately. 
Please refer to Pharmacy Manual for additional guidance on storage of study drug. Study drug not 
supplied by BMS will be stored in accordance with the package insert. Please refer to APPENDIX 2 
for guidance on IP records and documentation. 
Once study medication is reconstituted by the unblinded pharmacist, it will remain stable at room 
temperature for a maximum of 8 hours. Reconstituted study medication must be refrigerated 
immediately if dosing will not start within 1 hour. 
It is recommended that study medication be removed from the refrigerator and left at room 
temperature for approximately 30 minutes prior to the start of the infusion. 
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets). 
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations. 
Further guidance and information for final disposition of unused study treatment are provided in 
APPENDIX 2. 
6.5.1 
Retained Samples for Bioavailability / Bioequivalence 
Not applicable. 
6.6 
Treatment Compliance 
Not applicable. 
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7 
DISCONTINUATION CRITERIA 
7.1 
Discontinuation from Study Treatment 
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
 Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol-specified follow-
up procedures. The only exception to this is when a participant specifically withdraws consent for 
any further contact with him/her or persons previously authorized by participant to provide this 
information. 
 Any clinical 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 the program by BMS. 
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 Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. 
 If study medication has been interrupted for low blood pressure, resumed, and an episode of 
hypotension (or symptoms of hypotension) reoccurs. 
 Occurrence of pregnancy. 
 
Refer to the Schedule of Activities (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed. 
In the case of pregnancy, the investigator must immediately notify the 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. In most cases, the study treatment will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for participant safety). Please 
notify the Medical Monitor within 24 hours of awareness of the pregnancy. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of study treatment, a 
discussion between the investigator, the Medical Monitor/designee, and the patient must occur. 
All participants who discontinue study treatment should comply with protocol-specified follow-up 
procedures as outlined in the Schedule of Activities, Section 1.3. 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 CRF page. 
7.1.1 
Post-Study Treatment Study Follow-Up 
In this study, follow-up is a key endpoint of the study. Post-study follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 4 until death or the conclusion of the study. 
Participants who discontinue study treatment may continue to be followed. 
7.2 
Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons previously 
authorized by participant to provide this information.  
 Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
 The withdrawal of consent should be explained in detail in the medical records by the investigator 
and entered on the appropriate CRF page. 
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 In the event that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
 If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
7.3 
Lost to Follow-Up 
 All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
 Lost to follow-up is defined by the inability to reach the participant after a minimum of 3 
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. 
 If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
 If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining participant’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study.  
 The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
 If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 Study procedures and timing are summarized in the Schedule of Activities (Section 1.3).  
 Protocol waivers or exemptions are not allowed. 
 All immediate safety concerns must be discussed with the Medical Monitor 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 (Section 1.3), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria before randomization. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities (Section 1.3). 
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8.1 
Efficacy Assessments 
8.1.1 
Urinary Output 
4-Hour urinary output after the 40 mg furosemide bolus will be measured at the time points indicated 
in the Schedule of Activities (Section 1.3) and Table 8. The 4-hour urinary output after the 40 mg 
furosemide bolus in the BMS-986231 treatment period will be compared to baseline (4-hour urinary 
output after 40 mg furosemide bolus in placebo period). 
8.1.2 
Fractional Excretion of Na (FeNa) and K (FeK) 
The plasma and urine concentrations of Na and K will be measured at the time points in the Schedule 
of Activities (Section 1.3), in Table 7 (blood sampling time points) and in Table 8 (urine collection 
intervals). The FeNa (%), FeK (%) and the concentration ratio of urinary sodium to urinary 
furosemide after the 40 mg furosemide bolus (collected 4-8 hours post-start infusion) will be 
compared to baseline (4-8 hour levels post-start infusion placebo period). 
 
