Clinical trial NCT03016325
Conditions: Heart Failure
Sponsor: Bristol-Myers Squibb
Start date: 2017-01-13; Completion date: 2019-11-12
Enrollment: 329 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Study to Evaluate Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of HNO Donor in Hospitalized Patients with Heart Failure and Impaired Systolic Function

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: HNO Donor intervention 2: Placebo
Intervention descriptions: intervention 1: Infusion intervention 2: Infusion

Protocol documents:
Prot_002.pdf: 
Page:
1
Protocol Number:
CV013011
IND Number:
118,618
Ex-US
Non-IND
EUDRACT Number
2016-001685-29
Date:
28-Jun-2016
Revised Date:
09-Apr-2018
Clinical Protocol CV013011
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, 
Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of 
BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function
Revised Protocol 02
Study Director
Medical Monitor
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, 
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disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
09-Apr-2018
Expansion of screening period, addition of Holter Monitoring in a subset 
of patients, addition of Actigraphy monitoring in a subset of patients, and 
clarifications throughout the document.
Administrative 
Letter 02
05-Dec-2017
Clarifies secondary packaging of BMS986-231 as a carton containing 5 
or 6 vials.
Administrative 
Letter 01
14-Feb-2017
Administrative clarifications throughout the protocol.
Revised 
Protocol 01
11-Oct-2016
Incorporates changes from Amendment 01.
Amendment 01
11-Oct-2016
Addition of two unblinded interim analysis, addition of Sensory Motor 
Survey, clarification and updates to Eligibility criteria, and additional 
edits throughout the document to improve readability. 
Original 
Protocol
28-Jun-2016
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 02:
These changes serve to clarify procedures for Part II Cohort 2 of the study. Part I Cohort 1 of the 
study is not impacted. Changes include: 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 3.3.2
Exclusion
Criteria
Exclusion criteria # 2b was 
modified to clarify: 
Suspected acute lung disease (eg,
pneumonia or asthma) or severe 
chronic lung disease (eg, severe 
chronic obstructive pulmonary 
disease, pulmonary fibrosis, 
patients with hypercapnia or 
requiring home oxygen therapy or 
chronic oral steroids.)
Additional clarification for exclusion of 
patients with severe lung disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 3.1 
Study Design 
and Duration
Changed to:
Study Medication infusion must 
start within 18 hours of 
presentation (or 48 hours in Part II 
Cohort 2 of the trial), with 
presentation defined as the first 
dose of diuretic for current 
episode
 
 
Section 5.1.2
Treatment and 
In-Hospital 
Follow-up
Addition of window to collect 
vital signs within .25 hours of 
specified time points. 
 
 
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
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SYNOPSIS
Clinical Protocol CV013011
Protocol Title: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, 
Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in 
Hospitalized Patients with Heart Failure and Impaired Systolic Function
Investigational Products, Dose and Mode of Administration, Duration of Treatment with Investigational 
Products: The investigational medicinal product is a solution for IV infusion containing BMS-986231 drug product 
(reconstituted in sterile water for injection), 5% dextrose (glucose) in water for injection (D5W) and potassium acetate 
(to achieve a 10 mM concentration of potassium acetate).
Study Phase: Phase 2B
Purpose: The purpose of this study is to evaluate the safety, tolerability, and efficacy of BMS-986231in subjects with 
heart failure (HF) and reduced systolic function (LVEF < 40%) who are admitted to the hospital with signs and 
symptoms of acute decompensated heart failure (ADHF).
Research Hypothesis: BMS-986231 is safe and tolerated with regard to clinically relevant hypotension compared 
with placebo in hospitalized heart failure with reduced ejection fraction (HFrEF) subjects with ADHF.
Objectives:
Primary Objective:
The primary objective is to evaluate the effects of various doses of BMS-986231 compared to placebo on clinically 
relevant hypotension (defined by SBP < 90 mm Hg or symptoms of hypotension)
Secondary Objectives:

Assess the effect of BMS-986231 on NT-proBNP

Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 11-point Numerical 
Rating Scale (NRS)
 
 
 
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Safety Objectives:

Evaluate the effect of BMS-986231 on incidence of symptomatic hypotension

Evaluate the effects of BMS-986231 on the incidence of SBP < 90 mm Hg.

Evaluate the incidence of dose reductions, temporary interruptions, and permanent discontinuation of BMS-98623 
infusions

Evaluate the safety and tolerability of a continuous 48-hour infusion of BMS-986231 in hospitalized HFrEF 
subjects with ADHF

Evaluate the effect of BMS-986231 on high sensitivity (Hs) Troponin T

Assess the effect of BMS-986231 on mortality at Day 182
Study Design: This is a multi-center, randomized, placebo-controlled, double-blind study of continuous 48-hour 
intravenous (IV) infusions of BMS-986231 in hospitalized HFrEF subjects with ADHF. The trial was designed to 
identify the doses of BMS-986231 that are safe and tolerated with regard to clinically relevant hypotension.
The study consists of 2 parts, each with a unique cohort of subjects.
Patients that are randomized in Part I of the study will not be allowed to participate in Part II.
In Part I (Cohort 1) of the study, approximately 100 subjects will be randomized in a 1:1 ratio to placebo or an 
escalating dose of BMS-986231 (3 μg/kg/min for 4 hours, then 6 μg/kg/min for another 4 hours, then 12 μg/kg/min 
for the remaining 40 hours).
In Part II (Cohort 2) of the study, the 2 highest planned doses of BMS-986231 in Cohort 1, BMS-986231 6 g/kg/min 
and BMS-986231 12 g/kg/min, will be administered. Approximately 210 subjects will be randomized in a 1:1:1 ratio 
to one of the 2 active doses of BMS-986231 or placebo. If BMS-986231 12 g/kg/min is not considered to be a 
tolerated dose in Part I, then BMS-986231 3 g/kg/min and BMS-986231 6 g/kg/min will be evaluated in Part II. In 
the event that neither 6 g/kg/min nor 12 g/kg/min are tolerated, the protocol will require modification. 
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Study Schematic:
a Every effort should be made to initiate study drug administration promptly after randomization 
b Study Medication infusion must start within 18 hours of presentation (or 48 hours in Part II Cohort 2 of the 
trial), defined as the first dose of diuretic for current episode, but not within 2 hours after an IV bolus dose of 
intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV diuretic 
administered by continuous infusion
c Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring
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a 3 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
b 6 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
c Every effort should be made to initiate study drug administration promptly after randomization 
d Study Medication infusion must start within 18 hours of presentation, (or 48 hours in Part II Cohort 2 of the 
trial) defined as the first dose of diuretic for current episode, but not within 2 hours after an IV bolus dose of 
intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV diuretic
administered by continuous infusion
e Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring.
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Study Population: 
Key Inclusion Criteria:

Males and Females, at least age 18 (or age of majority) 

Subjects being hospitalized for ADHF

Have had at least 40 mg furosemide intravenous, or equivalent, (eg, 40 mg furosemide equivalent to 20 mg 
torsemide or to 1 mg bumetamide) for the current ADHF episode

Subject must be randomized and treated within 18 hours of first dose of intravenous diuretic for Part I Cohort 1 
(or 48 hours of first dose for Part II Cohort 2). 

Have dyspnea at rest or with minimal exertion after administration of at least 1 dose of intravenous diuretics. 
Subject must not be randomized within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours 
after the initiation or a dose increase of an IV diuretic administered by continuous infusion

Have a history of heart failure and a left ventricular ejection fraction (LVEF) 40%, as assessed by 
echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging (MRI) scan

Note: Ejection fraction documentation up to 18 months prior to screening may be used if there is no clinical 
expectation of improvement in ejection fraction in that timeframe (eg, the patient has not had biventricular 
pacing initiated during that period)

Have at least 2 of the following at time of screening: 

evidence for pulmonary congestion on chest x-ray

rales by chest auscultation

edema 2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in 15-30 seconds)

presence of jugular venous distention

Have an elevated NT-proBNP 1600 pg/mL (189 pmol/L) or BNP 400 pg/mL (116 pmol/L) as determined at 
the local laboratory within 18 hours prior to the start of study drug infusion for Part I Cohort 1 (or 48 hours for 
Part II Cohort 2)

For subjects with atrial fibrillation: NT-proBNP 2400 pg/ml or BNP 600 pg/ml

Body weight 50 kg and < 140 kg at screening

Women of childbearing potential must have negative serum or urine pregnancy test within 18 hours of start of 
drug for Part I Cohort 1 (or 48 hours for Part II Cohort 2)
Key Exclusion Criteria:

Screening OR baseline systolic blood pressure (SBP) of <105mm Hg or >160mm Hg at screening and just prior 
to randomization

Heart rate < 50 or >130 beats per minute (bpm) at screening and just prior to randomization

Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic 
or uncorrected severe valvular disease as defined by AHA/ACC/ESC criteria
Note: Functional mitral regurgitation, as well as restrictive mitral inflow pattern on echocardiography is not 
exclusionary

Have a body temperature 38.5C (101.3F) at any time from screening to randomization

Have an active infection requiring current IV anti-microbial treatment

Considered clinically unstable for other conditions than acute heart failure, either because of acute coronary 
syndrome or ongoing arrhythmia (or be receiving concomitant parenteral therapy with any antiarrhythmic drugs), 
or other unstable non-cardiovascular disease

Suspected acute lung disease (e.g. pneumonia or asthma) or severe chronic lung disease (e.g. severe chronic 
obstructive pulmonary disease, pulmonary fibrosis, patients with hypercapnia or requiring home oxygen therapy 
or chronic oral steroids.)

Have a history of sudden cardiac death with resuscitation within the past 6 months
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
Be hospitalized with acute coronary syndrome, coronary revascularization or acute myocardial infarction during 
the previous 90 days prior to screening

Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic attack (TIA) during the 
previous 90 days prior to screening

Serious comorbid non-cardiovascular disease in which the life expectancy of the subject is < 6 months (eg, acute 
systemic infection – sepsis, metastatic cancer, or other serious illnesses)

Severe liver disease defined as history of cirrhosis with evidence of portal hypertension such as varices, or 
encephalopathy, or total bilirubin > 3 mg/dL (> 51 µmol/L)

Prior cardiac or renal transplant 

Have persistent abnormal serum electrolytes not resolved before randomization, as defined by any of the 
following:

A sodium (Na+) concentration < 130 or >145 mEq/L (mmol/L)

A potassium (K+) concentration < 3.2 or >5.5 mEq/L (mmol/L)

Have severe anemia, as documented by a hemoglobin < 9 g/dL (< 5.59 mmol/L)

Have severe renal insufficiency before randomization (and during the current hospitalization) defined as an 
estimated glomerular filtration rate (eGFR)  < 30 mL/min/1.73m2 [based on any standard limit and equation 
employed by the local lab, eg, Modification of Diet in Renal Disease (MDRD) equation]. For patients with eGFR 
values less than but close to 30 mL/min/1.73m2 upon testing, retesting is allowed

Subjects administered IV or transdermal nitrate therapy prior to randomization, except if all 3 of the following 
criteria are met:

Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg AND 

The IV nitroglycerin dose is < 100 µg/min (or isosorbide dinitrate < 3 mg/hour), AND

The infusion rate and dose has been unchanged for > 2 hours

History of chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or peritoneal dialysis)

Subjects treated during the current hospitalization with IV vasoactive drugs such as dopamine, dobutamine, 
enoximone, nesiritide, nitroprusside, levosimendan, amrinone , milrinone, carperitide or nicorandil prior to start 
of study drug infusion, or have an anticipated need to be treated with any of these agents during the study drug 
infusion

Subjects receiving any mechanical ventilation at the time of screening

Subjects receiving non-invasive ventilation (CPAP/BiPAP) < 2 hours prior to randomization

Participation in an investigational clinical drug study within 30 days or 5 elimination half-lives, (whichever is 
longer) prior to randomization
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CV013011
Medication 
Potency 
IP/Non-IP 
BMS-98623 For Injection
BMS-986231 240 mg/vial
IP
Potassium Acetate
2 mEq/mL (20mL/vial)
Non-IP
BMS will provide Investigational drug product BMS-986231 for infusion (active pharmaceutical ingredient 
BMS-986231 formulated with Captisol® 3405 mg/vial) to all sites. In addition, Potassium acetate is to be locally 
sourced by sites within the US and will be supplied to all ex-US sites.
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Study Assessments:
Blood pressure assessment:
The primary endpoint of the study is the incidence of clinically relevant hypotension, defined by SBP < 90 mm Hg 
(confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug 
infusion. Thus hypotension will be assessed by collection of symptoms and blood pressure measurements. 
Symptomatic hypotension is defined as the presence of both low SBP and symptoms (eg, lightheadedness, dizziness, 
etc.) due to low blood pressure. 
Blood pressure measurements should be performed with the subject in a semi-recumbent (about a 30º angle) position, 
whenever possible. 
Blood pressure will be measured as indicated in Table 5.1-2. In addition, sites may perform measurements at intervals 
defined by institutional standard of care for subjects receiving vasodilators, but no less than what is described in 
Table 5.1-2.
If the study drug dose is modified (decreased, interrupted, resumed or discontinued), the frequency of blood pressure 
measurements will follow a more intensive schedule for up to 6 hours following the dose modification (see table 
below). Upon completion of the intensive schedule, measurements can be either resumed per the original schedule, or 
follow the discontinuation schedule if the drug is permanently discontinued. 
Schedule of Blood Pressure Collection Following a Dose Modification
30 minutes
Post
1 hour
post
2 hours
post
4 hours
post
6 hours
post
Dose reduction
X
X
X
X
X
Dose interruption
X
X
X
X
Dose resumption
X
X
X
X
X
Dose discontinuation
X
X
X
X
X
Details for management of low blood pressure are detailed in section 5.3.1
In addition to assessments of blood pressure, the Investigator will be asked to collect and assess signs and symptoms 
of low blood pressure.
Efficacy Outcome Measures: Efficacy assessments will include the following:
Patient assessments of dyspnea severity at rest as measured by the 11-point Numerical Rating Scale (NRS) scores at 
screening and at 0, 6, 12, 24, 48, 72, and 120 hours after the start of study drug infusion.
Patient assessments of dyspnea severity at rest, using the 7-point Likert scale at 6, 12, 24, 48, 72, and 120 hours after 
the start of study drug infusion.
Patient assessments of global clinical status using the 7-point Likert scale at 6, 12, 24, 48, 72, and 120 hours after the 
start of study drug infusion.
An investigator assessment of in-hospital worsening heart failure since the start of the study drug infusion based on 
signs and symptoms of worsening heart failure along with the need for initiation or intensification of intravenous 
treatment for heart failure such as diuretics, vasodilators, inotropes, and mechanical support (mechanical ventilation, 
circulatory support, ultrafiltration or hemodialysis), as indicators of worsening heart failure, will be made at Hours 24, 
48, 72, 96, and 120 or discharge, whichever comes first.
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Mortality Measures:
Investigators will follow all subjects to Day 182 for mortality.
Investigators will be asked to report deaths and categorize them as either cardiovascular or non-cardiovascular death. 
All deaths will be assumed to be cardiovascular unless a non-cardiovascular cause can be clearly provided. Below is 
guidance for Investigator classification:
Cardiovascular Death:
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death 
due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV 
hemorrhage, and death due to other CV causes.
Non-cardiovascular Death:
This category includes all deaths due to a clearly documented non-cardiovascular cause, such as respiratory failure 
(excluding cardiogenic pulmonary edema), hemorrhage (other than intracranial or CV hemorrhage), infections/sepsis, 
neoplasm, and trauma (including suicide and homicide).
Statistical considerations
Sample size:
For Part I (Cohort 1), approximately 50 subjects per group will be randomized to placebo or an incremental dose of 
BMS-986231 (3 - 6 - 12 μg/kg/min). Under a sample decision rule (eg, observed doubling with more than a 4% 
difference) and assuming clinically relevant hypotension incidences of 5% or 10% in the placebo group, the posterior 
probabilities of detecting an increase of 4-fold or 3-fold in incidence, respectively, are 86% and 80%, respectively. If 
there is no increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase 
are 11-12%.
For Part II (Cohort 2), approximately 70 subjects per group will be randomized to placebo or one of the two active 
dose levels of BMS-986231. Under a sample decision rule (eg, observed 1.8-fold increase with more than a 3% 
difference) and assuming clinically relevant hypotension incidences of 5% or 10% in the placebo group, the posterior 
probabilities of detecting an increase of 3-fold or 2.5-fold in incidence, respectively, are 82% and 80%, respectively. 
If there is no increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase 
are 13-15%. These probabilities do not reflect multiple comparison.
With regards to overall performance for selection of a maximally tolerated dose, a sample size of 50 per group for 
Part I (Cohort 1), along with 70 per group for Part II (Cohort 2) will identify a maximally tolerated dose approximately 
50-70%, based on detecting an increase of 3-fold or 2.5-fold in incidence, and using sample decision rules that are 
consistent with above. Also, the design will provide an option to select a titrated 12 μg/kg/min dose approximately 
60% of the time when that dose is tolerated, but a non-titrated 12 μg/kg/min dose is not tolerated. Conversely, the 
study design will not identify a maximally tolerated dose from Part II (Cohort 2) approximately 80%-85% of the time 
when no maximally tolerated dose exists.
Endpoints:
Primary Endpoint:
The primary endpoint is the incidence of clinically relevant hypotension, defined by SBP < 90 mm Hg (confirmed by 
a repeated value < 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug infusion.
Secondary Endpoints:

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge, whichever comes first, and at Day 32

Change in patient-reported resting dyspnea from baseline through Hour 72, as measured by the area under the 
curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at baseline, and Hours 6, 12, 24, 48, and 72
 
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a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Endpoints

The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion

The incidence of SBP < 90 mm Hg (confirmed by a repeated value)