8.1.3 
Imaging Assessment for the Study 
Echocardiography 
Assessments will be done at the time points indicated in the Schedule of Activities (Section 1.3). 
Echocardiography to assess congestion: A targeted echo protocol will be implemented with 
assessment of the diameter of inferior vena cava (IVC), LV systolic and diastolic volumes, Ejection 
Fraction (Simpson), ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity (E/e’), left atrial (LA) volumes (min and max), visual assessment of mitral regurgitation 
(MR) 
and 
tricuspid 
regurgitation 
(TR), 
tricuspid 
annular 
plane 
systolic 
excursion 
(TAPSE)/pulmonary artery systolic pressure (PASP) and jugular venous diameter.  
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the investigator as per standard 
medical/clinical judgment. 
Lung Ultrasound 
Lung ultrasonography (LUS) has emerged as a noninvasive, semi-quantitative diagnostic tool for the 
assessment of extravascular lung water in HF. B-lines on LUS are vertical, hyperechogenic artifacts 
which arise from the pleural line and can be quantified. B-lines count showed higher sensitivity than 
the clinical examination or chest radiography in the identification of pulmonary edema. B-lines counts 
(28 zones) will be done at the time points indicated in the Schedule of Activities (see Section 1.3) 
prior to start of study drug infusion, just before furosemide bolus and end of infusion. 
Whole Body Bio-impedance 
Noninvasive cardiac system (NiCaS) device will non-invasively assess CO, stroke volume index, 
total body water, total peripheral resistance based on whole body bio-impedance; it has been 
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demonstrated to meet Food and Drug Administration (FDA) standards for bioequivalence when 
compared to thermodilution-based CO methods.31 
8.2 
Adverse Events 
The definitions of an AE or SAE can be found in APPENDIX 3. 
AEs will be reported 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 specified in APPENDIX 3. 
 
8.2.1 
Time Period and Frequency for Collecting AE and SAE Information 
The Reference Safety Information in Sections 5.6.1 and 5.6.2 of the IB16 should be used to determine 
the expectedness of SAEs for expedited reporting. 
 
The collection of nonserious AE information should begin at initiation of study treatment until 
24 hours after end of infusion in each treatment period of dosing (Schedule of Activities in 
Section 1.3). Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the participants. 
 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing.  
 After these time periods, the investigator must report any SAE that occurs after these time periods 
and that is believed to be related to study drug or protocol-specified procedure (eg, a follow-up 
skin biopsy). 
 Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the paper Safety Report Form. 
 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 PRA Drug Safety within 24 hours of 
updated information being available. 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, 
if the investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event reasonably related to the study treatment 
or study participation, the investigator must promptly notify the Sponsor. 
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The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in APPENDIX 3. 
8.2.2 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should not 
be questioned regarding the specific occurrence of one or more AEs.) 
8.2.3 
Follow-up of AEs and SAEs 
 Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see APPENDIX 3). 
 Follow-up is also required for nonserious AEs that cause interruption or discontinuation of study 
treatment and for those present at the end of study treatment as appropriate. 
 All identified nonserious AEs must be recorded and described on the AE page of the CRF. 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study. 
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 7.3). 
Further information on follow-up procedures is given in APPENDIX 3. 
8.2.4 
Regulatory Reporting Requirements for SAEs 
 Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a product under 
clinical investigation are met. 
 An investigator who receives an investigator safety report describing SAEs or other specific safety 
information (eg, summary or listing of SAEs) from the Sponsor will file it along with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements. 
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 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. 
8.2.5 
Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify PRA Drug Safety 
of this event and complete and forward a Pregnancy Surveillance Form to PRA Drug Safety within 
24 hours of awareness of the event and in accordance with reporting procedures described in 
APPENDIX 3. 
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In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). 
Any pregnancy that occurs in a female partner of a male study participant should be reported to PRA 
Drug Safety. In order for the Sponsor or designee to collect any pregnancy surveillance information 
from the female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
8.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the AE CRF page. If a 
laboratory test result meets the definition of a serious adverse event, the laboratory test result should 
be reported as an SAE and submitted to PRA Drug Safety as specified in APPENDIX 3. 
 Any laboratory test result that is clinically significant or meets the definition of an AE or SAE  
 Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted 
 Any laboratory test result abnormality that required the participant to receive specific corrective 
therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
8.2.7 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the 
defined criteria, must be reported as SAEs (see Section 8.2 and APPENDIX 3 for reporting details). 
Potential DILI is defined as:  
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of aminotransferase 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. 
8.2.8 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
any other potential safety assessment required or not required by protocol should also be recorded as 
a nonserious or serious AE, as appropriate, and reported accordingly. 
8.3 
Overdose 
All occurrences of overdose must be reported as SAEs (see Section 8.2). 
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An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
an SAE (see Section 8.2). 
BMS-986231 
Since there is limited clinical experience with BMS-986231, there is no current knowledge with 
overdosing, hence no specific guidance is currently available. In case of acute overdose, it is not 
known if dialysis would accelerate drug clearance. BMS-986231 produces vasodilation as a 
component of its hemodynamic effects. Thus, the most immediate adverse effect in the case of 
overdose of BMS-986231 may be hypotension, mediated at least in part by mechanisms similar to 
the hypotensive activity of IV nitroglycerin through activation of soluble guanylate. No specific 
pharmacologic antidote to HNO effects exists. In previous studies with BMS-986231 in healthy 
volunteers and advanced HF subjects, cessation of drug was adequate to restore blood pressure within 
1-2 hours. In the event of an overdose, the infusion should be discontinued, and other therapies 
administered concurrently that have vasodilatory effects should be discontinued. Volume repletion, 
either orally or intravenously, can be used to counter the clinical effects of HNO mediated 
vasodilation, but should be used with extreme caution in decompensated HF subjects. If marked 
hypotension occurs, appropriate treatment, including IV pressor agents may be required to support 
blood pressure. 
Furosemide 
The principal signs and symptoms of overdose with furosemide are dehydration, blood volume 
reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are 
extensions of its diuretic action. The acute toxicity of furosemide has been determined in mice, rats 
and dogs. In all 3, the oral LD50 exceeded 1000 mg/kg body weight, while the IV LD50 ranged from 
300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats. 
The concentration of furosemide in biological fluids associated with toxicity or death is not known. 
Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte 
losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently. 
Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as 
prostatic hypertrophy). Hemodialysis does not accelerate furosemide elimination. 
8.4 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 1.3). 
8.4.1 
Physical Examinations 
Refer to Schedule of Activities (Section 1.3). 
8.4.2 
Vital Signs 
Refer to Schedule of Activities (Section 1.3). Vital Signs (blood pressure and heart rate) will be 
recorded after the participant has rested quietly for at least 5 minutes in a supine position. 
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8.4.3 
Peripheral Oxygen Saturation 
Refer to Schedule of Activities (Section 1.3). Peripheral oxygen saturation will be recorded after the 
participant has rested quietly for at least 5 minutes in a supine position. 
8.4.4 
Electrocardiograms 
Refer to Schedule of Activities (Section 1.3). 
All ECG recordings must be performed using a standard high-quality, high-fidelity machine equipped 
with computer-based interval measurements and automated interpretation. Automated ECG intervals 
and HR will be captured or calculated, and changes of the T-wave and U wave morphology will be 
documented. ECG will be recorded after the participant has rested quietly for at least 5 minutes in a 
supine position. 
8.4.5 
Continuous Cardiac Monitoring (Telemetry) 
Refer to Schedule of Activities (Section 1.3). 
Continuous ECG monitoring will be performed to help monitor patient safety, primarily to detect 
ventricular and atrial arrhythmias. The site will follow their normal operating procedures established 
for ECG monitoring by trained staff. Clinically significant findings from the monitoring will be 
recorded as AEs and SAEs per investigator’s decision, and at the investigator’s discretion the infusion 
may be discontinued for clinically significant arrhythmias. 
8.4.6 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. Subjects will have 
laboratory tests performed as described in the following sections. A central/local laboratory will 
perform the analyses and will provide reference ranges for these tests. 
Laboratory assessments for screening 
The following laboratory tests will be performed as part of the screening evaluation. Results will be 
recorded in the study eCRF. 
Hematology 
 Hemoglobin 
 Hematocrit 
 White blood cell count and differential 
 Platelet count 
 
Serum Chemistry 
 Aspartate Aminotransferase (AST, SGOT)
 Alanine Aminotransferase (ALT, SGPT)
 Blood Urea Nitrogen (BUN)
 Electrolytes
o Sodium 
o Potassium 
 Serum Creatinine (Scr)
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 eGFR by equation used locally 
 
Other Analyses 
 BNP or NT-pro BNP (according to local lab availability) will be performed at screening.  
 Pregnancy test (WOCBP only: screening, pre-dose (before start of infusion) in each treatment 
period). 
On each treatment day, the study drug infusion could start without waiting for the results of the 
laboratory assessments done in the morning of the treatment day at the study facility if the 
following criteria are met: 
 The results of the laboratory assessment at screening / previous period are within ranges 
compatible with inclusion criteria.
 The study participant was medically stable with no signs of overt HF decompensation or 
deteriorating signs and symptoms of congestion and without change in medication since the 
screening visit / previous period. 
Laboratory Assessments During Study 
The following laboratory tests will be performed and submitted to the Laboratory or Sponsor 
designated vendors for analysis as per the Study Assessment and Procedures. 
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Analyses 
Timing 
Hematology 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell count, including differential 
 
Platelet count 
 
H0 (before start of 
infusion), H4 and H8 
on each treatment 
day  
Serum 
Chemistry 
 
 
Aspartate Aminotransferase (AST, SGOT) 
 
Alanine Aminotransferase (ALT, SGPT) 
 