Change in Troponin T from baseline to Hour 24, 48, and 72

Percentage of subjects who have died (all- cause and CV related) through Day 182
Additionally, the percentage of subjects with discontinuation due to symptomatic hypotension, as well as percentage 
of subjects with down-titrations, interruptions or discontinuations as a result of low blood pressure, either protocol 
specified clinically relevant hypotension, or asymptomatic decreases will be assessed.  . Other safety endpoints include 
the incidence of Adverse Events and Marked Laboratory Abnormalities, changes from baseline in vital signs, ECGs, 
physical measurements and laboratory assessments through Hour 120 or discharge, whichever comes first. The 
incidence of Serious Adverse Events will be assessed though Day 32.
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Analyses: Results from Part I (Cohort 1) and Part II (Cohort 2) will be presented separately.
For analyses involving baseline, the baseline value is defined by the last value prior to the start of infusion, unless 
otherwise noted.
Primary Endpoint Analysis
The incidence of clinically relevant hypotension from the start to 6 hours after the end of study drug infusion will be 
summarized by treatment. Point estimates and 95% CIs for event rates will be presented by treatment, together with 
point estimates and 95% CIs for the risk difference and relative risk between each BMS-986231 arm and placebo.
Secondary Endpoint Analyses
NT-proBNP will be summarized descriptively by treatment for each time point, as well as change from baseline.
Analyses for changes from baseline in the resting dyspnea as measured by the 11-point NRS will be done using a 
longitudinal repeated measures model, with baseline value and region as covariates. A trapezoidal rule will be applied 
to calculate AUC using model-estimated values from the time points. Missing values for the dyspnea NRS will not be 
imputed, except if a NRS cannot be obtained because the subject has died or is physically unable to complete the form. 
In these cases, a worst score imputation will be used for that time point.
.
Safety Endpoint Analyses
Troponin T will be summarized descriptively by treatment for each time point, as well as change from baseline.
Percentage of subjects who have died (all- cause and CV related) through Day 182 will be summarized descriptively 
by treatment.
All recorded adverse events 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.
Percentage of subjects with  discontinuations due to symptomatic hypotension, as well as percentage of subjects with 
down-titrations or interruptions or discontinuations as a result of hypotension, either protocol specified clinically 
relevant hypotension, or asymptomatic decreases will be summarized descriptively by treatment.
In addition, the final infusion dose at the completion of 48 hours infusion will be summarized descriptively by 
treatment. The subjects who discontinued prematurely from infusion would be counted as having a final infusion dose 
of 0 g/kg/min.
Cardiodynamic ECG assessment (Subset of Subjects in Part II Cohort 2 only):
The analysis will be based on exposure-response modeling of the relationship between plasma concentrations of 
prodrug BMS-986231, its byproduct BMT-284730 and other metabolites (eg, BMT-279554 & CAR-000463) and 
change-from-baseline QTcF (∆QTcF) with the intent to exclude an effect > 10 msec at clinically relevant plasma 
levels. 
In addition, the effect of BMS-986231 on the placebo-corrected ∆QTcF (∆∆QTcF) will be evaluated at each post-
dosing time point ('by-time point' analysis) using the Intersection Union Test. An analysis of categorical outliers will 
be performed for changes in heart rate (HR), PR, QRS, QTcF, T-wave morphology and U-wave presence
Pharmacokinetic Analyses 
Blood samples will be collected from all subjects at 0.75, 4, 8, 14, and 48 hours during infusion and 4 hours after end 
of infusion and plasma concentrations will be measured using LC-MS. Pharmacokinetic parameters for BMS-986231 
and BMT-284730 and other metabolites (eg, BMT-279554 & CAR-000463) will be estimated as appropriate. The 
plasma concentration may also be used to conduct population pharmacokinetic analysis and exposure-response 
analysis with select efficacy and safety endpoints. Results of the population pharmacokinetic and exposure-response 
analysis will be reported in a separate report.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 02: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.4 Safety Objectives ...................................................................................... 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-Investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Reductions, Temporary Interruptions, and Permanent 
Discontinuations of Study Drug Due to Blood Pressure ............................ 
4.6 Blinding/Unblinding ......................................................................................... 
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4.6.1 Emergency Unblinding ............................................................................ 
4.6.2 Other Blinding and Unblinding ............................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction or Return of Investigational Product ............................................. 
4.9 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.1.2 Discharge ................................................................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Assessment of Blood Pressure and Symptoms for Hypotension .............. 
5.3.2 Physical Measurements ........................................................................... 
5.3.3 Physical Examination .............................................................................. 
5.3.4 Electrocardiogram ................................................................................... 
5.3.5 Laboratory Test Assessments ................................................................... 
5.3.5.1 Local Laboratory Assessments for Screening ................................. 
5.3.5.2 Central Laboratory Assessments .................................................... 
5.3.6 Telemetry Monitoring .............................................................................. 
5.3.7 Holter Recordings .................................................................................... 
5.3.8 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Assessments of Worsening Heart Failure ................................................ 
5.4.2 Investigator Assessment of Signs of Congestion ...................................... 
5.4.3 Physical activity monitoring using a wrist-worn actigraphy device 
(watch) ........................................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.7.1 Dyspnea Assessments ............................................................................... 
5.7.1.1 Dyspnea Numerical Rating Scale ................................................... 
5.7.1.2 Dyspnea Likert Scale ...................................................................... 
5.7.2 Healthcare Utilization ............................................................................. 
5.7.3 Mortality .................................................................................................. 
5.8 Other Assessments ............................................................................................ 
5.8.1 Sensory Motor Survey .............................................................................. 
5.9 Additional Research Collection ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
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6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Data Monitoring Committee ............................................................................. 
7.2 Executive Committee ........................................................................................ 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
 
8.3.4 Safety Endpoints....................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Primary, Secondary, and Exploratory Endpoints Analyses ..................... 
8.4.2.1 Primary Endpoint Analysis ............................................................. 
8.4.2.2 Secondary Endpoint Analyses ......................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 2 CORE AND EXTENDED ADME GENE LIST .................................. 
APPENDIX 3 COUNTRY SPECIFIC REQUIREMENTS ......................................... 
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1.2
Research Hypothesis 
BMS-986231 is safe and tolerated with regard to clinically relevant hypotension compared with 
placebo in hospitalized heart failure with reduced ejection fraction (HFrEF) subjects with ADHF.
1.3
Objectives
1.3.1
Primary Objective
The primary objective is to evaluate the effects of various doses of BMS-986231 compared to 
placebo on clinically relevant hypotension (defined by SBP < 90 mm Hg or symptoms of 
hypotension).
1.3.2
Secondary Objectives

Assess the effect of BMS-986231 on NT-proBNP

Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 
11-point NRS)
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.3.4
Safety Objectives

Evaluate the effect of BMS-986231 on incidence of symptomatic hypotension

Evaluate the effects of BMS-986231 on the incidence of SBP < 90 mm Hg.

Evaluate the incidence of dose reductions, temporary interruptions, and permanent 
discontinuation of BMS-98623 infusions. 

Evaluate the safety and tolerability of a continuous 48-hour infusion of BMS-986231 in 
hospitalized HFrEF subjects with ADHF

Evaluate the effect of BMS-986231 on high sensitivity (Hs) Troponin T

Assess the effect of BMS-986231 on mortality at Day 182
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
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The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates.
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports (ESR), amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate.
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood

Allow time necessary for subject or subject’s legally acceptable representative to inquire about 
the details of the study

Obtain an informed consent signed and personally dated by the subject or the subject’s legally 
acceptable representative and by the person who conducted the informed consent discussion
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
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject’s consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject’s legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject’s willingness to continue participation in the study. This communication should be 
documented
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF and, in 
the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a multi-center, randomized, placebo-controlled, double-blind study of continuous 48-hour 
intravenous (IV) infusions of BMS-986231 in hospitalized HFrEF subjects with ADHF. The trial 
was designed to identify the doses of BMS-986231 that are safe and tolerated with regard to 
clinically relevant hypotension. 
The study consists of 2 parts, each with a unique cohort of subjects. 
Subjects that are randomized in Part I of the study will not be allowed to participate in Part II. 
In Part I (Cohort 1) of the study, approximately 100 subjects will be randomized in a 1:1 ratio to 
an escalating dose of BMS-986231 (3 g/kg/min for 4 hours, then 6 g/kg/min for another 4 hours, 
then 12 g/kg/min for the remaining 40 hours) or an escalating dose of placebo. 
In Part II (Cohort 2) of the study, the 2 highest planned doses of BMS-986231 in Cohort 1,
BMS-986231 6 g/kg/min and BMS-986231 12 g/kg/min, will be administered. Approximately 
210 subjects will be randomized in a 1:1:1 ratio to one of the 2 active doses of BMS-986231 or 
placebo. If BMS-986231 12 g/kg/min is not considered to be a tolerated dose in Part I, then
BMS-986231 3 g/kg/min and BMS-986231 6 g/kg/min will be evaluated in Part II. In the event 
that neither 6 g/kg/min nor 12 g/kg/min are tolerated, the protocol will require modification. 
The study design schematic is presented in Figure 3.1-1 for Part I (Cohort 1) and Figure 3.1-2 for 
Part II (Cohort 2).
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Figure 3.1-1:
Study Design Schematic Part I (Cohort 1)
a Every effort should be made to initiate study drug administration promptly after randomization 
b Study Medication infusion must start within 18 hours of presentation (or 48 hours in Part II Cohort 2 of the 
trial), with presentation defined as the first dose of diuretic for current episode, but not within 2 hours after an 
IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV 
diuretic administered by continuous infusion
c Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring
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Figure 3.1-2:
Study Design Schematic Part II (Cohort 2)
a 3 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
b 6 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
c Every effort should be made to initiate study drug administration promptly after randomization 
d Study Medication infusion must start within 18 hours of presentation for Part I Cohort 1 (or 48 hours of 
presentation for Part II Cohort 2), with presentation defined as the first dose of diuretic for current episode, 
but not within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or 
an increase in the dose of an IV diuretic administered by continuous infusion
e Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring.
Subjects must be randomized and treated within 18 hours of presentation for Part I Cohort 1 (or 
48 hours of presentation for Part II Cohort 2). Presentation is defined as the first dose of IV diuretic 
for the current episode of ADHF. In addition, subjects must not be randomized within 2 hours 
following an IV bolus dose of diuretic, or within 2 hours after the initiation or an increase in the 
dose of an IV diuretic administered by continuous infusion. It is recommended that subjects remain 
in the hospital for at least 24 hours after the completion of the 48-hour infusion of study drug for 
safety monitoring.
Every effort must be made to initiate study drug administration promptly after 
randomization.
The inpatient period will end in conjunction with the final in-patient assessment at Hour 120 or 
discharge, whichever comes first. All subjects will be followed for safety and rehospitalization
endpoints through Day 32 and mortality through Day 182.
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The start of the trial is defined as the first subject screened. End of trial is defined as the last 
subject’s final follow-up visit on Day 182, or the last subject’s scheduled procedure shown in the 
Time & Events schedule.
3.2
Post Study Access to Therapy
At the end of the in-patient period, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that 
the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent
2) Target Population
a) Subjects being hospitalized for ADHF
b) Have had at least 40 mg furosemide intravenous, or equivalent (e.g 40 mg furosemide 
equivalent to 20 mg torsemide or to 1 mg bumetanide ) for the current ADHF episode 
c) Subject must be randomized and treated within 18 hours of first dose of intravenous 
diuretic for Part I Cohort 1 (or 48 hours of first dose for Part II Cohort 2).
d) Have dyspnea at rest or with minimal exertion after administration of at least 1 dose of 
intravenous diuretics. Subject must not be randomized within 2 hours after an IV bolus 
dose of intravenous diuretics, or within 2 hours after the initiation or a dose increase of an 
IV diuretic administered by continuous infusion
e) Have a history of heart failure and a left ventricular ejection fraction (LVEF) 40%, as 
assessed by echocardiography, a multigated acquisition (MUGA) scan or magnetic 
resonance imaging (MRI) scan
Note: Ejection fraction documentation up to 18 months prior to screening may be used if 
there is no clinical expectation of improvement in ejection fraction in that timeframe 
(eg, the patient has not had biventricular pacing initiated during that period)
f)
Have at least 2 of the following at time of screening: 
i)
evidence for pulmonary congestion on chest x-ray
ii) rales by chest auscultation,
iii) edema 2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in 
15-30 seconds)
iv) presence of jugular venous distention 
g) Have an elevated NT-proBNP 1600 pg/mL (189 pmol/L) or BNP 400 pg/mL 
(116 pmol/L) as determined at the local laboratory within 18 hours prior to the start of 
study drug infusion for Part I Cohort 1 (or 48 hours for Part II Cohort 2)
For subjects with atrial fibrillation: NT-proBNP 2400 pg/ml or BNP 600 pg/ml
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h) Body weight 50 kg and < 140 kg at screening
i)
Subject Re-Screening: This study permits the re-screening of a subject that has 
discontinued the study as a screen failure (has not been randomized). See Section 5.1.1 for 
more details
3) Age and Reproductive Status
a) Males and Females, at least age 18 (or age of majority) (Germany only, see Appendix 3)
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 18 hours 
prior to the start of study treatment for Part I Cohort 1 (or 48 hours for Part II Cohort 2)
c) Women must not be breastfeeding
d) WOCBP must agree to follow instruction for methods of contraception for 32 days after 
discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle)
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for 92 days after discontinuation (duration of study drug plus 
90 days (duration of sperm turnover)
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 1), 
which have a failure rate of < 1% when used consistently and correctly.
Local laws and regulations may require use of alternative and/or additional contraception methods.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg at screening
b) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg just prior to randomization
c) Heart rate < 50 beats per minute (bpm) or > 130 bpm at screening
d) Heart rate < 50 beats per minute (bpm) or > 130 bpm just prior to randomization
e) Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, 
idiopathic hypertrophic or uncorrected severe valvular disease as defined by 
AHA/ACC/ESC criteria
Note: Functional mitral regurgitation, as well as restrictive mitral inflow pattern on 
echocardiography is not exclusionary
f)
Have a body temperature 38.5C (101.3F) at any time from screening to randomization
g) Have an active infection requiring current IV anti-microbial treatment
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2. Medical History and Concurrent Diseases
a) Considered clinically unstable for other conditions than acute heart failure, either because 
of acute coronary syndrome or ongoing arrhythmia (or be receiving concomitant parenteral 
therapy with any antiarrhythmic drugs), or other unstable non-cardiovascular disease
b) Suspected acute lung disease (e.g. pneumonia or asthma) or severe chronic lung disease 
(e.g. severe chronic obstructive pulmonary disease, pulmonary fibrosis, patients with 
hypercapnia or requiring home oxygen therapy or chronic oral steroids.)
c) Have a history of sudden cardiac death with resuscitation within the past 6 months
d) Be hospitalized with acute coronary syndrome, coronary revascularization or acute 
myocardial infarction during the previous 90 days prior to screening
e) Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic 
attack (TIA) during the previous 90 days prior to screening
f)
Serious comorbid noncardiovascular disease in which the life expectancy of the subject is 
< 6 months (eg, acute systemic infection – sepsis, metastatic cancer, or other serious 
illnesses)
g) Severe liver disease defined as history of cirrhosis with evidence of portal hypertension 
such as varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 51 mol/L) (Germany 
only, see Appendix 3)
h) Prior cardiac or renal transplant 
3. Physical and Laboratory Test Findings
a) Have persistent abnormal serum electrolytes not resolved before randomization, 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) (Germany 
only, see Appendix 3)
c) Have severe renal insufficiency before randomization (and during the current 
hospitalization) 
defined 
as 
an 
estimated 
glomerular 
filtration 
rate 
(eGFR)
< 30 mL/min/1.73m2 [based on any standard limit and equation employed by the local lab, 
eg, Modification of Diet in Renal Disease (MDRD) equation]. For patients with eGFR 
values less than but close to 30 mL/min/1.73m2 upon testing, retesting is allowed.
4. Prior and Concomitant Medications or Treatments
a) Subjects administered IV or transdermal nitrate therapy prior to randomization, except if 
all 3 of the following criteria are met:
i)
Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg 
AND
ii) The IV nitroglycerin dose is < 100 g/min (or isosorbide dinitrate < 3 mg/hour), AND
iii) The infusion rate and dose has been unchanged for > 2 hours
b) History of chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or 
peritoneal dialysis)
c) Subjects treated during the current hospitalization with IV vasoactive drugs such as
dopamine, dobutamine, enoximone, nesiritide, nitroprusside, levosimendan, amrinone or 
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milrinone, carperitide or nicorandil prior to start of study drug infusion, or have an 
anticipated need to be treated with any of these agents during the study drug infusion
d) Subjects treated with oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil, vardenafil 
or avanafil within 24 hours of screening or treated with tadalafil within 4 days of screening, 
oral vasopressin V2 receptor antagonist (e.g. tolvaptan) or oral inotropic agents (e.g. 
pimobendan)
e) Subjects receiving any mechanical ventilation at the time of screening
f)
Subjects receiving
non-invasive ventilation (CPAP/BiPAP) < 2 hours prior to 
randomization
5. Allergies and Adverse Drug Reaction
a) Any history of allergic reaction to BMS-986231, or its components, Captisolor 
potassium acetate
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
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, CXL-1427, or CXL-1020
e) Alcohol beverage consumption within 6 hours prior to randomization
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products
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
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.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments

Initiation of PDE5 inhibitors or pimobendan is prohibited during study drug infusion and 24 
hours after the end of the study drug

The use of nitrates, except for subjects receiving stable IV dose of nitrates at randomization, 
should be avoided, unless clinically indicated (ie, episodes of angina, worsening HF)

Administration of IV vasoactive drugs (such as dopamine, dobutamine, enoximone, 
nitroprussiate, levosimendan or milrinone) should be discouraged unless clinically warranted 
(ie, if patient’s status requires use of vasoactive treatments for conditions such as worsening 
heart failure)
3.4.2
Other Restrictions and Precautions
Not applicable.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
The below discontinuation criteria apply to both Part I (Cohort 1) and Part II (Cohort 2) of the 
trial.
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

If study medication has been interrupted for low blood pressure, resumed, and an episode of 
hypotension (or symptoms of hypotension) reoccurs (see Section 4.5.1)
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee within 
24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion among the investigator and 
the Sponsor or designee and the patient must occur.
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All subjects who discontinue study drug are requested to comply with protocol specified follow-
up procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate electronic case report form (CRF) page.
3.6
Post Study Drug 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 subject safety and the integrity of the study. Subjects who discontinue 
study drug must continue to be followed for collection of outcome and/or survival follow-up data 
as required and in line with Section 5 until death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or 
post treatment study follow-up, and entered on the appropriate CRF page. In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with local 
law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
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lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/Non-IMP) 
and can consist of the following:
Treatments:
BMS will provide Investigational drug product BMS-986231 for infusion (active pharmaceutical ingredient BMS-986231 formulated 
with Captisol® 3405 mg/vial) to all sites as per Table 4-1. In addition, Potassium acetate is to be locally sourced by sites within the US 
and will be supplied to all ex-US sites as per Table 4-1.
Table 4-1:
Study Drugs for CV013011 - Part I (Cohort 1) and Part II (Cohort 2)
Product Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
BMS-986231
For Injection
BMS-986231 
240 mg/vial
IP
Open Label
White to pale yellow whole or fragmented 
cake in a 20 mL glass vial with Fluortec
stopper and a blue flip-off aluminum cap.
Secondary packaging is a carton containing 
5 or 6 vials.
2 to 8°C (36-46°F)
Store in original 
package, protect from 
light.
Potassium Acetate Injection, 
USPa
2 mEq/mL 
(20mL/vial)
Non-IMP
Open Label
Colorless solution in a 20 mL fliptop glass 
vial.
Secondary packaging is a carton containing 
6 vials
Store at 20 to 25°C
(68 to 77°F).
a Supplied by BMS only to ex-US sites
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
Study medication will be prepared by an unblinded pharmacist (or appropriate designee) at time 
of randomization. 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.
4.2
Non-Investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products. 
In this study, the required Potassium Acetate used in the active and placebo infusions is considered 
non-investigational product.
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS and listed in 
Table 4-1 and drug product label. If concerns regarding the quality or appearance of the study drug 
arise, the study drug should not be dispensed and BMS contacted 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 Section 9.2.2
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. 
4.4
Method of Assigning Subject Identification
At the time of screening for both Part I (Cohort 1) and Part II (Cohort 2), each subject will be 
assigned a unique sequential subject number by interactive response technology (IRT). The IRT
will be available 24 hours per day, 7 days a week. The subject number will consist of a unique 
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5 digit number which is assigned sequentially within a study (starting with 00001) by the IRT. 
This number will be used for identification throughout the study and will not be used for any other 
subject. Subjects screened for Part I, (Cohort 1) will be assigned sequential study numbers 
beginning with 00001, and subjects screened for Part II, (Cohort 2) will be assigned sequential 
study numbers beginning with 10001.
Randomization schedules will be generated by BMS and kept by the IRT vendor. Subjects who 
meet the inclusion/exclusion criteria will be randomly assigned by the IRT to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min) in a 1:1 ratio for Part I (Cohort 1) and 
placebo or 1 of the 2 active dose levels of BMS-986231 in a 1:1:1 ratio for Part II (Cohort 2).
Randomization will be stratified by region.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be administered study medication as a continuous IV infusion over 48 hours.
Body weight measured at screening will be used for dose calculations.
Every effort must be made to initiate study drug administration promptly after 
randomization.
See Pharmacy Manual for additional dosing information.
4.5.1
Dose Reductions, Temporary Interruptions, and Permanent 
Discontinuations of Study Drug Due to Blood Pressure
Any decision to lower the dosage level of study drug or discontinue study drug should be based 
on the Investigators assessment of the subject’s overall clinical stability, in the context of 
appropriate ongoing monitoring of the subject’s condition. A 50% dosage adjustment downward 
maybe be achieved by decreasing the rate of study drug infusion.
In Part I (Cohort 1) subjects who require a dose reduction or temporary interruption during the 
first infusion period, hours 0 to 4 (dose of 3 μg/kg/min), will be permanently discontinued from 
study drug.
Study drug infusion rate may be reduced by 50%, temporarily interrupted, or permanently 
discontinued. See Figure 4.5.1-1 and the following sections for more detail.
Dose Reduction:

If the subject experiences SBP < 95 mm Hg, without symptoms related to hypotension, the 
measurement must be repeated within 15 minutes. If the SBP remains < 95 mm Hg, the dose 
reduction must occur

A 50% dosage adjustment downward may be achieved by decreasing the rate of study drug 
infusion by half

After a dose reduction, the dose cannot be increased again
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Temporary interruption:

If the systolic blood pressure reduces below < 85 mm Hg, and remains < 85 mm Hg during a 
repeated measure within 15 minutes, the study drug must be interrupted for at least 1 hour

For subjects that report symptoms consistent with hypotension (eg, dizziness, lightheadedness, 
etc.), and are related to hypotension, study drug must be interrupted for at least 1 hour
Resuming Study Drug

Study drug may be resumed at 50% of the dose after 1 hour interruption, if SBP rises to values 
105 mm Hg and any symptoms of hypotension, if present, have resolved. 