Total bilirubin 
 
Serum Creatinine (Scr) 
 
eGFR 
 
BUN 
H0 (before start of 
infusion), H4 and H8 
on each treatment 
day 
 
Electrolytes: Na, K, Creatinine, eGFR 
 
Bicarbonate, free water clearance
H0 (before start of 
infusion), H4, H5, 
H6, H7, H8 on each 
treatment day 
Furosemide 
 
Furosemide plasma concentration 
Please refer to 
Table 7 
 
  
 
 
 
 
Urinalysis 
 
 
Fractional excretion of sodium 
 
Fractional excretion of potassium 
 
Urine Na, K, bicarbonate, creatinine, urea, phosphate, chloride, 
urine albumin-to-creatinine ratio (uACR) 
 
Furosemide urinary concentration 
 
Exploratory urinary biomarkers: including but not limited to urine 
kidney injury molecule-1 (KIM1) 
 
Please refer to 
Table 8 
 
 
The detailed methods for specimen collection, handling, processing, shipping, and storage will be 
supplied in the Investigator’s Laboratory Manual provided by the Laboratory. 
8.4.7 
Suicidal Risk Monitoring 
Not applicable. 
8.4.8 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the investigator as per standard 
medical/clinical judgment.  
8.5 
Pharmacokinetics 
Pharmacokinetic data of furosemide and BMS-986231 (and its metabolites) will be derived from 
plasma and urine concentration versus time data.  
 
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The primary possible PK parameters to be assessed for BMS-986231 (and its metabolites) and 
furosemide are included in Table 6:  
 
Table 6: 
Potential Pharmacokinetic Parameters Calculated for Furosemide 
Cmax 
Maximum observed plasma concentration 
AUC(INF) 
Area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC(0-T) 
AUC from time 0 up to time T, where T is the last time point with 
concentrations above the lower limit of quantitation 
Ae 
Total amount recovered in urine 
% UR 
Percent urine recovery 
CLR 
Renal clearance of drug from plasma 
Additional PK parameters may be calculated as deemed appropriate. 
The plasma and urine samples for furosemide and BMS-986231 (and its metabolites BMT-284730 
and BMT-279554) will be analyzed by a quantitative liquid chromatography with tandem mass 
spectrometry (LC-MS/MS) assay. 
Blood samples will be collected for PK assessments as described in Table 7. Urine samples can be 
taken from the urine collection intervals as described in Table 8. Detailed instructions for the PK 
blood and urine collection, labeling, processing, storage, and shipping will be provided to the site in 
the Laboratory Manual. 
In addition, collect a PK sample from the patient when the dose is lowered due to a safety event and 
also at time of early discontinuation of study drug. The sample should be collected immediately before 
or after the decision to change the dose was made. 
 
Detailed instructions for the PK blood collection, labeling, processing, storage, laboratories 
performing the analyses, and shipping will be provided to the site in the procedure manual. 
 
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8.5.1 
Blood Sampling and Urine Collection Intervals for PK and Efficacy 
 
Blood sampling time points for furosemide, BMS-986231 (and its metabolites), Na and K are 
indicated in Table 7. 
Table 7: 
Blood Sampling for Furosemide, BMS-986231 (and its metabolites) 
Study Day of 
Sample Collection 
(of Each Period) 
Event 
Time (Relative To Start of Infusion of 
BMS-986231)  
Hour: Min 
Blood Sample 
1 
Before start of 
infusiona 
00:00 
X 
1 
2.0 hoursa 
02:00 
X 
1 
4.0 hoursb 
04:00 
X 
1 
5.0 hours 
05:00 
X 
1 
6.0 hours 
06:00 
X 
1 
8.0 hours (EOI)c 
08:00 
X 
1 
10.0  
10:00 
X 
1 
Dose lowered 
due to safety 
event  
Misc. 
X 
a This time-point is not applicable for furosemide analysis 
b Just before furosemide bolus 
c EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. If end of infusion occurs prior to 8 hours after start of 
infusion (H8), the end of infusion should be considered early discontinuation. In case of an early discontinuation, the 
timing for the assessments will be adapted accordingly, ie, H8 will be immediately after end of infusion and H10 will 
be 2 hours after infusion. 
 
Time points for urine collection intervals are presented in Table 8.  
 