If after 4 hours, the subject’s SBP remains below < 105 mm Hg, or if symptoms persist, then
study drug must be permanently discontinued

After a dose reduction, the dose cannot be increased again
Permanent discontinuation of the infusion:

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 subject’s best interest 
to continue to receive study drug

Study drug will be permanently discontinued after it has been down titrated once, and criteria 
for dose reduction or interruption has been met again.
Figure 4.5.1-1:
Guidance for Dose Reduction Based on Blood Pressure Measurements 
and/or Symptoms of low blood pressure
* Confirmed by a second measure within 15 min
**No need to wait for confirmatory measures within 15 min
§ But no more than 4 hours
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4.6
Blinding/Unblinding
4.6.1
Emergency Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is via the Interactive Response 
Technology (IRT) system. For information on how to unblind in an emergency, consult the IRT 
manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
4.6.2
Other Blinding and Unblinding
The Data Monitoring Committee (DMC; see Section 7) will assess safety on an ongoing basis, and 
will have access to unblinded treatment codes for individual subjects. An analysis team, including 
a reporting statistician and programming support, who are not involved with the conduct of the 
study, will provide analyses to the DMC.
Two interim analyses will be performed in this study.
The first unblinded interim analysis will be performed by the analysis team at the completion of 
the last visit at Hour 120 in Part I (Cohort 1). This analysis will be reviewed by the DMC and will 
be reviewed in parallel and by the executive committee (see Section 7) and Sponsor 
representatives.  The rationale for a fully unblinded review by the executive committee and 
Sponsor is to determine whether 12 μg/kg/min is an appropriate dose to study in Part II. 
The second interim analysis will be performed following completion of the last visit at Day 32 in 
Part II (Cohort 2). The study analysis team will then provide top-line results to the project team.
The follow-up to Day 182 for both Part I and Part II will be site-and-subject blinded. 
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The Bioanalytical Sciences section or its designate may be unblinded to the randomized treatment 
assignments in order to minimize unnecessary assays of samples from control group subjects. 
Likewise, the Biotransformation section or its designate may be unblinded, if metabolite profiling 
work is conducted.
In certain circumstances a pharmacokineticist or designates in Clinical Pharmacology and 
Pharmacometrics, biostatisticians and programmers 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 assignments.
The pharmacist at the site and/or its designate will be unblinded to the randomized treatment 
assignments in order to dispense treatment from bulk supplies, as needed. An unblinded Site 
Monitor, not involved with other study conduct, will be assigned exclusively to reconcile study 
medication and assure accountability.
Except as noted above, other members of BMS Research and Development personnel, as well as 
all vendors responsible for the conduct of the trial (protocol team) will remain blinded.
4.7
Treatment Compliance
Not applicable.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site.
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed 
after being inspected and reconciled by the responsible 
Study Monitor unless IP containers must be immediately 
destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If IP will be returned, the return will be arranged by the 
responsible Study Monitor.
IP sourced by site, not supplied by BMS (or its 
vendors) (examples include IP sourced from the 
sites stock or commercial supply, or a specialty 
pharmacy)
It is the investigator’s or designee’s responsibility to 
dispose of all containers according to the institutional 
guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances
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
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced by the site, not 
supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
Eligibility Assessments
Informed Consent
X
Review Inclusion/Exclusion Criteria
X
X
Medical History
X
Confirm administration of IV diuretic and time of 
administration
X
Safety Assessments
Complete Physical Examination
X
Body Weight
X
Height
X
Vital Signs: Blood Pressure and Heart Rate
X
X*
Perform Semi-Recumbent (at a 30º angle).
*Within 15 minutes prior to randomization
Respiratory Rate
X
X
Use of Oxygen Supplementation, Oxygen Saturation
X
X
Temperature
X
X*
*Within 15 minutes prior to randomization
Chest X-ray
X
As applicable, refer to section 3.3.1
X-ray obtained for the current episode of ADHF as part 
of standard of care may be used.
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Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
12-Lead ECG (Electrocardiogram)
X
Telemetry Monitoring 
X
Begin within 2 hours prior to start of study medication 
infusion
Holter Monitoring (Part II Cohort 2 Only)
X
For participating sites. 
Begin within 2 hours prior to start of study medication 
infusion
Investigator Assessment of Congestion
X
Physical exam to assess signs and symptoms of 
congestion will include symptom assessments (dyspnea 
on exertion, dyspnea at rest, orthopnea, paroxysmal 
nocturnal dyspnea, persistent coughing or wheezing, 
fatigue, and abdominal discomfort), and signs 
assessment (peripheral edema, pulmonary rales, 
tachypnea and/or oxygen desaturation, increased jugular 
venous pressure, hepatomegaly, ascites).
Serious Adverse Events Assessment
X
X
Begins at time subject signs ICF
Review concomitant medications/procedures
X
X
Local Laboratory Assessments
See Section 5.3.5.1 for Analytes
Hematology and Serum Chemistry
X
eGFR
X
Trough Serum Digoxin
X
If receiving digitalis glycosides
Hs Troponin T
X
Coagulation Tests 
X
Prothrombin Time (PT or PT-INR) 
NT-proBNP or BNP
X
As per site preference
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Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
Pregnancy Test
X
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
Hs Troponin T
X
NT-proBNP, Serum Cystatin C, NGAL
X
CRP
X
Urinalysis
X
Urine creatinine, Na+, and K+
X
Efficacy Assessments
Resting Dyspnea measured by the Numerical Rating 
Scale (NRS)a
X
Other Assessments
Sensory Motor Survey
X
a If subject is receiving supplemental oxygen, perform NRS without removing oxygen
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Randomize Subject
X
Randomization must take place before 
Hour 0
Administer Study Medication
X
48 hour continuous infusion
*Study medication infusion begin
promptly after randomization*
Safety Assessments
Body Weight
X
X
X
X
X
Vital Signs: Blood Pressure and 
Heart Rated
X
X
X
X
X
X
Perform Semi-Recumbent (at a 30º 
angle) 
Day 1: Hours 0, 0.5, 1, 2, 4, 5*, 6, 8, 
9*, 10, 12, 14, 16, 18, 20, 22 
Hours: 24, 28, 32, 36, 40, 44
Hours 48, 54, 60, 66
Hour 72
Hour 96
Hour 120
Perform measurements before IV bag 
change, when possible.
Repeats as per Section 5.3.1
Perform also if signs or symptoms of 
hypotension
*Part I (Cohort 1) only
Respiratory Rate
X
X
X
X
X
X
Day 1: Hours 6 and 12
Use of Oxygen Supplementation, 
Oxygen Saturation
X
X
X
X
X
X
Day 1: Hours 6 and 12
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Temperature
X
X
X
X
X
12-Lead ECG
X
X
X
X
Telemetry Monitoring
X
Continuous monitoring through 
Hour 50
Holter Monitoring (Part II Cohort 
2 Only)
X
For participating sites. 
Continuous monitoring through 
Hour 52. 12-lead ECGs will be 
extracted at 3 timepoints prior to the 
start of the infusion and at the same 
timepoints as PK determinations up to 
and including 48 hours post-dose (See 
section 5.5)
Subjects will be supinely resting in a 
semi-recumbent position for at least 10 
minutes prior to and 5 minutes after 
each timepoint for ECG extraction (Day 
1: Hour 0.75, 4*, 8*, 14, 48 and Hour 
52). When ECG extractions coincide 
with 12-lead safety ECGs, blood draws 
and other assessments, ECG extractions 
should, when feasible, be performed in 
said order.
Investigator Assessment of Signs 
of Congestion
X
X
X
X
X
Physical exam to assess signs and 
symptoms of congestion will include 
symptom assessments (dyspnea on 
exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea, 
persistent coughing or wheezing, 
fatigue, and abdominal discomfort), and 
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
signs assessment (peripheral edema, 
pulmonary rales, tachypnea and/or 
oxygen desaturation, increased jugular 
venous pressure, hepatomegaly, 
ascites).
Assessment of Hypotension
X
X
X
Assessment of signs and symptoms of 
hypotension.  
Serious Adverse Event Assessment
X
Adverse Events Assessment
X
From Hour 0 to Hour 120.
If subject is discharged before 
Hour 120, site asked to contact subject
at Hour 120 for final AE collection
Concomitant Medications
X
Local Laboratory Assessments
Cumulative Urinary Output 
(Volume) 
X
X
X
X
X
Provide daily volume
Pregnancy Test
X
X
WOCBP only
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
X
X
X
Hs Troponin T
X
X
X
X
NT-proBNP, Serum Cystatin C,
NGAL
X
X
X
X
CRP
X
X
Urinalysis
X
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Urine creatinine, Na+ and K+
X
X
X
X
Pharmacokinetics
See Section 5.5
Pharmacokinetic Blood Samples
Collection and Preparation of 
Blood Samples 
X
X
X
Part I Cohort 1: Day 1: Hour 0.75, 4, 8, 
14
Hour 48
Hour 52
Part II Cohort 2: Day 1: Hour 0.75, 6, 
14
Hour 48
Hour 52
Perform measurements before IV bag 
change or stopping the infusion, 
whenever possible.
Collect sample when dose lowered due 
to a safety event and also at time of 
early discontinuation of study drug.
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Efficacy Assessments
Resting Dyspnea measured by 
Numerical Rating Scale (NRS)e
X
X
X
X
X
Day 1: Hours 6 and 12
Resting Dyspnea measured by 
7-point Likert Scalee
X
X
X
X
X
Day 1: Hours 6 and 12
Patient Global Assessment
measured by 7-point Likert Scalee
X
X
X
X
X
Day 1: Hours 6 and 12
Assessments of Worsening Heart 
Failure
X
X
X
X
X
Documentation of Worsening Physical 
Signs and Symptoms of Heart Failure, 
and Documentation of Initiation or 
Increased dose of Parenteral Diuretic, 
Vasodilator and/or Inotropes, or Need 
for Mechanical interventions 
(mechanical ventilation, circulatory 
support, ultrafiltration or dialysis). 
Assessments to cover prior 24 hour 
period.
Wristworn Actigraphy monitoring
device (watch) (Part II Cohort 2)
X
X
X
X
For participating sites. 
Provide the device to subjects at the end 
of the 48 hours infusion or when the 
study drug has been permanently 
discontinued
Other Assessments
Sensory Motor Survey
X
a Hour 0 defined as start of study medication infusion
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b Visit to occur at Hour 120 2 or Discharge, whichever comes first. If subject is discharged after Hour 120, no further protocol in-hospital visits are completed
c Assessments required at Discharge Visit should not be repeated if performed within previous 12 hours
d  Vital signs should be taken within (0.25) 
e If subject is receiving supplemental oxygen, perform NRS without removing oxygen
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Table 5.1-3:
Outpatient Follow-up (CV013011)
Procedure
Day 32 
(2 Days)
Clinic Visit
Day 182 
(5 Days)
Phone Visit
Notes
Safety Assessments
Vital Signs: Blood Pressure and Heart 
Rate
X
When possible, perform Semi-Recumbent (at a 30º angle)
Respiratory Rate
X
Body Weight
X
Temperature
X
Serious Adverse Events Assessment
X
Local Laboratory Assessments
Pregnancy Test
X
WOCBP only
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
NT-proBNP, Serum Cystatin C, NGAL
X
CRP
X
Urinalysis
X
Urine creatinine, Na+ and K+
X
Efficacy, Safety, and Other Assessments
Healthcare Utilization Assessment
X
Assessment of Mortality
X
X
Sensory Motor Survey
X
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Table 5.1-3:
Outpatient Follow-up (CV013011)
Procedure
Day 32 
(2 Days)
Clinic Visit
Day 182 
(5 Days)
Phone Visit
Notes
Actigraphy monitoring watch (Part II 
Cohort 2)
X
For participating sites. 
One time complete transfer of data from the actigraphy device to a dedicated 
website via an electronic docking station to occur during or immediately
following the 32-days study visit
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5.1.1
Retesting During Screening or Lead-in Period
All screening laboratory will be performed locally, and tests may be repeated at the discretion of 
the Investigator as per site policy.
Any new result will override the previous result (ie, the most current result prior to Randomization) 
and is the value by which study inclusion will be assessed, as it represents the subject’s most 
current, clinical state.
In an effort to find all possible well-qualified subjects, subjects that have discontinued the study 
as a screen failure (have not been randomized) are eligible for re-screening upon presentation for 
a subsequent episode of ADHF at the discretion of the Investigator.
If re-screened, the subject must be re-consented and a new subject number will be assigned by the 
IRT. Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening 
Procedural Outline, must be repeated. The subject numbers and data will be linked in the clinical 
database.
5.1.2
Discharge
Discharge may occur as per institutions standard medical practice. It is recommended that subjects 
remain in the hospital for at least 24 hours after the completion of the 48-hour infusion of study 
drug for safety monitoring. 
Subjects discharged prior to Hour 120 should complete the Hour 120/Discharge visit. Assessments 
required at the Hour 120/Discharge Visit as per Table 5.1-1 should not be repeated if performed 
within the previous 12 hours. 
5.2
Study Materials

11-item Numerical Rating Scale

7-point to Likert Scale

Sensory Motor Survey

Pharmacy Manual

Clinical Laboratory Manual

Subject education materials and other site support tools
5.3
Safety Assessments
Additional procedures and assessments may be performed as a part of the subject’s standard of 
care; however, data for these assessments will remain in the subject’s medical record and is not be 
provided to BMS, unless needed to support an AE, SAE report, or as specifically requested by the 
Sponsor.
5.3.1
Assessment of Blood Pressure and Symptoms for Hypotension
The primary endpoint of the study is the incidence of clinically relevant hypotension, defined by 
SBP < 90 mm Hg (confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up 
to 6 hours after the end of study drug infusion. Thus hypotension will be assessed by collection of 
symptoms and blood pressure measurements.
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Symptomatic hypotension is defined as the presence of both low SBP and significant and/or 
non-resolving symptoms due to low blood pressure (eg, lightheadedness, dizziness, etc.). 
Blood pressure measurements should be performed with the subject in a semi-recumbent (about a 
30º angle) position, whenever possible. 
Blood pressure will be measured as indicated in Table 5.1-2, within (0.25) of the specified time 
points. In addition, sites may perform measurements at intervals defined by institutional standard 
of care for subjects receiving vasodilators, but no less than what is described in Table 5.1-2.
If the study drug dose is modified (decreased, interrupted, resumed or discontinued) the frequency 
of blood pressure measurements will follow a more intensive schedule for up to 6 hours following 
the dose modification (Table 5.3.1-1). Upon completion of the intensive schedule, measurements 
can be either resumed per the original schedule, or follow the discontinuation schedule if the drug 
is permanently discontinued. 
Table 5.3.1-1:
Schedule of Intensive Blood Pressure Collection Following a 
Dose Modification
30 minutes
post
1 hour
post
2 hours
Post
4 hours
post
6 hours
post
Dose reduction
X
X
X
X
X
Dose interruptiona
X
X
X
X
Dose resumptionb
X
X
X
X
X
Dose discontinuation
X
X
X
X
Xc
a dose must be resumed within 4 hours of dose interruption. If interruption last beyond 4 hours, dose must be 
discontinued and discontinuation schedule must be followed.
b If dose is restarted within 4 hours following interruption, follow schedule for dose resumption
c After 6 hours, continue collecting blood pressure measurement at a minimum of every 12 hours through hour 72 or 
follow the local institutional standard of care protocol, whichever is more frequent.
In addition to assessments of blood pressure, the Investigator will be asked to collect and assess
signs and symptoms of low blood pressure The details to be captured will include:

Onset date/time

Total duration of episode

Lowest blood pressure during the episode

Signs and symptoms associated with low blood pressure (such as confusion, dizziness, fatigue, 
auditory disturbances (such as tinnitus), lightheadedness, chest pain, visual disturbances, 
vomiting, syncope, etc)
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Events of clinically relevant hypotension will also be recorded as an Adverse Event (see Section 6)
Management of study drug (interruption, discontinuation, re-start) is detailed in Section 4.5.1.
Hypotension endpoints are defined in Section 8.3.
5.3.2
Physical Measurements
Height: Measurement of height should be performed with the subject’s shoes removed, if possible. 
The subject’s knees should be straightened, head held erect, and eyes forward.
Weight: Measurement of weight should be performed with the subject having pockets empty, 
shoes removed, and bladder empty, when possible.
5.3.3
Physical Examination
A complete physical examination should include general appearance, head, eyes, ears, nose, throat, 
neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, and 
musculoskeletal.
The individual performing the physical examinations must be licensed by state law 
(or applicable local law) to perform a physical examination.
5.3.4
Electrocardiogram
The Investigator should review and assess all ECGs for any clinically significant abnormalities, 
and initial and date the report.
The site should follow their standard practices for performing ECGs. Below is guidance to be used 
as a reference, if needed:
In preparation for the ECG, ensure there is minimal interference between the skin surface and the 
electrode. Use alcohol to prepare the skin at each electrode site. Thick chest hair should be shaved 
to ensure sufficient contact.
Before attaching electrodes to pick-up points, spread the electrode with electrode gel. Place the 
electrodes on bony areas, avoiding large muscle masses, to achieve better tracings as described 
below. The subject must be supine and should refrain from movement during the ECG recording.
Ensure that the subject and the electrodes (including the neutral electrode) are not exposed to 
conducting objects, even if grounded.