 
 
 
 
 
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Table 8: 
Urine Collection Intervals for Urine Output and Assessment of Furosemide, 
BMS-986231, K, Na, P, Bicarbonate, Creatinine, and Cl  
Study Day of 
Sample 
Collection (of 
Each Period) 
Event 
Time (Relative To 
Start of Infusion of 
BMS-986231)  
Hour: Min 
Urine Sample 
Collection 
Intervalsa 
1 
Before start of infusion 
00:00 
X 
1 
2.0 hours 
02:00 
0-2 hours 
1 
4.0 hoursb  
04:00 
2-4 hours 
1 
5.0 hours 
05:00 
4-5 hours 
1 
6.0 hours 
06:00 
5-6 hours 
1 
7.0 hours 
07:00 
6-7 hours 
1 
8.0 hours (EOI)c 
08:00 
7-8 hours 
1 
10.0 hours 
10:00 
8-10 hours 
a In the first 4 hours of the study drug infusion, and before furosemide bolus, urine collection will be done every 2 hours, 
thereafter the void will be hourly 
b Just before furosemide bolus 
c EOI=End of Infusion, This sample should be taken immediately prior to stopping the infusion (preferably within 
2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond the nominal infusion duration, the 
collection of this sample should also be delayed accordingly. If end of infusion occurs prior to 8 hours after start of 
infusion (H8), the end of infusion should be considered early discontinuation. In case of an early discontinuation, the 
timing for the assessments will be adapted accordingly, ie, H8 will be immediately after end of infusion and H10 will 
be 2 hours after infusion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.6.1 
Additional Research Collection 
This protocol will include residual sample storage for additional research. All samples, including all 
residual samples may be stored and the exploratory research with these samples described in the 
protocol may continue for 15 years post end of study, which is defined as 2 years after the final study 
report. The scope of work involves using serum, plasma, to assess markers of heart failure, cardiac 
remodeling, neurohormonal activation, angiogenesis, oxidative and myocyte stress, renal function, 
congestion, inflammation, and fibrosis and associated diseases and pathways. Work may also include 
studies on the HNO pathway and mechanism of action as well as any pathways impacted by 
BMS-986231, as well as development of new or improved assays for pathway and functional markers 
associated with either BMS-986231and cardiovascular diseases. The goal is to better understand HF, 
cardiovascular and associated diseases/syndromes and any effects of the drug, BMS-986231. 
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 
 
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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.  
 
Sample Collection and Storage 
All serum, plasma, and urine samples from PK, pharmacodynamic and exploratory biomarker 
collections (as defined in Table 8, 
 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 
 Transfers of samples by research 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. 
 
8.6.2 
Immunogenicity Assessments 
Not applicable. 
8.7 
Health Economics OR Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Determination  
The number of subjects to be enrolled was chosen based on practical considerations. Approximately 
20 patients with HFrEF will be randomized in a 1:1 ratio to one of 2 sequences: 
BMS-986231/furosemide followed by placebo/furosemide or placebo/furosemide followed by BMS-
986231/furosemide. The difference between BMS-986231 and placebo in total urine output in the 4 
hours following furosemide administration will be estimated and presented with 95% confidence 
intervals (CIs). 
Normal healthy volunteers have a urinary output around 0.5-1.0 mL/kg/H (40-100 mL/H), which 
could be decreased in people over 65 years old or patients with HF at around 0.2-0.5 mL/kg/H 
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(20-40 mL/H). Patients with HF given a bolus of IV loop diuretics is estimated to have their diuresis 
increased to 250-300 mL/H in the 4 hours following the administration. Assuming the standard 
deviation of urine output change is 20~35 mL/H based on the estimated range of the changes, with 
20 patients, the study will be able to demonstrate a 20% increase in urinary output compared to 
placebo, with 90% power. 
9.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All participants who sign informed consent. 
Randomized 
All randomized subjects who have started study drug infusion in 
at least one treatment period. This is also known as the Intent to 
Treat (ITT) population. Data in this data set will be analyzed 
based on randomized sequence of treatments. 
Treated (per protocol) 
All randomized participants who were given both study 
treatments and completed the study as per protocol. Participants 
will be included in the treatment group they received in each 
period. 
Safety 
All randomized participants who take at least 1 dose of double-
blind study treatment. Participants will be included in the 
treatment group they received in each period. 
 
9.3 
Endpoints  
9.3.1 
Primary Endpoint 
 The total volume of urinary output 4 hours after 40 mg furosemide bolus given to patients 
with HFrEF while on BMS-986231 compared to placebo: absolute difference in total volume 
and % change from placebo. 
9.3.2 
Secondary Endpoints 
 FeNa, FeK, furosemide urinary and plasma concentration and ratio urinary sodium to urinary 
furosemide at 8 hours post-start infusion. Parameter values while patient is on BMS-986231 
compared to placebo: absolute differences and % change from placebo. 
9.3.3 
Safety Endpoints 
 Clinically relevant hypotension (defined as SBP < 90 mmHg or symptomatic hypotension) 
during infusion, incidence of AEs, abnormal clinical laboratory values, vital signs, ECGs, 
telemetry, physical examinations. 
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9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before 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. For analyses involving baseline, the baseline value is defined as 
the last value prior to the start of infusion for the specific period, unless otherwise noted. 
 