RL: On the right leg (inside calf, midway between knee and ankle)

LL: On the left leg (inside calf, midway between knee and ankle)

RA: Right arm (on the inside)

LA: Left arm (on the inside)

V1: 4th intercostal space, at right sternal margin

V2: 4th intercostal space, at left sternal margin

V3: Midway between V2 and V4

V4: 5th intercostal space at left midclavicular line

V5: Same transverse level at V4, at anterior axillary line

V6: Same transverse level at V4, at left midaxillary line
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Keep one original ECG (print-out or electronic copy) in the medical chart and ensure a copy, 
assessed, initialed and dated by the Investigator, is maintained in the source documents for the 
study.
5.3.5
Laboratory Test Assessments
Subjects will have laboratory tests performed locally as necessary for treatment of ADHF 
following local practices. In addition, laboratory tests will be performed locally and centrally as 
described in the following sections.
5.3.5.1
Local Laboratory Assessments for Screening
The following local laboratory tests will be assessed as part of the screening evaluation. Local 
Laboratory results obtained for the current episode of heart failure as part of standard of care may 
be used. 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)

Alkaline Phosphatase

Total Bilirubin

Blood Urea Nitrogen (BUN)

Electrolytes

Sodium

Potassium

Serum Creatinine (Scr)
Other Assessments

eGFR, by locally used equation

Trough Serum Digoxin (if receiving digitalis glycosides)

Hs Troponin T (or other based on site’s available assays)

Coagulation Tests

Prothrombin Time (PT or PT-INR)

NT-ProBNP or BNP (as per site preference)
5.3.5.2
Central Laboratory Assessments 
The following laboratory tests will be performed and submitted to the Central Laboratory for 
analysis as per the Study Assessment and Procedures in Section 5.
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Hematology

Hemoglobin

Hematocrit

White blood cell count and differential

Erythrocytes (RBC)

Erythrocyte mean corpuscular volume (MCV)*

Erythrocyte mean corpuscular hemoglobin (MCH)*

Erythrocyte mean corpuscular hemoglobin concentration (MCHC)*

Platelet count

Reticulocyte count*
*performed at baseline, Hour 120 or Discharge, whichever comes first, and Day 32
Serum chemistry

Aspartate Aminotransferase (AST, SGOT)

Alanine Aminotransferase (ALT, SGPT)

Alkaline Phosphatase

Creatine Kinase (Creatine Phosphokinase) (CK) (CPK)

Total Bilirubin

Uric Acid

Blood Urea Nitrogen (BUN)

Electrolytes

Sodium

Potassium

Chloride

Bicarbonate

Glucose

Anion gap

Magnesium

Total Protein

Albumin

Serum Creatinine (Scr)

Calcium*

Phosphorus*
*performed at baseline, Hour 24, Hour 48 and Hour 120 or Discharge, whichever comes first.
Other Assessments

eGFR, by MDRD 

Trough Serum Digoxin (if receiving digitalis glycosides)

Hs Troponin T 

Coagulation Tests

Prothrombin Time (PT and PT-INR) 

Partial thromboplastin time (PTT) 
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
NT-ProBNP

Cystatin C

CRP

NGAL
Urinalysis

pH, protein, glucose, leukocyte esterase, blood by dipstick

Microalbumin

Albumin: creatinine ratio

Microscopy if dipstick positive for blood, leukocyte esterase or protein
The Central Laboratory and designated reference laboratories for this study will perform the
analysis of all scheduled laboratory tests and will provide reference ranges for these tests. Urine
dipstick testing for pregnancy (in WOCBP) at specified visits is to be done at the investigative site. 
The detailed methods for specimen collection, handling, processing, shipping, and storage will be 
supplied in the Investigator’s Laboratory Manual provided by the Central Laboratory.
5.3.6
Telemetry Monitoring
Telemetry monitoring will be performed to help monitor subject safety. The site will follow their 
normal operating procedures established for telemetry monitoring. Clinically significant findings 
from the telemetry monitoring will be recorded as AEs and SAEs per the Investigators decision.
5.3.7
Holter Recordings
Holter monitoring with extraction of serial ECGs will be performed in a sub-set of 51 patients in 
Part II Cohort 2 only, randomized 1:1:1 to placebo and the two active doses in Part II Cohort 2 of 
the study. The 12-lead Holter and ECG equipment will be supplied and supported by the sponsor 
and a core electrocardiographic laboratory. ECGs to be used in the analyses will be selected by 
pre-determined time points as defined in the Table of Assessments, and will be read centrally by a 
core electrocardiographic laboratory. The analysis will be described in detail in a separate analysis 
plan.
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer-assisted and statistical process utilized by a 
core electrocardiographic laboratory. 
At each protocol-specified timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG 
window” (typically, the last 5 minutes of the 15-minute period when the subject is maintained in 
a supine or semi-recumbent quiet position.  Subjects must be instructed to rest in a quiet position 
15 minutes before each PK draw.
5.3.8
Imaging Assessment for the Study
Not Applicable.
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5.4
Efficacy Assessments
5.4.1
Assessments of Worsening Heart Failure
The Investigator will be asked to indicate if a subject has experienced worsening heart failure, to 
document the signs, and symptoms that led to the assessment of worsening heart failure, and to 
document the intensification of treatment implemented for worsening heart failure.  Assessment is 
to be done once daily covering the prior 24-hour period as per the scheduled times in Table 5.1-2.
In this trial, worsening heart failure is defined as new or worsening signs and/or symptoms of 
heart failure that require:

Intensification of IV therapy for heart failure (such as initiation, restart or up-titration of IV 
diuretics, IV nitrates or other IV vasoactive drugs), and/or

Addition of a mechanical support, either:

Ventilatory (mechanical ventilation, noninvasive ventilation), 

Circulatory (Intra-Aortic Balloon Pump (IABP), ventricular assist device) or 

Use of ultrafiltration, hemofiltration or hemodialysis specifically for the management of 
WHF
The presence of WHF must be documented by the investigator recording the signs, symptoms, 
and/or laboratory assessments that led the conclusion that the subject had worsened.
Symptoms of heart failure may include: dyspnea on exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea, persistent coughing or wheezing, fatigue, and abdominal 
discomfort.
Signs of heart failure might include: pulmonary rales, tachypnea and/or oxygen desaturation, 
increased jugular venous pressure, hepatomegaly, peripheral edema, an increase in body weight, 
oliguria, and signs of hypo-perfusion such as mental confusion, hypotension, and cool skin
5.4.2
Investigator Assessment of Signs of Congestion
The Investigator will be asked to assess the subject’s signs of congestion using the following 
criteria:
1) Bilateral peripheral edema using a 4-point scale
a) 0 absent
b) 1+ Trace (Barely perceptible indent, skin rebounds quickly)
c) 2+ Feet and ankles (Easily identifiable indent, skin rebounds in 15-30 sec, edema limited 
to feet and ankles)
d)
3+ Lower legs or thighs (Easily identifiable indent, skin rebounds in > 30 sec, edema 
extended to lower legs or thighs)
2) Bilateral pulmonary rales: Auscultation of the lungs applying a 3-point scale
a) 0 absent
b) 1+ < 1/3 up lung fields,
c) 2+ 1/3 up lung fields
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3) Jugular venous distension (absent / present) 
4) Hepatic enlargement (absent / present)
5) Orthopnea: The subject should be observed after being in the lowest recumbent position for 
10-15 minutes
a) Absent – subject has no sensation of dyspnea in recumbent position
b) Present - dyspnea develops in the recumbent position and is relieved by elevation of the 
head with pillows
6) Ascites
a) Absent
b) Present
5.4.3
Physical activity monitoring using a wrist-worn actigraphy device
(watch)
Physical activity will be measured in a subset of approximately 100 patients in Part II of the trial 
only, using an actigraphy wearable device worn on the wrist (wristwatch) that utilizes an 
accelerometer to monitor the occurrence and degree of motion47.
All sites participating in the accelerometry sub-study will provide the device to subjects at the end 
of the 48 hours infusion or when the study drug has been permanently discontinued. Study 
participants accepting to participate in the sub-study will wear the device continuously during 30 
days follow-up period, with the exception of the charging period (battery life expected to be 
approximately 10-12 days), via a charger provided to the patient. Data collected by the device will 
be uploaded during the 32-days study visit via an electronic docking station at the site. 
5.5
Pharmacokinetic Assessments
Blood samples will be collected for pharmacokinetic assessments as described in Table 5.5-1.
Table 5.5-1:
Pharmacokinetic Assessments
Time 
Relative to Dosing
Hour (window)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
0.75 (0.25)
00:45
X
4 (0.5) 
04:00
X
8 (0.5) 
8:00
X
14 (4) 
14:00
X
48 (1) 
48:00
X
52 (1)
52:00
X
Dose lowered due to safety event (0.5)
Misc.
X
Early Discontinuation
Misc.
X
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Collect the 4 and 8 hour PK samples immediately prior to the IV bag change whenever possible.
In addition, collect a PK sample from the subject 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
5.7.1
Dyspnea Assessments
The sensation of dyspnea is subjective, but dyspnea relief is important to subjects and has been 
long quantified in clinical trials using patient-reported outcome scales that have previously been 
used to assess the efficacy of other interventions in ADHF subjects.
In this trial, subjects are asked to report their absolute current severity of dyspnea on an 11-point 
numerical rating scale (NRS; range 0 to 10) and their current level of dyspnea relative to baseline 
using 7-level Likert scales.
5.7.1.1
Dyspnea Numerical Rating Scale
The numerical rating scale (NRS) will be used to assess the degree of dyspnea (breathlessness), 
measured using an 11-point scale provided by the Sponsor.
5.7.1.2
Dyspnea Likert Scale
Subject will be presented with the following question: “We would like to measure how you think 
your breathing is. Please circle the number next to the description that best indicates how you are 
breathing right now, compared to when you first started the study drug.”
3 = Markedly better
2 = Moderately better
1 = Minimally better
0 = No change
-1 = Minimally worse
-2 = Moderately worse
-3 = Markedly worse
5.7.2
Healthcare Utilization
Following discharge from the index hospitalization, the occurrence of rehospitalizations and 
emergency department visits for heart failure and other causes of cardiovascular disease will be 
documented. Rehosptalizations will include subjects who are either under observation or admitted 
as an inpatient with a length of stay 24 hours. Emergency department visits will include urgent, 
unplanned visits in a monitored healthcare setting with a length of stay < 24 hours. Only 
emergency department visits that do not result in a hospitalization will be counted as separate 
healthcare encounters.
In the event that the subject reports rehospitalizations or emergency department visits through 
Day 32 after the index hospitalization, the reason for the rehospitalization/ED visit will be recorded 
and, where possible, will be confirmed with the hospital or the subject’s physician. The 
investigator should make every effort to obtain a discharge summary. If the subject is currently 
hospitalized and unable to attend the visit, then the investigator should make every effort to 
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reschedule the visit when medically appropriate and to obtain the discharge summary when 
available.
The primary reason for the rehospitalization/ED visit will be categorized by the investigator into 
1 of the following categories:

Heart failure related event involves a primary diagnosis of HF, where the subject has new or 
worsening symptoms, objective evidence of new or worsening HF, and receives new or 
intensification of treatment including an IV diuretic

Other cardiovascular, non-heart failure related event involves a primary diagnosis of 
cardiovascular disease other than HF including MI, resuscitate sudden cardiac death or other 
cardiovascular cause (eg, stroke)

Non-cardiovascular event involves primary diagnoses other than HF and CV disease
5.7.3
Mortality
Investigators will follow all subjects to Day 182 for mortality.
Investigators will be asked to report deaths and categorize them as either cardiovascular or non-
cardiovascular death. All deaths will be assumed to be cardiovascular unless a non-cardiovascular 
cause can be clearly provided. Below is guidance for Investigator classification:
Cardiovascular Death:
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden 
cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular 
(CV) procedures, death due to CV hemorrhage, and death due to other CV causes
Non-cardiovascular Death:
This category includes all deaths due to a clearly documented non-cardiovascular cause, such as 
respiratory failure (excluding cardiogenic pulmonary edema), hemorrhage (other than intracranial
or CV hemorrhage), infections/sepsis, neoplasm, and trauma (including suicide and homicide).
5.8
Other Assessments
5.8.1
Sensory Motor Survey  
Subject will be complete a 5 question interview relating to presence and degree of specified 
characteristics relating to sensory and motor function, with responses indicating either none, 
mild, moderate, or severe felt over the past 24 hours.
5.9
Additional Research Collection
Additional research collections and retention are mandatory for all subjects, except where 
prohibited by local laws or regulations.
This protocol will include residual sample storage for additional research (AR).
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
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requests for analysis, and the advancement of pharmacodiagnostic development to better target 
drugs to the right patients. This may also include genetic/genomic exploration aimed at exploring 
disease pathways, progression and response to treatment etc.
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study Sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities.

Residual plasma and serum samples from exploratory biomarker collections (see Table 5.6-1
and Table 5.9-1) will be retained for additional research purposes

Samples will be securely stored by the BMS Biorepository in Hopewell, NJ or at a BMS 
approved third party storage management facility

Samples will be stored in a coded fashion; and no researcher will have access to the key, which 
is securely held at the clinical site, so that there is no direct ability for a researcher to connect 
a sample to a specific individual

Additional research samples will be retained for 15 years or the maximum allowed by 
applicable law. No additional sampling is required for residual collections
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 5.9-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be retained
Plasma exploratory biomarker
All
Serum exploratory biomarker
All
Urine
All
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
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The term “reasonable causal relationship” means there is evidence to suggest a causal relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE
below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 6.1.1
for reporting pregnancies).
Worsening heart failure, including hospital readmission is considered an SAE and should be 
reported as such.
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
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
routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor 
or designee within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The preferred 
method for SAE data reporting collection is through the electronic case report form (eCRF). The 
paper SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF 
system is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact: (required for SAE and pregnancy reporting): Refer to Contact
Information list.
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If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to Sponsor or 
designee using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according to 
local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug and continue 
through Hour 120.
AEs will be collected from Hour 0 to Hour 120. If a subject is discharged prior to Hour 120, the 
site is asked to follow-up with the subject at Hour 120 to complete AE collection.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE 
page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE eCRF 
page or SAE Report Form electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
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6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half 
lives after product administration, the investigator must immediately notify the Sponsor or 
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS Designee 
within 24 hours of awareness of the event and in accordance with SAE reporting procedures 
described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the Sponsor or designee within 24 hours of 
awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours of awareness of 
the event and in accordance with SAE reporting procedures described in Section 6.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
Include any project specific definition of overdose in addition to the following mandatory 
statement as the last sentence:
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 intravenous 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 heart failure 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 
heart failure subjects. If marked hypotension occurs, appropriate treatment, including intravenous 
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pressor agents may be required to support blood pressure. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
Potential drug induced liver injury is defined as:
Aminotransaminases (ALT or AST) elevation > 3 times upper limit of normal (ULN) if baseline 
values are within the normal range, or > 2 times the baseline values in case of baseline values 
above the upper limit of normal (ULN) AND Total bilirubin > 2 times ULN, without initial 
findings of cholestasis (elevated serum alkaline phosphatase)
AND No other immediately apparent possible causes of aminotransaminases (AT) elevation and 
hyperbilirubinemia, including, but not limited to, worsening heart failure, viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other drug(s), herbal medications 
or substances known to be hepatotoxic
Given the short treatment course, baseline liver enzyme testing will be performed at Pre-
randomization and post-treatment liver enzyme testing will be performed at Hour 120 and Day 32.
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.1.1 for reporting details).
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Data Monitoring Committee
An independent DMC will review safety data to ensure subjects safety. The full role of the DMC 
will be defined in the DMC charter. The DMC will review unblinded accumulating data on a 
regular basis and make recommendations to BMS and the Executive Committee regarding subjects
currently enrolled and yet to be enrolled in the trial. The DMC may recommend suspension of 
enrolment or early termination of the trial, for safety reasons. See Section 8.5 for additional 
information.
The DMC will consider available endpoint information, in addition to safety events, before making 
any study stopping recommendations to the Executive Committee and Sponsor, as per guidelines 
set forth in the DMC charter.
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7.2
Executive Committee
The executive committee will be a small body comprised of academic leaders. The executive 
committee will provide advice on overall design, study endpoints and recommendations for study 
sites, and will review results from interim and final analyses with Sponsor.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
For Part I (Cohort 1), approximately 50 subjects per group will be randomized to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min). Under a sample decision rule 
(eg, observed doubling with more than a 4% difference) and assuming clinically relevant 
hypotension incidences of 5% or 10% in the placebo group, the posterior probabilities of detecting 
an increase of 4-fold or 3-fold in incidence, respectively, are 86% and 80%, respectively. If there 
is no increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting 
an increase are 11-12%.
For Part II (Cohort 2), approximately 70 subjects per group will be randomized to placebo or one 
of the two active dose levels of BMS-986231. Under a sample decision rule (eg, observed 1.8-fold 
increase with more than a 3% difference) and assuming clinically relevant hypotension incidences 
of 5% or 10% in the placebo group, the posterior probabilities of detecting an increase of 3-fold 
or 2.5-fold in incidence, respectively, are 82% and 80%, respectively. If there is no increase in 
clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase are 
13-15%. These probabilities do not reflect multiple comparison.
With regards to overall performance for selection of a maximally tolerated dose, a sample size of 
50 per group for Part I (Cohort 1), along with 70 per group for Part II (Cohort 2) will identify a 
maximally tolerated dose approximately 50-70%, based on detecting an increase of 3-fold or 
2.5-fold in incidence, and using sample decision rules that are consistent with above. Also, the 
design will provide an option to select a titrated 12 μg/kg/min dose approximately 60% of the time 
when that dose is tolerated, but a non-titrated 12 μg/kg/min dose is not tolerated. Conversely, the 
study design will not identify a maximally tolerated dose from Part II (Cohort 2) approximately 
80%-85% of the time when no maximally tolerated dose exists
8.2
Populations for Analyses

The Enrolled Subjects Data Set will consist of all subjects who sign informed consent

The Randomized Subjects Data Set will consist of all randomized subjects who have started 
study drug infusion. This is also known as the Intent to Treat (ITT) population. Data in this 
data set will be analyzed based on randomized treatment group
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
The Treated Subjects Data Set will consist of all subjects who receive any study drug infusion. 
This will be the primary safety data set. Data in this data set will be analyzed based on 
randomized treatment, except in the following cases:
o
If a subject received the same incorrect treatment throughout the 48 hours study drug 
infusion or until discontinuation of the study drug, then the subject will be analyzed based 
on the treatment received
o
If a subject received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
subject will be analyzed based on the first treatment received

The Pharmacokinetic analysis dataset will consist of all subjects who receive BMS-986231 
and have at least one post dose PK sample
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint is the incidence of clinically relevant hypotension, defined by SBP 
< 90 mm Hg (confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up to 
6 hours after the end of study drug infusion.
8.3.2
Secondary Endpoints

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes 
first), and at Day 32

Change in patient-reported resting dyspnea from baseline through Hour 72, as measured by the 
area under the curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at
baseline, and Hours 6, 12, 24, 48, and 72
 
 
 
 
 
 
 
 
 
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8.3.4
Safety Endpoints.
Safety endpoints consist of the following:

The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion

The incidence of SBP < 90 mm Hg (confirmed by a repeated value)

Change in Troponin T from baseline to Hour 24, 48, and 72

Percentage of subjects who have died (all- cause and CV related) through Day 182
Additionally, the percentage of subjects with discontinuation due to symptomatic hypotension, as
well as percentage of subjects with down-titrations, interruptions or discontinuations as a result of 
low blood pressure, either protocol specified clinically relevant hypotension, or asymptomatic 
decreases will be assessed.  Other safety endpoints include the incidence of Adverse Events and 
Marked Laboratory Abnormalities, changes from baseline in vital signs, ECGs, physical 
measurements and laboratory assessments through Hour 120 or discharge, whichever comes first. 
The incidence of Serious Adverse Events will be assessed though Day 32.
8.4
Analyses
Results from Part I (Cohort 1) and Part II (Cohort 2) will be presented separately.
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For analyses involving baseline, the baseline value is defined by the last value prior to the start of 
infusion, unless otherwise noted.
8.4.1
Demographics and Baseline Characteristics
Frequency distributions and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined. Demographic variables to be 
summarized include: age, gender, race, and geographic region.
Baseline variables to be summarized include physical measurements (height, body weight, body 
mass index), vital signs (systolic blood pressure, diastolic blood pressure, and heart rate), disease 
characteristics (New York Heart Association Class prior to admission, ejection fraction, heart 
failure etiology, number of heart failure hospitalizations in past year, time since original HF 
diagnosis and since first diuretic use in the current episode of decompensation to first treatment, 
commorbities, including history of coronary artery disease, hypertension, or diabetes, and presence 
of atrial fibrillation), important laboratory variables (including NT-proBNP, serum sodium and 
eGFR), and current heart failure medications.
8.4.2
Primary, Secondary, and Exploratory Endpoints Analyses
8.4.2.1
Primary Endpoint Analysis
The incidence of clinically relevant hypotension from the start to 6 hours after the end of study 
drug infusion will be summarized by treatment. Point estimates and 95% CIs for event rates will 
be presented by treatment, together with point estimates and 95% CIs for the risk difference and 
relative risk between each BMS-986231 arm and placebo.
8.4.2.2
Secondary Endpoint Analyses
NT-proBNP will be summarized descriptively by treatment for each time point, as well as change 
from baseline.
Analyses for changes from baseline in the resting dyspnea as measured by the 11-point NRS will 
be done using a longitudinal repeated measures model, with baseline value and region as 
covariates. A trapezoidal rule will be applied to calculate AUC using model-estimated values from 
the time points. Missing values for the dyspnea NRS will not be imputed, except if a NRS cannot 
be obtained because the subject has died or is physically unable to complete the form. In these 
cases, a worst score imputation will be used for that time point. 
 
 
 
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8.4.3
Safety Analyses
Troponin T will be summarized descriptively by treatment for each time point, as well as change 
from baseline.
Percentage of subjects who have died (all- cause and CV related) through Day 182 will be 
summarized descriptively by treatment.
All recorded adverse events 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.
Percentage of subjects with discontinuations due to symptomatic hypotension, as well as 
percentage of subjects with down-titrations or interruptions or discontinuations as a result of 
hypotension, either protocol specified clinically relevant hypotension, or asymptomatic decreases 
will be summarized descriptively by treatment.
In addition, the final infusion dose at the completion of 48 hours infusion will be summarized 
descriptively by treatment. The subjects who discontinued prematurely from infusion would be 
counted as having a final infusion dose of 0 g/kg/min. 
8.4.4
Pharmacokinetic Analyses
Blood samples will be collected from all subjects at 0.75, 4, 8, 14, and 48 hours during infusion 
and 4 hours after end of infusion and plasma concentrations will be measured using LC-MS. 
Pharmacokinetic parameters for BMS-986231 and BMT-284730 and other metabolites 
(eg, BMT-279554 & CAR-000463) will be estimated as appropriate. The plasma concentration 
may also be used to conduct population pharmacokinetic analysis and exposure-response analysis 
with select efficacy and safety endpoints. Results of the population pharmacokinetic and 
exposure-response analysis will be reported in a separate report.
 
 
 
 
 
 
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8.4.6
Outcomes Research Analyses
Healthcare utilization is defined as the percentage of subjects with rehospitalizations and 
emergency department visits will be summarized descriptively by treatment group for HF or other 
cardiovascular disease separately.
8.4.7
Other Analyses
Not applicable.
8.5
Interim Analyses
Two interim analyses will be performed for this study. An interim analysis will be performed 
following the completion of the last visit at Hour 120 in Part I (Cohort 1). The analysis will include 
data for all Cohort 1 subjects through at least Hour 120. The DMC, Executive Committee and 
representatives from the Sponsor will assess hypotension, as well as additional safety information, 
in addition to any available endpoint events. The outcome will determine whether 12 μg/kg/min is 
a sufficiently tolerated dose to be used in Part II (Cohort 2). The dose selection decision for Part 
II will be made by the Sponsor in collaboration with the Executive Committee, with input from 
the DMC. The doses for Part II (Cohort 2) will be determined based on general guiding principles 
and considered in the context of the totality of the data. For example, some of the critical 
information that will be considered evaluating the suitability 12 μg/kg/min for Part II will include 
the percentage of subjects completing the 48 hour infusion, percentage of subjects with temporary 
interruptions or permanent discontinuation of study drug, percentage of subjects with clinically 
relevant hypotension, percentage of subjects with symptomatic hypotension, and other key safety 
endpoints of interest (eg, renal function).  
The second interim analysis will be performed following completion of the last visit at Day 32 in 
Part II (Cohort 2) in order to facilitate drug development decisions. The study analysis team will 
then provide top-line results to the project team.
After each DMC review, the Sponsor will be advised by the DMC Chair as to whether the study 
is safe to proceed as written, that the study should be modified, or that the study should be stopped. 
In addition to these periodic reviews, the DMC will review the unblinded data from Part I in 
parallel with the review by the executive committee and the Sponsor.  A similar recommendation 
will be provided to the Sponsor, that the study is to proceed as written, or should be modified or 
stopped.  
Analyses will consist of summaries of the available data. No formal inferences requiring any 
adjustment to statistical significance level will be performed
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
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hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:

IRB/IEC 

Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the subject: (1) the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS or designee representatives will review data centrally to identify potential issues to determine 
a schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by BMS or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to BMS or designee.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
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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.
9.2
Records
9.2.1
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 or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records 
Records for IP and Non-IMP (whether supplied by BMS, its vendors, or the site) must substantiate 
IP integrity and traceability from receipt, preparation, administration, and through destruction or 
return. Records must be made available for review at the request of BMS/designee or a Health 
Authority.
If...
Then...
Supplied by BMS (or its vendors):
Records or logs must comply with applicable regulations and guidelines 
and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique 
subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

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.
These records should include:

label identification number or batch number 
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If...
Then...

amount dispensed to and returned by each subject, including unique 
subject identifiers

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee.
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS, or designee, electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report.
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For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
BMS or designee at the earliest practicable time prior to submission or presentation and otherwise 
within the time period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. This also means that 
abstinence is the preferred and usual lifestyle of the patient. This does not mean 
periodic abstinence (eg, calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and withdrawal, which are not 
acceptable methods of contraception. Women must continue to have pregnancy tests.
Acceptable alternate methods of highly or less effective contraception’s must be 
discussed in the event that the subject chooses to forego complete abstinence.
Presentation
First dose of IV diuretic for the current episode
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ADHF
acute decompensated heart failure
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
Aminotransaminases
AUC
area under the concentration-time curve
BiPAP
bilevel positive airway pressure
BMS
Bristol-Myers Squibb
BNP
brain natriuretic peptide
BP
blood pressure
bpm
Beats per minute
BUN
blood urea nitrogen
C
Celsius
CCU
coronary care unit
CFR
Code of Federal Regulations 
CI
cardiac index
CPAP
continuous positive airway pressure
CRF
Case Report Form, paper or electronic
CVA
cerebral vascular accident
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
ESR
Expedited Safety Report
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
H
Hour
HF
heart failure
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Term
Definition
HFrEF
heart failure with reduced ejection fraction
HNO
Nitroxyl
HRT
hormone replacement therapy
Hs
high sensitivity
IABP
Intra-Aortic Balloon Pump 
ICH
International Conference on Harmonisation 
ICU
intensive care unit
Ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
K3EDTA
potassium ethylenediaminetetraacetic acid
Kg
Kilogram
LVEF
left ventricular ejection fraction
mg
Milligram
min
Minute
Mm Hg
millimeters of mercury
MS
mass spectrometry
MUGA
multigated acquisition
g
Microgram
Na+
Sodium
NIMP
non-investigational medicinal products 
NO
nitric oxide
NRS
numerical rating scale
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
PADP
Pulmonary Artery Diastolic Pressure
PC
peripheral capillary wedge pressure
PDE3
phosphodiesterase 3
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Term
Definition
PDE5
phosphodiesterase type 5
PK
pharmacokinetics
PT
prothrombin time
PTT
partial thromboplastin time
RBC
red blood cell
SAE
serious adverse event
TIA
transient ischemic attack
WOCBP
women of childbearing potential
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APPENDIX 1
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH level
is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use 
one of the highly effective methods of contraception listed below. Male subjects must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as follows:
1. Nonhormonal IUDs, such as ParaGard
2. Bilateral tubal occlusion
3. Vasectomised partner with documented azoospermia 90 days after procedure
a.
Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success
4. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse (refer to Glossary of Terms)
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b. Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days)
c.
It is not necessary to use any other method of contraception when complete 
abstinence is elected
d. Subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 5
e.
Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence
f.
The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject
UNACCEPTABLE METHODS OF CONTRACEPTION
A. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
B. Withdrawal (coitus interruptus)
C. Spermicide only
D. Lactation amenorrhea method (LAM)
E. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
F. Withdrawal (coitus interruptus)
G. Spermicide only
H. Lactation amenorrhea method (LAM)
I.
Progestogen only hormonal contraception associated with inhibition of ovulation or where 
inhibition of ovulation is not the primary mode of action
J.
Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena
K. Intrauterine hormone-releasing system (IUS)
L. Diaphragm with spermicide
M. Cervical cap with spermicide
N. Vaginal sponge with spermicide
O. Male or female condom with or without spermicide*
 