9.4.1 
Efficacy Analyses 
9.4.1.1 
Primary Efficacy Analysis 
All primary efficacy analyses will be performed using the treated (per protocol) population. Total 
amount of urine excreted over 4 hours after a bolus injection of 40 mg furosemide while receiving 
BMS-986231 or placebo will be summarized and analyzed. Volumes at each urinary collection 
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interval as well as total volume will be tabulated. Graphical presentations may be provided. All data 
will be listed. 
A within patient analysis using a paired T-test will be performed to compare the volumes of urinary 
excretion and to test if there is a significantly different amount of urine secreted while receiving 
BMS-986231 versus placebo. 
9.4.1.2 
Secondary Efficacy Analysis 
Secondary efficacy analyses will be performed using the randomized population. The FeNa, FeK, 
furosemide urinary and plasma concentration and the ratio of urinary sodium to urinary furosemide 
will be calculated at each time point over 4-hour urine/plasma collection after a bolus injection of 
40 mg furosemide while receiving BMS-986231 or placebo. All data will be listed and tabulated. 
Graphical presentations may be provided. 
A similar analysis as described in the primary efficacy analysis section will be conducted on the 
values derived at the 8-hour time point (8 hours after start of infusion). 
 
9.4.2 
Safety Analyses 
All safety analyses will be performed on the safety population (see Section 9.2). For safety analyses, 
all recorded AEs for each period will be listed and tabulated by system organ class, preferred term 
and treatment. Vital signs and clinical laboratory test results will be listed and summarized by 
treatment. Any significant physical examination findings, and clinical laboratory results will be listed. 
ECG readings will be evaluated by the investigator and abnormalities, if present, will be listed. 
9.4.3 
Pharmacokinetic Analyses 
Descriptive summaries will be presented for continuous variables using number of participants (n), 
mean, standard deviation (SD), median, minimum, and maximum. Descriptive summaries of PK data 
will additionally include geometric mean and coefficient of variation (CV%). Descriptive summaries 
for categorical variables will utilize counts (n) and percentages (%). 
9.4.4 
Other Analyses  
Results for other endpoints will be summarized descriptively. Model-based analyses may be 
performed, using models similar to the model for the primary endpoint.  
9.4.5 
Interim Analyses  
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11 
APPENDICES 
 
 
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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
ACC 
American College of Cardiology 
ACEi 
angiotensin-converting-enzyme inhibitor 
ADHF 
acute decompensated heart failure 
ADME 
absorption, distribution, metabolism, and excretion 
AE 
adverse event 
AHA 
American Heart Association 
AHF 
acute heart failure 
ALT 
alanine aminotransferase 
ARB 
angiotensin-receptor blockers 
ARNI 
angiotensin-receptor/neprilysin inhibitor 
AST 
aspartate aminotransferase 
AVP 
arginine-vasopressin system 
BMS 
Bristol-Myers Squibb 
BNP 
brain natriuretic peptide 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CA125 
cancer antigen 125 
CI 
cardiac index 
CIs 
confidence intervals 
CONSORT 
Consilidated Standards of Reporting Trials 
CRF 
case report form 
CV 
cardiovascular 
CVA 
cerebrovascular accident 
D5W 
5% dextrose in water 
DBP 
diastolic blood pressure 
DILI 
drug induced liver injury 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DTI 
doppler tissue imaging 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
HCG 
human chorionic gonadotropin 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
HNO 
Nitroxyl 
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Term 
Definition 
HR 
heart rate 
IB 
investigator brochure 
IEC 
independent ethics committee 
I(M)P 
investigational (medicinal) product 
IRB 
institutional review board 
ITT 
intent to treat 
IV 
intravenous 
K+ 
Potassium 
LA 
left atrium 
LC-MS 
liquid chromatography–mass spectrometry 
LDH 
lactate dehydrogenase 
LV 
left ventricle 
LVEF 
left ventricular ejection fraction 
mARC 
mitochondrial amidoxime-reducing component 
MI 
myocardial infarction 
MMRM 
mixed model repeated measures 
MRA 
mineralocorticoid receptor antagonists 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
MVO2 
myocardial oxygen consumption 
Na+ 
Sodium 
NCV 
nerve conduction velocities 
N-GAL 
gelatinase-associated lipocalin 
NiCaS 
noninvasive cardiac system 
NO 
nitric oxide 
NT-pro BNP 
N terminal- pro BNP 
NYHA 
New York Heart Association 
PASP 
pulmonary artery systolic pressure 
PCWP 
pulmonary capillary wedge pressure 
PDE5 
phosphodiesterase type 5 
pH 
potential of hydrogen 
PK 
pharmacokinetic 
RA 
right atrium 
RAAS 
renin-angiotensin-aldosterone system 
RAP 
right atrial pressure 
RV 
right ventricle 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
sCD146 
cluster of differentiation 146 
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Term 
Definition 
Scr 
serum creatinine 
SD 
standard deviation 
SERCA 
sarcoplasmic reticulum calcium adenosine triphosphatase 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SNS 
sympathetic nervous system 
SUSAR 
suspected, unexpected serious adverse reaction 
TAPSE 
tricuspid annular plane systolic excursion 
TIA 
transient ischemic attack 
TR 
tricuspid regurgitation 
uACR 
urine albumin-to-creatinine ratio 
ULN 
upper limit of normal 
WOCBP 
women of child bearing potential 
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APPENDIX 2 
STUDY GOVERANCE 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: 
 Good Clinical Practice (GCP)
 as defined by the International Council on Harmonisation (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 (e.g., 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 (e.g., 
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 (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
 