 
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APPENDIX 2
CORE AND EXTENDED ADME GENE LIST
Core ADME Gene List:
Gene 
Symbol
Full Gene Name
Class
ABCB1
ATP-binding cassette, sub-family B (MDR/TAP), member 1
Transporter
ABCC2
ATP-binding cassette, sub-family C (CFTR/MRP), member 2
Transporter
ABCG2
ATP-binding cassette, sub-family G (WHITE), member 2
Transporter
CYP1A1
cytochrome P450, family 1, subfamily A, polypeptide 1
Phase I
CYP1A2
cytochrome P450, family 1, subfamily A, polypeptide 2
Phase I
CYP2A6
cytochrome P450, family 2, subfamily A, polypeptide 6
Phase I
CYP2B6
cytochrome P450, family 2, subfamily B, polypeptide 6
Phase I
CYP2C19
cytochrome P450, family 2, subfamily C, polypeptide 19
Phase I
CYP2C8
cytochrome P450, family 2, subfamily C, polypeptide 8
Phase I
CYP2C9
cytochrome P450, family 2, subfamily C, polypeptide 9
Phase I
CYP2D6
cytochrome P450, family 2, subfamily D, polypeptide 6
Phase I
CYP2E1
cytochrome P450, family 2, subfamily E, polypeptide 1
Phase I
CYP3A4
cytochrome P450, family 3, subfamily A, polypeptide 4
Phase I
CYP3A5
cytochrome P450, family 3, subfamily A, polypeptide 5
Phase I
DPYD
dihydropyrimidine dehydrogenase
Phase I
GSTM1
glutathione S-transferase M1
Phase II
GSTP1
glutathione S-transferase pi
Phase II
GSTT1
glutathione S-transferase theta 1
Phase II
NAT1
N-acetyltransferase 1 (arylamine N-acetyltransferase)
Phase II
NAT2
N-acetyltransferase 2 (arylamine N-acetyltransferase)
Phase II
SLC15A2
solute carrier family 15 (H+/peptide transporter), member 2
Transporter
SLC22A1
solute carrier family 22 (organic cation transporter), member 1
Transporter
SLC22A2
solute carrier family 22 (organic cation transporter), member 2
Transporter
SLC22A6
solute carrier family 22 (organic anion transporter), member 6
Transporter
SLCO1B1
solute carrier organic anion transporter family, member 1B1
Transporter
SLCO1B3
solute carrier organic anion transporter family, member 1B3
Transporter
SULT1A1
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1
Phase II
TPMT
thiopurine S-methyltransferase,
Phase II
UGT1A1
UDP glucuronosyltransferase 1 family, polypeptide A1
Phase II
UGT2B15
UDP glucuronosyltransferase 2 family, polypeptide B15
Phase II
UGT2B17
UDP glucuronosyltransferase 2 family, polypeptide B17
Phase II
UGT2B7
UDP glucuronosyltransferase 2 family, polypeptide B7
Phase II
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Extended ADME Gene List:
Gene 
Symbol
Full Gene Name
Class
ABCB8
ATP-binding cassette, sub-family B (MDR/TAP), member 8
Transporter
ABCC12
ATP-binding cassette, sub-family C (CFTR/MRP), member 12
Transporter
ABCC3
ATP-binding cassette, sub-family C (CFTR/MRP), member 3
Transporter
ABCC4
ATP-binding cassette, sub-family C (CFTR/MRP), member 4
Transporter
AHR
aryl hydrocarbon receptor
Modifier
ALDH4A1
aldehyde dehydrogenase 4 family, member A1
Phase I
ALDH5A1
aldehyde dehydrogenase 5 family, member A1
Phase I
ALDH6A1
aldehyde dehydrogenase 6 family, member A1
Phase I
CES1
carboxylesterase 1 (monocyte/macrophage serine esterase 1)
Phase I
CES2
carboxylesterase 2 (intestine, liver)
Phase I
CYP7A1
cytochrome P450, family 7, subfamily A, polypeptide 1
Phase I
EPHX1
epoxide hydrolase 1, microsomal (xenobiotic)
Phase I
FMO3
flavin containing monooxygenase 3
Phase I
GSTA1
glutathione S-transferase A1
Phase II
GSTA2
glutathione S-transferase A2
Phase II
GSTA3
glutathione S-transferase A3
Phase II
GSTA4
glutathione S-transferase A4
Phase II
GSTA5
glutathione S-transferase A5
Phase II
GSTM2
glutathione S-transferase M2 (muscle),glutathione S-transferase M4
Phase II
GSTM3
glutathione S-transferase M3 (brain)
Phase II
GSTM4
glutathione S-transferase M4
Phase II
GSTO1
glutathione S-transferase omega 1,glutathione S-transferase omega 
2
Phase II
GSTO2
glutathione S-transferase omega 2
Phase II
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Gene 
Symbol
Full Gene Name
Class
GSTT2
glutathione S-transferase theta 2
Phase II
SLC10A1
solute carrier family 10 (sodium/bile acid cotransporter family), 
member 1
Transporter
SLC15A1
solute carrier family 15 (oligopeptide transporter), member 1
Transporter
SLC22A11
solute carrier family 22 (organic anion/cation transporter), member 11
Transporter
SLC22A8
solute carrier family 22 (organic anion transporter), member 8
Transporter
SLC7A5
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 5
Transporter
SLCO1A2
solute carrier organic anion transporter family, member 1A2
Transporter
SLCO2B1
solute carrier organic anion transporter family, member 2B1
Transporter
SULT1A2
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 2
Phase II
SULT1A3
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3
Phase II
SULT1B1
sulfotransferase family, cytosolic, 1B, member 1
Phase II
UGT1A3
UDP glucuronosyltransferase 1 family, polypeptide A3
Phase II
UGT1A6
UDP glucuronosyltransferase 1 family, polypeptide A6
Phase II
UGT1A7
UDP glucuronosyltransferase 1 family, polypeptide A7
Phase II
UGT1A8
UDP glucuronosyltransferase 1 family, polypeptide A8
Phase II
UGT1A9
UDP glucuronosyltransferase 1 family, polypeptide A9
Phase II
UGT2A1
UDP glucuronosyltransferase 2 family, polypeptide A1
Phase II
UGT2B11
UDP glucuronosyltransferase 2 family, polypeptide B11
Phase II
UGT2B28
UDP glucuronosyltransferase 2 family, polypeptide B28
Phase II
UGT2B4
UDP glucuronosyltransferase 2 family, polypeptide B4
Phase II
ABCA1
ATP-binding cassette, sub-family A (ABC1), member 1
Transporter
ABCA4
ATP-binding cassette, sub-family A (ABC1), member 4
Transporter
ABCB11
ATP-binding cassette, sub-family B (MDR/TAP), member 11
Transporter
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Gene 
Symbol
Full Gene Name
Class
ABCB4
ATP-binding cassette, sub-family B (MDR/TAP), member 4
Transporter
ABCB5
ATP-binding cassette, sub-family B (MDR/TAP), member 5
Transporter
ABCB6
ATP-binding cassette, sub-family B (MDR/TAP), member 6
Transporter
ABCB7
ATP-binding cassette, sub-family B (MDR/TAP), member 7
Transporter
ABCC1
ATP-binding cassette, sub-family C (CFTR/MRP), member 1
Transporter
ABCC10
ATP-binding cassette, sub-family C (CFTR/MRP), member 10
Transporter
ABCC11
ATP-binding cassette, sub-family C (CFTR/MRP), member 11
Transporter
ABCC5
ATP-binding cassette, sub-family C (CFTR/MRP), member 5
Transporter
ABCC6
ATP-binding cassette, sub-family C (CFTR/MRP), member 6
Transporter
ABCC8
ATP-binding cassette, sub-family C (CFTR/MRP), member 8
Transporter
ABCC9
ATP-binding cassette, sub-family C (CFTR/MRP), member 9
Transporter
ABCG1
ATP-binding cassette, sub-family G (WHITE), member 1
Transporter
ADH1A
alcohol dehydrogenase 1A (class I), alpha polypeptide
Phase I
ADH1B
alcohol dehydrogenase IB (class I), beta polypeptide
Phase I
ADH1C
alcohol dehydrogenase 1C (class I), gamma polypeptide
Phase I
ADH4
alcohol dehydrogenase 4 (class II), pi polypeptide
Phase I
ADH5
alcohol dehydrogenase 5 (class III), chi polypeptide,methionyl 
aminopeptidase 1
Phase I
ADH6
alcohol dehydrogenase 6 (class V)
Phase I
ADH7
alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide
Phase I
ALDH1A1
aldehyde dehydrogenase 1 family, member A1
Phase I
ALDH1A2
aldehyde dehydrogenase 1 family, member A2
Phase I
ALDH1A3
aldehyde dehydrogenase 1 family, member A3
Phase I
ALDH1B1
aldehyde dehydrogenase 1 family, member B1
Phase I
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Gene 
Symbol
Full Gene Name
Class
ALDH2
aldehyde dehydrogenase 2 family (mitochondrial)
Phase I
ALDH3A1
aldehyde dehydrogenase 3 family, memberA1
Phase I
ALDH3A2
aldehyde dehydrogenase 3 family, member A2
Phase I
ALDH3B1
aldehyde dehydrogenase 3 family, member B1
Phase I
ALDH3B2
aldehyde dehydrogenase 3 family, member B2
Phase I
ALDH7A1
aldehyde dehydrogenase 7 family, member A1
Phase I
ALDH8A1
aldehyde dehydrogenase 8 family, member A1
Phase I
ALDH9A1
aldehyde dehydrogenase 9 family, member A1
Phase I
AOX1
aldehyde oxidase 1
Phase I
ARNT
aryl hydrocarbon receptor nuclear translocator
Modifier
CBR1
carbonyl reductase 1
Phase I
CBR3
carbonyl reductase 3
Phase I
CDA
cytidine deaminase
Modifier
CYB5R3
cytochrome b5 reductase 3
Phase I
CYP11A1
cytochrome P450, family 11, subfamily A, polypeptide 1
Phase I
CYP11B1
cytochrome P450, family 11, subfamily B, polypeptide 1
Phase I
CYP11B2
cytochrome P450, family 11, subfamily B, polypeptide 2
Phase I
CYP17A1
cytochrome P450, family 17, subfamily A, polypeptide 1
Phase I
CYP1B1
cytochrome P450, family 1, subfamily B, polypeptide 1
Phase I
CYP20A1
cytochrome P450, family 20, subfamily A, polypeptide 1
Phase I
CYP20A1
cytochrome P450, family 20, subfamily A, polypeptide 1
Phase I
CYP21A2
cytochrome P450, family 21, subfamily A, polypeptide 2
Phase I
CYP24A1
cytochrome P450, family 24, subfamily A, polypeptide 1
Phase I
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Gene 
Symbol
Full Gene Name
Class
CYP26A1
cytochrome P450, family 26, subfamily A, polypeptide 1
Phase I
CYP27A1
cytochrome P450, family 27, subfamily A, polypeptide 1
Phase I
CYP2A13
cytochrome P450, family 2, subfamily A, polypeptide 13
Phase I
CYP2A7
cytochrome P450, family 2, subfamily A, polypeptide 7
Phase I
CYP2C18
cytochrome P450, family 2, subfamily C, polypeptide 18
Phase I
CYP2F1
cytochrome P450, family 2, subfamily F, polypeptide 1
Phase I
CYP2J2
cytochrome P450, family 2, subfamily J, polypeptide 2
Phase I
CYP39A1
cytochrome P450, family 39, subfamily A, polypeptide 1
Phase I
CYP3A43
cytochrome P450, family 3, subfamily A, polypeptide 43
Phase I
CYP3A7
cytochrome P450, family 3, subfamily A, polypeptide 7
Phase I
CYP4B1
cytochrome P450, family 4, subfamily B, polypeptide 1
Phase I
CYP4F11
cytochrome P450, family 4, subfamily F, polypeptide 11
Phase I
CYP51A1
cytochrome P450, family 51, subfamily A, polypeptide 1
Phase I
EPHX2
epoxide hydrolase 2, cytoplasmic
Phase I
FMO1
flavin containing monooxygenase 1
Phase I
FMO2
flavin containing monooxygenase 2
Phase I
FMO4
flavin containing monooxygenase 4
Phase I
FMO5
flavin containing monooxygenase 5
Phase I
GPX2
glutathione peroxidase 2 (gastrointestinal)
Phase I
GPX3
glutathione peroxidase 3 (plasma)
Phase I
GPX7
glutathione peroxidase 7
Phase I
GSR
glutathione reductase
Phase I
GSTK1
glutathione S-transferase kappa 1
Phase II
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Gene 
Symbol
Full Gene Name
Class
GSTM5
glutathione S-transferase M5
Phase II
GSTZ1
glutathione transferase zeta 1 (maleylacetoacetate isomerase)
Phase II
NNMT
nicotinamide N-methyltransferase
Phase II
NR1I2
nuclear receptor subfamily 1, group I, member 2
Modifier
NR1I3
nuclear receptor subfamily 1, group I, member 3
Modifier
PNMT
phenylethanolamine N-methyltransferase
Phase II
PON1
paraoxonase 1
Phase I
PON2
paraoxonase 2
Phase I
PON3
paraoxonase 3
Phase I
POR
P450 (cytochrome) oxidoreductase
Modifier
PPARD
peroxisome proliferative activated receptor, delta
Modifier
PPARG
peroxisome proliferative activated receptor, gamma
Modifier
RXRA
retinoid X receptor, alpha
Modifier
SLC10A2
solute carrier family 10 (sodium/bile acid cotransporter family), 
member 2
Transporter
SLC13A1
solute carrier family 13 (sodium/sulfate symporters), member 1
Transporter
SLC13A2
solute carrier family 13 (sodium-dependent dicarboxylate 
transporter), member 2
Transporter
SLC13A3
solute carrier family 13 (sodium-dependent dicarboxylate 
transporter), member 3
Transporter
SLC16A1
solute carrier family 16 (monocarboxylic acid Transporter), member 1
Transporter
SLC19A1
solute carrier family 19 (folate transporter), member 1
Transporter
SLC22A10
solute carrier family 22 (organic anion/cation transporter), member 10
Transporter
SLC22A12
solute carrier family 22 (organic anion/cation transporter), member 12
Transporter
SLC22A13
solute carrier family 22 (organic cation transporter), member 13
Transporter
SLC22A14
solute carrier family 22 (organic cation transporter), member 14
Transporter
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Gene 
Symbol
Full Gene Name
Class
SLC22A15
solute carrier family 22 (organic cation transporter), member 15
Transporter
SLC22A16
solute carrier family 22 (organic cation transporter), member 16
Transporter
SLC22A17
solute carrier family 22 (organic cation transporter), member 17
Transporter
SLC22A18
solute carrier family 22 (organic cation transporter), member 18
Transporter
SLC22A18AS
solute carrier family 22 (organic cation transporter), member 18 
antisense
Transporter
SLC22A3
solute carrier family 22 (extraneuronal monoamine transporter), 
member 3
Transporter
SLC22A4
solute carrier family 22 (organic cation transporter), member 4
Transporter
SLC22A5
solute carrier family 22 (organic cation transporter), member 5
Transporter
SLC22A7
solute carrier family 22 (organic anion transporter), member 7
Transporter
SLC22A9
solute carrier family 22 (organic anion/cation transporter), member 9
Transporter
SLC27A1
solute carrier family 27 (fatty acid transporter), member 1
Transporter
SLC28A1
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 1
Transporter
SLC28A2
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 2
Transporter
SLC28A3
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 3
Transporter
SLC29A1
solute carrier family 29 (nucleoside Transporter), member 1
Transporter
SLC29A2
solute carrier family 29 (nucleoside Transporter), member 2
Transporter
SLC2A4
solute carrier family 2 (facilitated glucose transporter), member 4
Transporter
SLC2A5
solute carrier family 2 (facilitated glucose/fructose transporter), 
member 5
Transporter
SLC5A6
solute carrier family 5 (sodium-dependent vitamin transporter)
Transporter
SLC6A6
solute carrier family 6 (neurotransmitter transporter, taurine), member 
6
Transporter
SLC7A8
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 8
Transporter
SLCO1C1
solute carrier organic anion transporter family, member 1C1
Transporter
SLCO2A1
solute carrier organic anion transporter family, member 2A1
Transporter
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Gene 
Symbol
Full Gene Name
Class
SLCO3A1
solute carrier organic anion transporter family, member 3A1
Transporter
SLCO4A1
solute carrier organic anion transporter family, member 4A1
Transporter
SLCO4C1
solute carrier organic anion transporter family, member 4C1
Transporter
SLCO5A1
solute carrier organic anion transporter family, member 5A1
Transporter
SLCO6A1
solute carrier organic anion transporter family, member 6A1
Transporter
SULT1C1
sulfotransferase family, cytosolic, 1C, member 1
Phase II
SULT1C2
sulfotransferase family, cytosolic, 1C, member 2
Phase II
SULT1E1
sulfotransferase family 1E, estrogen-preferring, member 1
Phase II
SULT2A1
sulfotransferase family, cytosolic, 2A, DHEA preferring, member 1
Phase II
SULT2B1
sulfotransferase family, cytosolic, 2B, member 1
Phase II
TAP1
transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
Transporter
UGT1A10
UDP glucuronosyltransferase 1 family, polypeptide A10
Phase II
UGT1A4
UDP glucuronosyltransferase 1 family, polypeptide A4
Phase II
UGT1A5
UDP glucuronosyltransferase 1 family, polypeptide A5
Phase II
UGT2B10
UDP glucuronosyltransferase 2 family, polypeptide B10
Phase II
ABCC13
ATP-binding cassette, sub-family C (CFTR/MRP), member 13
Transporter
ARSA
arylsulfatase A
Modifier
CAT
catalase
Modifier
CHST8
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 8
Phase II
CYP19A1
cytochrome P450, family 19, subfamily A, polypeptide 1
Phase I
CYP26C1
cytochrome P450, family 26, subfamily C, polypeptide 1
Phase I
CYP27B1
cytochrome P450, family 27, subfamily B, polypeptide 1
Phase I
CYP2R1
cytochrome P450, family 2, subfamily R, polypeptide 1
Phase I
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Gene 
Symbol
Full Gene Name
Class
CYP2S1
cytochrome P450, family 2, subfamily S, polypeptide 1
Phase I
CYP46A1
cytochrome P450, family 46, subfamily A, polypeptide 1
Phase I
CYP4A11
cytochrome P450, family 4, subfamily A, polypeptide 11
Phase I
CYP4F12
cytochrome P450, family 4, subfamily F, polypeptide 12
Phase I
CYP4F2
cytochrome P450, family 4, subfamily F, polypeptide 2
Phase I
CYP4F3
cytochrome P450, family 4, subfamily F, polypeptide 3
Phase I
CYP4F8
cytochrome P450, family 4, subfamily F, polypeptide 8
Phase I
CYP4Z1
cytochrome P450, family 4, subfamily Z, polypeptide 1
Phase I
CYP7B1
cytochrome P450, family 7, subfamily B, polypeptide 1
Phase I
CYP8B1
cytochrome P450, family 8, subfamily B, polypeptide 1
Phase I
DHRS13
dehydrogenase/reductase (SDR family) member 13
Phase I
DHRS2
dehydrogenase/reductase (SDR family) member 2
Phase I
GPX1
glutathione peroxidase 1
Phase I
GPX4
glutathione peroxidase 4 (phospholipid hydroperoxidase)
Phase I
GPX5
glutathione peroxidase 5 (epididymal androgen-related protein)
Phase I
GPX6
glutathione peroxidase 6 (olfactory)
Phase I
GSS
glutathione synthetase
Phase I
GSTCD
glutathione S-transferase, C-terminal domain containing
Phase II
HNF4A
hepatocyte nuclear factor 4, alpha
Modifier
HNMT
histamine N-methyltransferase
Phase II
HSD11B1
hydroxysteroid (17-beta) dehydrogenase 11
Phase I
HSD17B11
hydroxysteroid (17-beta) dehydrogenase 11
Phase I
HSD17B14
hydroxysteroid (17-beta) dehydrogenase 14
Phase I
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Gene 
Symbol
Full Gene Name
Class
LOC731356
similar to dehydrogenase/reductase (SDR family) member 4 like 2
Phase I
MGST1
microsomal glutathione S-transferase 1
Phase II
MGST2
microsomal glutathione S-transferase 2
Phase II
MGST3
microsomal glutathione S-transferase 3
Phase II
MPO
myeloperoxidase
Modifier
NOS1
nitric oxide synthase 1 (neuronal)
Phase I
NOS2A
nitric oxide synthase 2A (inducible, hepatocytes)
Phase I
NOS3
nitric oxide synthase 3 (endothelial cell)
Phase I
PPARA
peroxisome proliferator-activated receptor alpha
Modifier
SERPINA7
serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, 
antitrypsin), member 7
Modifier
SLC7A7
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 7
Transporter
SOD1
superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 
(adult))
Modifier
SOD2
superoxide dismutase 2, mitochondrial
Modifier
SOD3
superoxide dismutase 3, extracellular precursor
Modifier
SULF1
sulfatase 1
Phase I
SULT4A1
sulfotransferase family 4A, member 1
Phase II
TAP2
transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
Transporter
UGT8
UDP glycosyltransferase 8 (UDP-galactose ceramide 
galactosyltransferase)
Phase II
XDH
xanthine dehydrogenase
Phase I
ADHFE1
alcohol dehydrogenase, iron containing, 1
Phase I
CHST1
carbohydrate (keratan sulfate Gal-6) sulfotransferase 1
Phase II
CHST10
carbohydrate sulfotransferase 10
Phase II
CHST11
carbohydrate (chondroitin 4) sulfotransferase 11
Phase II
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Gene 
Symbol
Full Gene Name
Class
CHST12
carbohydrate (chondroitin 4) sulfotransferase 12
Phase II
CHST13
carbohydrate (chondroitin 4) sulfotransferase 13
Phase II
CHST2
carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2
Phase II
CHST3
carbohydrate (chondroitin 6) sulfotransferase 3
Phase II
CHST4
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4
Phase II
CHST5
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 5
Phase II
CHST6
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6
Phase II
CHST7
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7
Phase II
CHST9
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9
Phase II
CYP2D7P1
cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 1
Phase I
DDO
D-aspartate oxidase
Phase I
DHRS1
dehydrogenase/reductase (SDR family) member 1
Phase I
DHRS12
dehydrogenase/reductase (SDR family) member 12
Phase I
DHRS3
dehydrogenase/reductase (SDR family) member 3
Phase I
DHRS4
dehydrogenase/reductase (SDR family) member 4
Phase I
DHRS4L1
dehydrogenase/reductase (SDR family) member 4 like 1
Phase I
DHRS4L2
dehydrogenase/reductase (SDR family) member 4 like 2
Phase I
DHRS7
dehydrogenase/reductase (SDR family) member 7
Phase I
DHRS7B
dehydrogenase/reductase (SDR family) member 7B
Phase I
DHRS7C
dehydrogenase/reductase (SDR family) member 7C
Phase I
DHRS9
dehydrogenase/reductase (SDR family) member 9
Phase I
DHRSX
dehydrogenase/reductase (SDR family) X-linked
Phase I
DPEP1
dipeptidase 1 (renal)
Phase I
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Gene 
Symbol
Full Gene Name
Class
FMO6P
flavin containing monooxygenase 6
Phase I
HAGH
hydroxyacylglutathione hydrolase
Phase I
IAPP
islet amyloid polypeptide
Modifier
KCNJ11
potassium inwardly-rectifying channel, subfamily J, member 11
Modifier
LOC728667
similar to dehydrogenase/reductase (SDR family) member 2 isoform 
1
Phase I
LOC731931
similar to dehydrogenase/reductase (SDR family) member 2 isoform 
1
Phase I
MAT1A
methionine adenosyltransferase I, alpha
Modifier
METAP1
methionyl aminopeptidase 1
Phase I
PDE3A
phosphodiesterase 3A, cGMP-inhibited
Phase I
PDE3B
phosphodiesterase 3B, cGMP-inhibited
Phase I
PLGLB1
plasminogen-like B1
Phase I
ATP7A
ATPase, Cu++ transporting, alpha polypeptide (Menkes syndrome)
Modifier
ATP7B
ATPase, Cu++ transporting, beta polypeptide
Modifier
CFTR
cystic fibrosis transmembrane conductance regulator 
Modifier
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APPENDIX 3
COUNTRY SPECIFIC REQUIREMENTS 
Regulations in Germany require that:
Inclusion criteria related to upper age limit of eligible participants and key exclusion criteria for 
anemia and hepatic function. Amendment also adds safety information about the Captisol
excipient being used and provides for an additional 24-hour ECG to be collected after treatment.
 
 
 
 
 
 
 
 
 
 
 
 

Section 3.3.1, Inclusion Criteria, Age and Reproductive Status

a. Males and Females, at least age 18 (or age of majority), and no more than 85 years

Section 3.3.2, Exclusion Criteria, Medical History and Concurrent Diseases

g. Severe liver disease defined as history of cirrhosis with evidence of portal hypertension 
such as varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 51 mmol/L), or elevated 
AST or elevated ALT > 3 times ULN

Section 3.3.2, Exclusion Criteria, Physical and Laboratory Test Findings

b. Have severe anemia, as documented by a hemoglobin < 10 g/dL (< 6.21 mmol/L)

Section 4, Study Drug under Treatments

BMS will provide Investigational drug product BMS-986231 for infusion (active 
pharmaceutical ingredient BMS-986231 240 mg/vial formulated with Captisol® 
3405 mg/vial) to all sites as per Table 4-1.

Section 5.1, Flow Chart/Time and Events Schedule, Table 5.1-2

Addition of ECG at Hour 24 2
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Page:
1
Protocol Number:
CV013011
IND Number:
118,618
Ex-US
Non-IND
EUDRACT Number
2016-001685-29
Date:
28-Jun-2016
Revised Date:
24-Sep-2019
Clinical Protocol CV013011
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, 
Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of 
BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function
Revised Protocol 02c - Japan Specific
Study Director
Medical Monitor
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 
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Revised Protocol No.: 02c
Date: 24-Sep-2019
2
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Revised Protocol No.: 02c
Date: 24-Sep-2019
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02c
24-Sep-2019
Advise that Japan subjects who were enrolled after the end of global Part 
II enrollment will be followed for safety and rehospitalization endpoints 
through Day 32 only.  The global study provides adequate safety follow 
up data and additional Day 182 data from the Japanese population is not 
necessary.
Revised 
Protocol 02b
30-May-2019
Additional blood pressure and heart rate measurements at 15 minutes, 45 
minutes and 1.5 hours. Clarification that blood pressure measurements 
within 5 min in the first hour, then 15 min of the specified timepoints 
in Table 5.1-2.
Revised 
Protocol 02a
13-Mar-2019
Clarify the milestone, timing of enrollment and inclusion/exclusion 
criteria of the Japanese population. While the enrollment in the main 
study protocol will continue until 210 patients have been randomized 
globally in Part II (Cohort 2), enrollment in Japan may continue further 
only in Japan until approximately 18 total Japanese subjects are 
randomized.
Administrative 
Letter 04
02-Aug-2018
Clarified participation in the actigraphy and Holter monitoring sub-
studies is optional for sites and patients. Furthermore, minor revisions are 
made to the PK Sampling schedule to reflect the required samples for 
Part II. In addition, a note is added to the 12-lead ECG procedure at hour 
24 to clarify that it is only applicable to sites in Germany. Additional 
minor administrative corrections are also added.
Administrative 
Letter 03
27-Apr-2018
Corrected a typographical error in the “summary of key changes for 
revised protocol 02” table, which incorrectly noted the actigraphy and 
holter monitor sub-studies as exploratory endpoints. The actigraphy and 
holter monitor sub-studies are exploratory objectives.
Revised 
Protocol 02
09-Apr-2018
Expansion of screening period, addition of Holter Monitoring in a subset 
of patients, addition of Actigraphy monitoring in a subset of patients, and 
clarifications throughout the document.
Administrative 
Letter 02
05-Dec-2017
Clarifies secondary packaging of BMS986-231 as a carton containing 5 
or 6 vials.
Administrative 
Letter 01
14-Feb-2017
Administrative clarifications throughout the protocol.
Revised 
Protocol 01
11-Oct-2016
Incorporates changes from Amendment 01.
Amendment 01
11-Oct-2016
Addition of two unblinded interim analysis, addition of Sensory Motor 
Survey, clarification and updates to Eligibility criteria, and additional 
edits throughout the document to improve readability. 
Original 
Protocol
28-Jun-2016
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 02C:
The purpose of this amendment to advise that subjects in Japan who were enrolled after the end of 
global Part II enrollment will be followed for safety and rehospitalization endpoints through Day 
32 only. The global study provides adequate safety follow up data and additional Day 182 data 
from the Japanese population is not necessary. A final analysis will be performed following 
completion of the last visit (Day 32) of the last enrolled Japanese subject to complete an analysis 
of the Japanese patient data. This revision applies to all subjects enrolled in Japan, excluding the 
subjects enrolled as part of the 210 subject global cohort (Part II, Cohort 2). 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02C
Section 
Number & 
Title
Description of Change
Brief Rationale
Synopsis & 
Section 1.3.4:  
Safety 
Objectives
Revise the Day 182 mortality 
follow-up safety objective: 
Assess the effect of BMS-986231 
on mortality at Day 182, in the 
Global Cohorts only (including 
the Japanese subjects enrolled in 
Global Part II).
Figure 3.1-2 
Study Design 
Schematic 
Part II (Cohort 
II)
Add note to schematic to specify
that Day 32 follow up visit is the 
last visit for Subjects in Japan
who were enrolled after the end of 
global Part II enrollment.
Section 3.1: 
Study Design 
and Duration
Revise the following statements to 
distinguish Day 182 follow up for 
main study subjects from Day 32 
follow up for subjects in Japan: 
The inpatient period will end in 
conjunction with the final in-
patient assessment at Hour 120 or 
discharge, whichever comes first. 
All subjects enrolled as part of 
global Part II will be followed for 
Revised Protocol No.: 02c
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02C
Section 
Number & 
Title
Description of Change
Brief Rationale
safety and rehospitalization 
endpoints through Day 32 and 
mortality through Day 182.
Subjects in Japan who were 
enrolled after the end of global 
Part II enrollment will be 
followed for safety and 
rehospitalization endpoints 
through Day 32
For subjects in Japan who were 
enrolled after the end of global 
Part II, The end of trial is defined 
as the last subject’s final follow-
up visit on Day 32, or the last 
subject’s scheduled procedure 
shown in the Time & Events 
schedule.
Section 4.6.2:
Other 
Blinding and 
Unblinding
Revise the below statement to 
include Day 32 follow up for 
subjects in Japan: 
The follow-up for Day 182 and/or 
Day 32 for both Part I and Part II 
will be site-and subject blinded
Table 5.1-3
Outpatient 
Follow-up 
(CV013011)
Revised to add the followed notes 
a and b: 
a: Subjects in Japan who were 
enrolled after the end of global 
Part II enrollment will be 
followed for safety and 
rehospitalization endpoints 
through Day 32.
b: Day 182 Phone Visit not 
applicable for subjects in Japan
who were enrolled after the end of 
global Part II enrollment, as they 
will be followed for safety and 
Revised Protocol No.: 02c
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02C
Section 
Number & 
Title
Description of Change
Brief Rationale
rehospitalization endpoints 
through Day 32 only.
Synopsis & 
Section 5.7.3
Mortality
Revise the following statement to 
distinguish Day 182 follow up for 
main study subjects from Day 32 
follow up for subjects in Japan: 
Investigators will follow all 
subjects in global part II to Day 
182 for mortality.  Subjects in 
Japan who were enrolled after the 
end of global Part II enrollment 
will be followed for through Day 
32.
Section 8.3.4:
Safety 
Endpoints
Revise safety endpoint to remove 
reference to Day 182: 
Percentage of subjects who have 
died (all- cause and CV related)
Section 8.4: 
Analyses
Revise statement below to add 
reference the Day 182 analysis: 
Subjects in Japan who started 
treatment after last patient 
randomization date of subjects 
who were enrolled before closure 
of the 210 subject global 
enrollment will not be part of the 
main global part II Day 32 interim 
analysis or the main global part II 
Day 182 analysis.  Details will be 
provided in the statistical analysis 
plan
Synopsis; 
Section 8.4.3:
Safety 
Analyses
Revise the statement to remove 
reference to Day 182: 
Percentage of subjects who have 
died (all- cause and CV related) 
will be summarized descriptively 
by treatment.
Revised Protocol No.: 02c
Date: 24-Sep-2019
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02C
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 8.5: 
Interim 
Analyses
Remove reference to an interim 
analysis in Japan, as one will not 
be completed. 
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HNO donor
SYNOPSIS
Clinical Protocol CV013011
Protocol Title: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, 
Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in 
Hospitalized Patients with Heart Failure and Impaired Systolic Function
Investigational Products, Dose and Mode of Administration, Duration of Treatment with Investigational 
Products: The investigational medicinal product is a solution for IV infusion containing BMS-986231 drug product 
(reconstituted in sterile water for injection), 5% dextrose (glucose) in water for injection (D5W) and potassium acetate 
(to achieve a 10 mM concentration of potassium acetate).
Study Phase: Phase 2B
Purpose: The purpose of this study is to evaluate the safety, tolerability, and efficacy of BMS-986231in subjects with 
heart failure (HF) and reduced systolic function (LVEF < 40%) who are admitted to the hospital with signs and 
symptoms of acute decompensated heart failure (ADHF).
Research Hypothesis: BMS-986231 is safe and tolerated with regard to clinically relevant hypotension compared 
with placebo in hospitalized heart failure with reduced ejection fraction (HFrEF) subjects with ADHF.
Objectives:
Primary Objective:
The primary objective is to evaluate the effects of various doses of BMS-986231 compared to placebo on clinically 
relevant hypotension (defined by SBP < 90 mm Hg or symptoms of hypotension)
Secondary Objectives:

Assess the effect of BMS-986231 on NT-proBNP

Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 11-point Numerical 
Rating Scale (NRS)
 
 
 
Revised Protocol No.: 02c
Date: 24-Sep-2019
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Safety Objectives:

Evaluate the effect of BMS-986231 on incidence of symptomatic hypotension

Evaluate the effects of BMS-986231 on the incidence of SBP < 90 mm Hg.