 
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator should not implement any deviation or change to the protocol without prior review 
and documented approval/favorable opinion of an amendment from the IRB/IEC (and if applicable, 
also by local health authority) except where necessary to eliminate an immediate hazard(s) to study 
subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to: 
 IRB/IEC for
 Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the 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 (i.e., Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles that 
have their origin in the Declaration of Helsinki. 
 
 
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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. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
SOURCE DOCUMENTS 
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic devices) 
as part of regulated clinical 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), AE 
tracking/reporting, protocol required assessments, and/or drug accountability records). 
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
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original information that has been verified, as indicated by a dated signature, as an exact copy having 
all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS 
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee or 
a Health Authority. 
 
If 
Then 
Supplied by BMS (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include: 
 amount received and placed in storage area 
 amount currently in storage area 
 label identification number or batch number 
 amount dispensed to and returned by each 
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 drug integrity in 
accordance with requirements applicable under law 
and the SOPs/standards of the sourcing pharmacy. 
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These records should include: 
 label identification number or batch number 
 amount dispensed to and returned by each 
participant, including unique participant 
identifiers 
 dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form. 
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 
 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the investigation on each individual treated or 
entered as a control in the investigation. Data that are derived from source documents and reported 
on the CRF must be consistent with the source documents or the discrepancies must be explained. 
Additional clinical information may be collected and analyzed in an effort to enhance understanding 
of product safety. CRFs may be requested for AEs and/or laboratory abnormalities that are reported 
or identified during the course of the study. 
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be prepared 
for all data collection fields except for fields specific to SAEs and pregnancy, which will be collected 
and reported on the paper Safety Report Form and paper Pregnancy Surveillance Form, respectively. 
Spaces may be left blank only in those circumstances permitted by study-specific CRF, Safety Report 
Form, or Pregnancy Surveillance Form completion guidelines provided by PRA. 
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 and/or pregnancy forms, must be promptly reviewed, signed, and dated 
by the investigator or qualified physician who is a sub-investigator and who is delegated this task 
on the Delegation of Authority Form. Sub-investigators in Japan may not be delegated the CRF 
approval task. For electronic CRFs, review and approval/signature is completed electronically 
through the BMS electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections. Each individual electronically signing electronic 
CRFs must meet Sponsor or designee training requirements and must only access the BMS 
electronic data capture tool using the unique user account provided by Sponsor or designee. User 
accounts are not to be shared or reassigned to other individuals. 
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MONITORING 
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents: 
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential. 
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or institution 
procedures, or for the period specified by BMS or designee, whichever is longer. The investigator 
(or head of the study site in Japan) must contact BMS prior to destroying any records associated 
with the study. 
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed. 
If the investigator withdraws from the study (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. 
 
 
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RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
 
If.. 
Then 
Study treatments supplied by BMS (including 
its vendors) 
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (e.g., cytotoxics or 
biologics). 
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor. 
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or commercial supply, or a specialty 
pharmacy) 
It is the investigator’s or designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
 On-site disposal practices must not expose humans to risks from the drug.
 On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
 Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
 Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., 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 
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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. 
For this study, study treatments (those supplied by BMS or its vendors) such as full or partially used 
study treatment containers, vials, syringes cannot be destroyed on site. 
It is however, the investigator’s or designee’s responsibility to arrange for disposal of all empty 
study treatment containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. The return of full or partially used study 
treatments supplied by BMS or its vendors will be arranged by the responsible Study Monitor. 
CLINICAL STUDY REPORT AND PUBLICATIONS 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria: 
 External Principal Investigator designated at protocol development
 National Coordinating Investigator
 Study Steering Committee chair or their designee
 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 (CTA) governing [Study site or investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to Sponsor or 
designee at the earliest practicable time prior to submission or presentation and otherwise within the 
time period set forth in the CTA. 
 
 
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APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP AND REPORTING 
ADVERSE EVENTS  
Adverse Event Definition: 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation 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 drug, whether or not 
considered related to the study drug. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis. 
 Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, as a verbatim term (as reported by the 
investigator), should not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae and should specify “intentional overdose” as the verbatim term. 
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Events NOT Meeting the AE Definition 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
 
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SERIOUS ADVERSE EVENTS 
Serious Adverse Event Definition: Any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening (defined as an event in which the 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 (e.g., 
routine colonoscopy) 
 medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
 admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
 admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols) 
Results in persistent or significant disability or permanent damage 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [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 8.2.7 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 8.2.5 for reporting pregnancies). 
 
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Any component of a study endpoint that is considered related to study therapy should be reported 
as a SAE (e.g., death is an endpoint; if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
EVALUATING AES AND SAES 
Assessment of Intensity 
The intensity of AEs is determined by a physician and will use the following levels: 
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.  
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. A “reasonable possibility of a relationship” conveys 
that there are facts, evidences, and/or arguments to suggest a causal relationship rather 
than a relationship cannot be ruled out.   
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor. 
 The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
 
 
 
 
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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 drug, and pregnancies must be reported to PRA 
Drug Safety within 24 hours of awareness of the event. 
SAEs must be recorded on the SAE Report Form. For studies capturing SAEs through 
electronic data capture (EDC), electronic submission is the required method for reporting. In 
the event the electronic system is unavailable for transmission, paper forms must be used and 
submitted immediately. When paper forms are used, the original paper forms are to remain on 
site. 
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission to: 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
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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 postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
and bilateral oophorectomy. 
Women in the Following Categories Are not Considered WOCBP 
 Premenarchal
 Premenopausal female with 1 of the following:
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
 Postmenopausal female
 A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause. 
 
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH level. 
The duration of the washout period is a function of the type of HRT used. The duration of the 
washout period below are suggested guidelines and the investigators should use their judgment in 
checking serum FSH levels. 
 1 week minimum for vaginal hormonal products (rings, creams, gels)
 4 week minimum for transdermal products
 8 week minimum for oral products
 
Other parenteral products may require washout periods as long as 6 months. If the serum FSH level 
is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal. 
 
 
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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as # Days/ Weeks Relevant Exposure 
days/weeks after the end of study treatment, plus 30 days. 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
Highly Effective Methods That Are User Independent 
 Nonhormonal intraurine devices (IUDs), such as ParaGard 
 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. 
 
Complete 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. 
 Complete abstinence is an acceptable form of contraception for all study drugs and must be 
used throughout the duration of the study treatment (plus 5 half-lives of the investigational 
drug plus 30 days) 
 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 
 
 
 
Unacceptable Methods of Contraception 
 Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 Withdrawal (coitus interruptus) 
 Spermicide only 
 Lactation amenorrhea method (LAM) 
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 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
 Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and IUDs such as Mirena 
 Intrauterine hormone-releasing system (IUS) 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal Sponge with spermicide 
 Male or female condom with or without spermicide*. Male and female condoms cannot be 
used simultaneously 
 
 
 
 
 
 
 
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 91 Days after 
discontinuation (duration of study drug plus 90 days [duration of sperm turnover] of treatment 
in the male participant.
 Female partners of males participating in the study to consider use of effective methods of 
contraception until 91 Days after discontinuation (duration of study drug plus 90 days [duration 
of sperm turnover] of treatment in the male participant.
 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 91 Days after discontinuation (duration of study drug plus 90 
days [duration of sperm turnover] of treatment in the male participant. 
 Refrain from donating sperm for the duration of the study treatment until 91 Days after 
discontinuation (duration of study drug plus 90 days [duration of sperm turnover] of treatment 
in the male participant .
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COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 8.2.5 and the APPENDIX 3 for AE and SAE 
Definitions and procedures for Evaluating, Follow-up and Reporting. 
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