Evaluate the incidence of dose reductions, temporary interruptions, and permanent discontinuation of BMS-98623 
infusions

Evaluate the safety and tolerability of a continuous 48-hour infusion of BMS-986231 in hospitalized HFrEF 
subjects with ADHF

Evaluate the effect of BMS-986231 on high sensitivity (Hs) Troponin T

Assess the effect of BMS-986231 on mortality at Day 182, in the Global Cohorts only (including the Japanese
subjects enrolled in Global Cohort II)
Study Design: This is a multi-center, randomized, placebo-controlled, double-blind study of continuous 48-hour 
intravenous (IV) infusions of BMS-986231 in hospitalized HFrEF subjects with ADHF. The trial was designed to 
identify the doses of BMS-986231 that are safe and tolerated with regard to clinically relevant hypotension.
The study consists of 2 parts, each with a unique cohort of subjects.
Patients that are randomized in Part I of the study will not be allowed to participate in Part II.
In Part I (Cohort 1) of the study, approximately 100 subjects will be randomized in a 1:1 ratio to placebo or an 
escalating dose of BMS-986231 (3 μg/kg/min for 4 hours, then 6 μg/kg/min for another 4 hours, then 12 μg/kg/min 
for the remaining 40 hours).
In Part II (Cohort 2) of the study, the 2 highest planned doses of BMS-986231 in Cohort 1, BMS-986231 6 g/kg/min 
and BMS-986231 12 g/kg/min, will be administered. Approximately 210 subjects will be randomized in a 1:1:1 ratio 
to one of the 2 active doses of BMS-986231 or placebo. If BMS-986231 12 g/kg/min is not considered to be a 
tolerated dose in Part I, then BMS-986231 3 g/kg/min and BMS-986231 6 g/kg/min will be evaluated in Part II. In 
the event that neither 6 g/kg/min nor 12 g/kg/min are tolerated, the protocol will require modification. 
While the enrollment in the main study protocol will continue until 210 patients have been randomized globally in 
Part II (Cohort 2), enrollment in Japan may continue further only in Japan until approximately 18 total Japanese 
subjects are randomized. 
Revised Protocol No.: 02c
Date: 24-Sep-2019
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BMS-986231
HNO donor
Study Schematic:
a Every effort should be made to initiate study drug administration promptly after randomization 
b Study Medication infusion must start within 18 hours of presentation (or 48 hours in Part II Cohort 2 of the 
trial), defined as the first dose of diuretic for current episode, but not within 2 hours after an IV bolus dose of 
intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV diuretic 
administered by continuous infusion
c Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring
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a 3 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
b 6 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
c Every effort should be made to initiate study drug administration promptly after randomization 
d Study Medication infusion must start within 18 hours of presentation, (or 48 hours in Part II Cohort 2 of the 
trial) defined as the first dose of diuretic for current episode, but not within 2 hours after an IV bolus dose of 
intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV diuretic
administered by continuous infusion
e Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring.
f Day 32 visit is the last visit for subjects in Japan who were enrolled after the end of global part II enrollment
g All subjects enrolled as part of global part II will be followed for mortality through Day 182
Revised Protocol No.: 02c
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Study Population: 
Key Inclusion Criteria:

Males and Females, at least age 18 (or age of majority) 

Subjects being hospitalized for ADHF

Have had at least 40 mg furosemide intravenous, or equivalent, (eg, 40 mg furosemide equivalent to 20 mg 
torsemide or to 1 mg bumetamide) for the current ADHF episode

Subject must be randomized and treated within 18 hours of first dose of intravenous diuretic for Part I Cohort 1 
(or 48 hours of first dose for Part II Cohort 2). 

Have dyspnea at rest or with minimal exertion after administration of at least 1 dose of intravenous diuretics. 
Subject must not be randomized within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours 
after the initiation or a dose increase of an IV diuretic administered by continuous infusion

Have a history of heart failure and a left ventricular ejection fraction (LVEF) 40%, as assessed by 
echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging (MRI) scan

Note: Ejection fraction documentation up to 18 months prior to screening may be used if there is no clinical 
expectation of improvement in ejection fraction in that timeframe (eg, the patient has not had biventricular 
pacing initiated during that period)

Have at least 2 of the following at time of screening: 

evidence for pulmonary congestion on chest x-ray

rales by chest auscultation

edema 2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in 15-30 seconds)

presence of jugular venous distention

Have an elevated NT-proBNP 1400 pg/mL (166 pmol/L) or BNP350 pg/mL (101 pmol/L) as determined at 
the local laboratory within 18 hours prior to the start of study drug infusion for Part I Cohort 1 (or 48 hours for 
Part II Cohort 2)

For subjects with atrial fibrillation: NT-proBNP 2400 pg/ml or BNP 600 pg/ml

Body weight 40 kg and < 140 kg at screening

Women of childbearing potential must have negative serum or urine pregnancy test within 18 hours of start of 
drug for Part I Cohort 1 (or 48 hours for Part II Cohort 2)
Key Exclusion Criteria:

Screening OR baseline systolic blood pressure (SBP) of <105mm Hg or >160mm Hg at screening and just prior 
to randomization

Heart rate < 50 or >130 beats per minute (bpm) at screening and just prior to randomization

Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic 
or uncorrected severe valvular disease as defined by AHA/ACC/ESC criteria
Note: Functional mitral regurgitation, as well as restrictive mitral inflow pattern on echocardiography is not 
exclusionary

Have a body temperature 38.5C (101.3F) at any time from screening to randomization

Have an active infection requiring current IV anti-microbial treatment

Considered clinically unstable for other conditions than acute heart failure, either because of acute coronary 
syndrome or ongoing arrhythmia (or be receiving concomitant parenteral therapy with any antiarrhythmic drugs), 
or other unstable non-cardiovascular disease

Suspected acute lung disease (e.g. pneumonia or asthma) or severe chronic lung disease (e.g. severe chronic 
obstructive pulmonary disease, pulmonary fibrosis, patients with hypercapnia or requiring home oxygen therapy 
or chronic oral steroids.)

Have a history of sudden cardiac death with resuscitation within the past 6 months
Revised Protocol No.: 02c
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
Be hospitalized with acute coronary syndrome, coronary revascularization or acute myocardial infarction during 
the previous 90 days prior to screening

Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic attack (TIA) during the 
previous 90 days prior to screening

Serious comorbid non-cardiovascular disease in which the life expectancy of the subject is < 6 months (eg, acute 
systemic infection – sepsis, metastatic cancer, or other serious illnesses)

Severe liver disease defined as history of cirrhosis with evidence of portal hypertension such as varices, or 
encephalopathy, or total bilirubin > 3 mg/dL (> 51 µmol/L)

Prior cardiac or renal transplant 

Have persistent abnormal serum electrolytes not resolved before randomization, as defined by any of the 
following:

A sodium (Na+) concentration < 130 or >145 mEq/L (mmol/L)

A potassium (K+) concentration < 3.2 or >5.5 mEq/L (mmol/L)

Have severe anemia, as documented by a hemoglobin < 9 g/dL (< 5.59 mmol/L)

Have severe renal insufficiency before randomization (and during the current hospitalization) defined as an 
estimated glomerular filtration rate (eGFR)  < 30 mL/min/1.73m2 [based on any standard limit and equation 
employed by the local lab, eg, Modification of Diet in Renal Disease (MDRD) equation]. For patients with eGFR 
values less than but close to 30 mL/min/1.73m2 upon testing, retesting is allowed

Subjects administered IV or transdermal nitrate therapy prior to randomization, except if all 3 of the following 
criteria are met:

Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg AND 

The IV nitroglycerin dose is < 100 µg/min (or isosorbide dinitrate < 3 mg/hour), AND

The infusion rate and dose has been unchanged for > 2 hours

History of chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or peritoneal dialysis)

Subjects treated during the current hospitalization with IV vasoactive drugs such as dopamine, dobutamine, 
enoximone, nesiritide, nitroprusside, levosimendan, amrinone , milrinone, carperitide or nicorandil prior to start 
of study drug infusion, or have an anticipated need to be treated with any of these agents during the study drug 
infusion

Subjects receiving any mechanical ventilation at the time of screening

Subjects receiving non-invasive ventilation (CPAP/BiPAP) < 2 hours prior to randomization

Participation in an investigational clinical drug study within 30 days or 5 elimination half-lives, (whichever is 
longer) prior to randomization
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug for CV013011
Medication 
Potency 
IP/Non-IP 
BMS-98623 For Injection
BMS-986231 240 mg/vial
IP
Potassium Acetate
2 mEq/mL (20mL/vial)
Non-IP
BMS will provide Investigational drug product BMS-986231 for infusion (active pharmaceutical ingredient 
BMS-986231 formulated with Captisol® 3405 mg/vial) to all sites. In addition, Potassium acetate is to be locally 
sourced by sites within the US and will be supplied to all ex-US sites.
Revised Protocol No.: 02c
Date: 24-Sep-2019
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BMS-986231
HNO donor
Study Assessments:
Blood pressure assessment:
The primary endpoint of the study is the incidence of clinically relevant hypotension, defined by SBP < 90 mm Hg 
(confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug 
infusion. Thus hypotension will be assessed by collection of symptoms and blood pressure measurements. 
Symptomatic hypotension is defined as the presence of both low SBP and symptoms (eg, lightheadedness, dizziness, 
etc.) due to low blood pressure. 
Blood pressure measurements should be performed with the subject in a semi-recumbent (about a 30º angle) position, 
whenever possible. 
Blood pressure will be measured as indicated in Table 5.1-2 within (5 min in the first hour then 0.25 (15 min)) of 
the specified time points. In addition, sites may perform measurements at intervals defined by institutional standard 
of care for subjects receiving vasodilators, but no less than what is described in Table 5.1-2.
If the study drug dose is modified (decreased, interrupted, resumed or discontinued), the frequency of blood pressure 
measurements will follow a more intensive schedule for up to 6 hours following the dose modification (see table 
below). Upon completion of the intensive schedule, measurements can be either resumed per the original schedule, or 
follow the discontinuation schedule if the drug is permanently discontinued. 
Schedule of Blood Pressure Collection Following a Dose Modification
30 minutes
Post
1 hour
post
2 hours
post
4 hours
post
6 hours
post
Dose reduction
X
X
X
X
X
Dose interruption
X
X
X
X
Dose resumption
X
X
X
X
X
Dose discontinuation
X
X
X
X
X
Details for management of low blood pressure are detailed in section 5.3.1
In addition to assessments of blood pressure, the Investigator will be asked to collect and assess signs and symptoms 
of low blood pressure.
Efficacy Outcome Measures: Efficacy assessments will include the following:
Patient assessments of dyspnea severity at rest as measured by the 11-point Numerical Rating Scale (NRS) scores at 
screening and at 0, 6, 12, 24, 48, 72, and 120 hours after the start of study drug infusion.
Patient assessments of dyspnea severity at rest, using the 7-point Likert scale at 6, 12, 24, 48, 72, and 120 hours after 
the start of study drug infusion.
Patient assessments of global clinical status using the 7-point Likert scale at 6, 12, 24, 48, 72, and 120 hours after the 
start of study drug infusion.
An investigator assessment of in-hospital worsening heart failure since the start of the study drug infusion based on 
signs and symptoms of worsening heart failure along with the need for initiation or intensification of intravenous 
treatment for heart failure such as diuretics, vasodilators, inotropes, and mechanical support (mechanical ventilation, 
Revised Protocol No.: 02c
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HNO donor
circulatory support, ultrafiltration or hemodialysis), as indicators of worsening heart failure, will be made at Hours 24, 
48, 72, 96, and 120 or discharge, whichever comes first.
Mortality Measures:
Investigators will follow all subjects to in global part II Day 182 for mortality. Subjects in Japan who were enrolled 
after the end of global Part II enrollment will be followed for through Day 32.
Investigators will be asked to report deaths and categorize them as either cardiovascular or non-cardiovascular death. 
All deaths will be assumed to be cardiovascular unless a non-cardiovascular cause can be clearly provided. Below is 
guidance for Investigator classification:
Cardiovascular Death:
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death 
due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV 
hemorrhage, and death due to other CV causes.
Non-cardiovascular Death:
This category includes all deaths due to a clearly documented non-cardiovascular cause, such as respiratory failure 
(excluding cardiogenic pulmonary edema), hemorrhage (other than intracranial or CV hemorrhage), infections/sepsis, 
neoplasm, and trauma (including suicide and homicide).
Statistical considerations
Sample size:
For Part I (Cohort 1), approximately 50 subjects per group will be randomized to placebo or an incremental dose of 
BMS-986231 (3 - 6 - 12 μg/kg/min). Under a sample decision rule (eg, observed doubling with more than a 4% 
difference) and assuming clinically relevant hypotension incidences of 5% or 10% in the placebo group, the posterior 
probabilities of detecting an increase of 4-fold or 3-fold in incidence, respectively, are 86% and 80%, respectively. If 
there is no increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase 
are 11-12%.
For Part II (Cohort 2), approximately 70 subjects per group will be randomized to placebo or one of the two active 
dose levels of BMS-986231. Under a sample decision rule (eg, observed 1.8-fold increase with more than a 3% 
difference) and assuming clinically relevant hypotension incidences of 5% or 10% in the placebo group, the posterior 
probabilities of detecting an increase of 3-fold or 2.5-fold in incidence, respectively, are 82% and 80%, respectively. 
If there is no increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase 
are 13-15%. These probabilities do not reflect multiple comparison.
With regards to overall performance for selection of a maximally tolerated dose, a sample size of 50 per group for 
Part I (Cohort 1), along with 70 per group for Part II (Cohort 2) will identify a maximally tolerated dose approximately 
50-70%, based on detecting an increase of 3-fold or 2.5-fold in incidence, and using sample decision rules that are 
consistent with above. Also, the design will provide an option to select a titrated 12 μg/kg/min dose approximately 
60% of the time when that dose is tolerated, but a non-titrated 12 μg/kg/min dose is not tolerated. Conversely, the 
study design will not identify a maximally tolerated dose from Part II (Cohort 2) approximately 80%-85% of the time 
when no maximally tolerated dose exists.
Endpoints:
Primary Endpoint:
The primary endpoint is the incidence of clinically relevant hypotension, defined by SBP < 90 mm Hg (confirmed by 
a repeated value < 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug infusion.
Secondary Endpoints:

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge, whichever comes first, and at Day 32

Change in patient-reported resting dyspnea from baseline through Hour 72, as measured by the area under the 
curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at baseline, and Hours 6, 12, 24, 48, and 72
Revised Protocol No.: 02c
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HNO donor
 
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Endpoints

The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion

The incidence of SBP < 90 mm Hg (confirmed by a repeated value)

Change in Troponin T from baseline to Hour 24, 48, and 72

Percentage of subjects who have died (all- cause and CV related) 
Additionally, the percentage of subjects with discontinuation due to symptomatic hypotension, as well as percentage 
of subjects with down-titrations, interruptions or discontinuations as a result of low blood pressure, either protocol 
specified clinically relevant hypotension, or asymptomatic decreases will be assessed.  . Other safety endpoints include 
the incidence of Adverse Events and Marked Laboratory Abnormalities, changes from baseline in vital signs, ECGs, 
Revised Protocol No.: 02c
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physical measurements and laboratory assessments through Hour 120 or discharge, whichever comes first. The 
incidence of Serious Adverse Events will be assessed though Day 32.
Analyses: Results from Part I (Cohort 1) and Part II (Cohort 2) will be presented separately.
Subjects in Japan who started treatment after last patient randomization date of subjects who were enrolled before 
closure of the 210 subject global enrollment will not be part of the main global Part II Day 32 interim analysis or the 
main global Part II Day 182 analysis. Details will be provided in the statistical analysis plan
For analyses involving baseline, the baseline value is defined by the last value prior to the start of infusion, unless 
otherwise noted.
Primary Endpoint Analysis
The incidence of clinically relevant hypotension from the start to 6 hours after the end of study drug infusion will be 
summarized by treatment. Point estimates and 95% CIs for event rates will be presented by treatment, together with 
point estimates and 95% CIs for the risk difference and relative risk between each BMS-986231 arm and placebo.
Secondary Endpoint Analyses
NT-proBNP will be summarized descriptively by treatment for each time point, as well as change from baseline.
Analyses for changes from baseline in the resting dyspnea as measured by the 11-point NRS will be done using a 
longitudinal repeated measures model, with baseline value and region as covariates. A trapezoidal rule will be applied 
to calculate AUC using model-estimated values from the time points. Missing values for the dyspnea NRS will not be 
imputed, except if a NRS cannot be obtained because the subject has died or is physically unable to complete the form. 
In these cases, a worst score imputation will be used for that time point.
Safety Endpoint Analyses
Troponin T will be summarized descriptively by treatment for each time point, as well as change from baseline.
Percentage of subjects who have died (all- cause and CV related) will be summarized descriptively by treatment.
All recorded adverse events 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.
Percentage of subjects with  discontinuations due to symptomatic hypotension, as well as percentage of subjects with 
down-titrations or interruptions or discontinuations as a result of hypotension, either protocol specified clinically 
relevant hypotension, or asymptomatic decreases will be summarized descriptively by treatment.
In addition, the final infusion dose at the completion of 48 hours infusion will be summarized descriptively by 
treatment. The subjects who discontinued prematurely from infusion would be counted as having a final infusion dose 
of 0 g/kg/min.
Cardiodynamic ECG assessment (Subset of Subjects in Part II Cohort 2 only):
The analysis will be based on exposure-response modeling of the relationship between plasma concentrations of 
prodrug BMS-986231, its byproduct BMT-284730 and other metabolites (eg, BMT-279554 & CAR-000463) and 
change-from-baseline QTcF (∆QTcF) with the intent to exclude an effect > 10 msec at clinically relevant plasma 
levels. 
In addition, the effect of BMS-986231 on the placebo-corrected ∆QTcF (∆∆QTcF) will be evaluated at each post-
dosing time point ('by-time point' analysis) using the Intersection Union Test. An analysis of categorical outliers will 
be performed for changes in heart rate (HR), PR, QRS, QTcF, T-wave morphology and U-wave presence
Revised Protocol No.: 02c
Date: 24-Sep-2019
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HNO donor
Pharmacokinetic Analyses 
Blood samples will be collected from all subjects at 0.75, 4, 8, 14, and 48 hours during infusion and 4 hours after end 
of infusion and plasma concentrations will be measured using LC-MS. Pharmacokinetic parameters for BMS-986231 
and BMT-284730 and other metabolites (eg, BMT-279554 & CAR-000463) will be estimated as appropriate. The 
plasma concentration may also be used to conduct population pharmacokinetic analysis and exposure-response 
analysis with select efficacy and safety endpoints. Results of the population pharmacokinetic and exposure-response 
analysis will be reported in a separate report.
Revised Protocol No.: 02c
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 02C: .................................. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02C ...................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
 
 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
 
1.3.4 Safety Objectives ...................................................................................... 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-Investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Reductions, Temporary Interruptions, and Permanent 
Discontinuations of Study Drug Due to Blood Pressure ............................ 
4.6 Blinding/Unblinding ......................................................................................... 
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4.6.1 Emergency Unblinding ............................................................................ 
4.6.2 Other Blinding and Unblinding ............................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction or Return of Investigational Product ............................................. 
4.9 Retained Samples for Bioavailability / Bioequivalence ................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.1.2 Discharge ................................................................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Assessment of Blood Pressure and Symptoms for Hypotension .............. 
5.3.2 Physical Measurements ........................................................................... 
5.3.3 Physical Examination .............................................................................. 
5.3.4 Electrocardiogram ................................................................................... 
5.3.5 Laboratory Test Assessments ................................................................... 
5.3.5.1 Local Laboratory Assessments for Screening ................................. 
5.3.5.2 Central Laboratory Assessments .................................................... 
5.3.6 Telemetry Monitoring .............................................................................. 
5.3.7 Holter Recordings .................................................................................... 
5.3.8 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Assessments of Worsening Heart Failure ................................................ 
5.4.2 Investigator Assessment of Signs of Congestion ...................................... 
5.4.3 Physical activity monitoring using a wrist-worn actigraphy device 
(watch) ........................................................................................................ 
5.5 Pharmacokinetic Assessments .......................................................................... 
 
5.7 Outcomes Research Assessments ..................................................................... 
5.7.1 Dyspnea Assessments ............................................................................... 
5.7.1.1 Dyspnea Numerical Rating Scale ................................................... 
5.7.1.2 Dyspnea Likert Scale ...................................................................... 
5.7.2 Healthcare Utilization ............................................................................. 
5.7.3 Mortality .................................................................................................. 
5.8 Other Assessments ............................................................................................ 
5.8.1 Sensory Motor Survey .............................................................................. 
5.9 Additional Research Collection ........................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
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6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Data Monitoring Committee ............................................................................. 
7.2 Executive Committee ........................................................................................ 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
 
8.3.4 Safety Endpoints....................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Primary, Secondary, and Exploratory Endpoints Analyses ..................... 
8.4.2.1 Primary Endpoint Analysis ............................................................. 
8.4.2.2 Secondary Endpoint Analyses ......................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
APPENDIX 1 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 2 CORE AND EXTENDED ADME GENE LIST .................................. 
APPENDIX 3 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
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1.2
Research Hypothesis 
BMS-986231 is safe and tolerated with regard to clinically relevant hypotension compared with 
placebo in hospitalized heart failure with reduced ejection fraction (HFrEF) subjects with ADHF.
1.3
Objectives
1.3.1
Primary Objective
The primary objective is to evaluate the effects of various doses of BMS-986231 compared to 
placebo on clinically relevant hypotension (defined by SBP < 90 mm Hg or symptoms of 
hypotension).
1.3.2
Secondary Objectives

Assess the effect of BMS-986231 on NT-proBNP

Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 
11-point NRS)
 
 
 
 
 
 
 
 
 
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1.3.4
Safety Objectives

Evaluate the effect of BMS-986231 on incidence of symptomatic hypotension

Evaluate the effects of BMS-986231 on the incidence of SBP < 90 mm Hg.

Evaluate the incidence of dose reductions, temporary interruptions, and permanent 
discontinuation of BMS-98623 infusions. 

Evaluate the safety and tolerability of a continuous 48-hour infusion of BMS-986231 in 
hospitalized HFrEF subjects with ADHF

Evaluate the effect of BMS-986231 on high sensitivity (Hs) Troponin T

Assess the effect of BMS-986231 on mortality at Day 182, in the Global Cohorts only 
(including the Japanese subjects enrolled in Global Part II).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates.
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and 
other information (eg, expedited safety reports (ESR), amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate.
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
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Investigators must:

Provide a copy of the consent form and written information about the study in the language
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood

Allow time necessary for subject or subject’s legally acceptable representative to inquire
about the details of the study

Obtain an informed consent signed and personally dated by the subject or the subject’s 
legally acceptable representative and by the person who conducted the informed consent 
discussion

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject

Revise the informed consent whenever important new information becomes available that is 
relevant to the subject’s consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject’s legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject’s willingness to continue participation in the study. This communication should be 
documented
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects’ signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a multi-center, randomized, placebo-controlled, double-blind study of continuous 48-hour 
intravenous (IV) infusions of BMS-986231 in hospitalized HFrEF subjects with ADHF. The trial 
was designed to identify the doses of BMS-986231 that are safe and tolerated with regard to 
clinically relevant hypotension. 
The study consists of 2 parts, each with a unique cohort of subjects. 
Subjects that are randomized in Part I of the study will not be allowed to participate in Part II. 
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In Part I (Cohort 1) of the study, approximately 100 subjects will be randomized in a 1:1 ratio to 
an escalating dose of BMS-986231 (3 g/kg/min for 4 hours, then 6 g/kg/min for another 4
hours, then 12 g/kg/min for the remaining 40 hours) or an escalating dose of placebo. 
In Part II (Cohort 2) of the study, the 2 highest planned doses of BMS-986231 in Cohort 1,
BMS-986231 6 g/kg/min and BMS-986231 12 g/kg/min, will be administered. Approximately 
210 subjects will be randomized in a 1:1:1 ratio to one of the 2 active doses of BMS-986231 or 
placebo. If BMS-986231 12 g/kg/min is not considered to be a tolerated dose in Part I, then
BMS-986231 3 g/kg/min and BMS-986231 6 g/kg/min will be evaluated in Part II. In the 
event that neither 6 g/kg/min nor 12 g/kg/min are tolerated, the protocol will require 
modification. 
While the enrollment in the main study protocol will continue until 210 patients have been 
randomized globally in Part II (Cohort 2), enrollment in Japan may continue further only in 
Japan until approximately 18 total Japanese subjects are randomized. 
The study design schematic is presented in Figure 3.1-1 for Part I (Cohort 1) and Figure 3.1-2 for 
Part II (Cohort 2).
Figure 3.1-1:
Study Design Schematic Part I (Cohort 1)
a Every effort should be made to initiate study drug administration promptly after randomization 
b Study Medication infusion must start within 18 hours of presentation (or 48 hours in Part II Cohort 2 of the 
trial), with presentation defined as the first dose of diuretic for current episode, but not within 2 hours after 
an IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an 
IV diuretic administered by continuous infusion
c Discharge may occur as per standard medical practice. It is recommended that subjects remain in the 
hospital for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring
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Figure 3.1-2:
Study Design Schematic Part II (Cohort 2)
a 3 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
b 6 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
c Every effort should be made to initiate study drug administration promptly after randomization 
d Study Medication infusion must start within 18 hours of presentation for Part I Cohort 1 (or 48 hours of 
presentation for Part II Cohort 2), with presentation defined as the first dose of diuretic for current episode, 
but not within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or 
an increase in the dose of an IV diuretic administered by continuous infusion
e Discharge may occur as per standard medical practice. It is recommended that subjects remain in the 
hospital for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring.
f Day 32 visit is the last visit for subjects in Japan who were enrolled after the end of global part II enrollment
g All subjects enrolled as part of global part II will be followed for mortality through Day 182
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Subjects must be randomized and treated within 18 hours of presentation for Part I Cohort 1 (or 
48 hours of presentation for Part II Cohort 2). Presentation is defined as the first dose of IV 
diuretic for the current episode of ADHF. In addition, subjects must not be randomized within 
2 hours following an IV bolus dose of diuretic, or within 2 hours after the initiation or an 
increase in the dose of an IV diuretic administered by continuous infusion. It is recommended 
that subjects remain in the hospital for at least 24 hours after the completion of the 48-hour 
infusion of study drug for safety monitoring.
Every effort must be made to initiate study drug administration promptly after 
randomization.
The inpatient period will end in conjunction with the final in-patient assessment at Hour 120 or discharge, 
whichever comes first.
The in-patient period will end in conjunction with the final in-patient assessment at Hour 120 or
discharge, whichever comes first. All subjects enrolled as part of global part II will be followed 
for safety and rehospitalization endpoints through Day 32 and mortality through Day 182.
Subjects in Japan who were enrolled after the end of global Part II enrollment will be followed 
for safety and rehospitalization endpoints through Day 32.
The start of the trial is defined as the first subject screened. End of trial is defined as the last 
subject’s final follow-up visit on Day 182, or the last subject’s scheduled procedure shown in the 
Time & Events schedule. For Subjects in Japan who were enrolled after the end of global Part II, 
The end of trial is defined as the last subject’s final follow-up visit on Day 32, or the last 
subject’s scheduled procedure shown in the Time & Events schedule. 
3.2
Post Study Access to Therapy
At the end of the in-patient period, BMS will not continue to provide BMS supplied study drug 
to subjects/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent
2) Target Population
a) Subjects being hospitalized for ADHF
b) Have had at least 40 mg furosemide intravenous, or equivalent (e.g 40 mg furosemide 
equivalent to 20 mg torsemide or to 1 mg bumetanide ) for the current ADHF episode 
c) Subject must be randomized and treated within 18 hours of first dose of intravenous 
diuretic for Part I Cohort 1 (or 48 hours of first dose for Part II Cohort 2).
d) Have dyspnea at rest or with minimal exertion after administration of at least 1 dose of 
intravenous diuretics. Subject must not be randomized within 2 hours after an IV bolus 
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dose of intravenous diuretics, or within 2 hours after the initiation or a dose increase of an 
IV diuretic administered by continuous infusion
e) Have a history of heart failure and a left ventricular ejection fraction (LVEF) 40%, as 
assessed by echocardiography, a multigated acquisition (MUGA) scan or magnetic 
resonance imaging (MRI) scan
Note: Ejection fraction documentation up to 18 months prior to screening may be used if 
there is no clinical expectation of improvement in ejection fraction in that timeframe 
(eg, the patient has not had biventricular pacing initiated during that period)
f)
Have at least 2 of the following at time of screening: 
i)
evidence for pulmonary congestion on chest x-ray
ii) rales by chest auscultation,
iii) edema 2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in 
15-30 seconds)
iv) presence of jugular venous distention 
g) Have an elevated NT-proBNP 1400 pg/mL (166 pmol/L) or BNP 350 pg/mL 
(101 pmol/L) as determined at the local laboratory within 18 hours prior to the start of 
study drug infusion for Part I Cohort 1 (or 48 hours for Part II Cohort 2)
For subjects with atrial fibrillation: NT-proBNP 2400 pg/ml or BNP 600 pg/ml
h) Body weight 40 kg and < 140 kg at screening
i)
Subject Re-Screening: This study permits the re-screening of a subject that has 
discontinued the study as a screen failure (has not been randomized). See Section 5.1.1
for more details
3) Age and Reproductive Status
a) Males and Females, at least age 18 (or age of majority) (Germany only, see Appendix 3)
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
18 hours prior to the start of study treatment for Part I Cohort 1 (or 48 hours for Part II 
Cohort 2)
c) Women must not be breastfeeding
d) WOCBP must agree to follow instruction for methods of contraception for 32 days after 
discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle)
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for 92 days after discontinuation (duration of study drug plus 
90 days (duration of sperm turnover)
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
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Investigators shall advise on the use of highly effective methods of contraception (Appendix 1), 
which have a failure rate of < 1% when used consistently and correctly.
Local laws and regulations may require use of alternative and/or additional contraception 
methods.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg at screening
b) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg just prior to randomization
c) Heart rate < 50 beats per minute (bpm) or > 130 bpm at screening
d) Heart rate < 50 beats per minute (bpm) or > 130 bpm just prior to randomization
e) Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, 
idiopathic hypertrophic or uncorrected severe valvular disease as defined by 
AHA/ACC/ESC criteria
Note: Functional mitral regurgitation, as well as restrictive mitral inflow pattern on 
echocardiography is not exclusionary
f)
Have a body temperature 38.5C (101.3F) at any time from screening to 
randomization
g) Have an active infection requiring current IV anti-microbial treatment
2. Medical History and Concurrent Diseases
a) Considered clinically unstable for other conditions than acute heart failure, either because 
of acute coronary syndrome or ongoing arrhythmia (or be receiving concomitant 
parenteral therapy with any antiarrhythmic drugs), or other unstable non-cardiovascular 
disease
b) Suspected acute lung disease (e.g. pneumonia or asthma) or severe chronic lung disease 
(e.g. severe chronic obstructive pulmonary disease, pulmonary fibrosis, patients with 
hypercapnia or requiring home oxygen therapy or chronic oral steroids.)
c) Have a history of sudden cardiac death with resuscitation within the past 6 months
d) Be hospitalized with acute coronary syndrome, coronary revascularization or acute 
myocardial infarction during the previous 90 days prior to screening
e) Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic 
attack (TIA) during the previous 90 days prior to screening
f)
Serious comorbid noncardiovascular disease in which the life expectancy of the subject is 
< 6 months (eg, acute systemic infection – sepsis, metastatic cancer, or other serious 
illnesses)
g) Severe liver disease defined as history of cirrhosis with evidence of portal hypertension 
such as varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 51 mol/L) (Germany 
only, see Appendix 3)
h) Prior cardiac or renal transplant 
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3. Physical and Laboratory Test Findings
a) Have persistent abnormal serum electrolytes not resolved before randomization, 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)
(Germany only, see Appendix 3)
c) Have severe renal insufficiency before randomization (and during the current 
hospitalization) 
defined 
as 
an 
estimated 
glomerular 
filtration 
rate 
(eGFR)
< 30 mL/min/1.73m2 [based on any standard limit and equation employed by the local 
lab, eg, Modification of Diet in Renal Disease (MDRD) equation]. For patients with 
eGFR values less than but close to 30 mL/min/1.73m2 upon testing, retesting is allowed.
4. Prior and Concomitant Medications or Treatments
a) Subjects administered IV or transdermal nitrate therapy prior to randomization, except if 
all 3 of the following criteria are met:
i)
Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg 
AND
ii) The IV nitroglycerin dose is < 100 g/min (or isosorbide dinitrate < 3 mg/hour), 
AND
iii) The infusion rate and dose has been unchanged for > 2 hours
b) History of chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or 
peritoneal dialysis)
c) Subjects treated during the current hospitalization with IV vasoactive drugs such as
dopamine, dobutamine, enoximone, nesiritide, nitroprusside, levosimendan, amrinone or 
milrinone, carperitide or nicorandil prior to start of study drug infusion, or have an 
anticipated need to be treated with any of these agents during the study drug infusion
d) Subjects treated with oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil, 
vardenafil or avanafil within 24 hours of screening or treated with tadalafil within 4 days 
of screening, oral inotropic agents (eg, pimobendan) or oral vasopressin V2 receptor 
antagonist (eg, tolvaptan) initiated for the current ADHF episode. NOTE: chronic use of 
tolvaptan is not exclusionary.
e) Subjects receiving any mechanical ventilation at the time of screening
f)
Subjects receiving
non-invasive ventilation (CPAP/BiPAP) < 2 hours prior to 
randomization
5. Allergies and Adverse Drug Reaction
a) Any history of allergic reaction to BMS-986231, or its components, Captisolor 
potassium acetate
6. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is 
required.
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b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, 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, CXL-1427, or 
CXL-1020
e) Alcohol beverage consumption within 6 hours prior to randomization
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators should use 
their judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum 
FSH level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments

Initiation of PDE5 inhibitors or pimobendan is prohibited during study drug infusion and 24 
hours after the end of the study drug

The use of nitrates, except for subjects receiving stable IV dose of nitrates at randomization, 
should be avoided, unless clinically indicated (ie, episodes of angina, worsening HF)

Administration of IV vasoactive drugs (such as dopamine, dobutamine, enoximone, 
nitroprussiate, levosimendan or milrinone) should be discouraged unless clinically warranted 
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(ie, if patient’s status requires use of vasoactive treatments for conditions such as worsening 
heart failure)
3.4.2
Other Restrictions and Precautions
Not applicable.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
The below discontinuation criteria apply to both Part I (Cohort 1) and Part II (Cohort 2) of the 
trial.
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

If study medication has been interrupted for low blood pressure, resumed, and an episode of 
hypotension (or symptoms of hypotension) reoccurs (see Section 4.5.1)
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for subject safety). Please contact the Sponsor or designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion among the 
investigator and the Sponsor or designee and the patient must occur.
All subjects who discontinue study drug are requested to comply with protocol specified follow-
up procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate electronic case report form (CRF) page.
3.6
Post Study Drug 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 subject safety and the integrity of the study. Subjects 
who discontinue study drug must continue to be followed for collection of outcome and/or 
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survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if possible. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or 
post treatment study follow-up, and entered on the appropriate CRF page. In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with local 
law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
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4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] Product (Non-IP/Non-
IMP) and can consist of the following:
Treatments:
BMS will provide Investigational drug product BMS-986231 for infusion (active pharmaceutical ingredient BMS-986231 formulated 
with Captisol® 3405 mg/vial) to all sites as per Table 4-1. In addition, Potassium acetate is to be locally sourced by sites within the 
US and will be supplied to all ex-US sites as per Table 4-1.
Table 4-1:
Study Drugs for CV013011 - Part I (Cohort 1) and Part II (Cohort 2)
Product Description / Class 
and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
BMS-986231
For Injection
BMS-986231 
240 mg/vial
IP
Open Label
White to pale yellow whole or fragmented 
cake in a 20 mL glass vial with Fluortec
stopper and a blue flip-off aluminum cap.
Secondary packaging is a carton containing 
5 or 6 vials.
2 to 8°C (36-46°F)
Store in original 
package, protect from 
light.
Potassium Acetate Injection, 
USPa
2 mEq/mL 
(20mL/vial)
Non-IMP
Open Label
Colorless solution in a 20 mL fliptop glass 
vial.
Secondary packaging is a carton containing 
6 vials
Store at 20 to 25°C
(68 to 77°F).
a Supplied by BMS only to ex-US sites
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
Study medication will be prepared by an unblinded pharmacist (or appropriate designee) at time 
of randomization. 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.
4.2
Non-Investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
In this study, the required Potassium Acetate used in the active and placebo infusions is 
considered non-investigational product.
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS and listed in 
Table 4-1 and drug product label. If concerns regarding the quality or appearance of the study 
drug arise, the study drug should not be dispensed and BMS contacted 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 Section 
9.2.2 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. 
4.4
Method of Assigning Subject Identification
At the time of screening for both Part I (Cohort 1) and Part II (Cohort 2), each subject will be 
assigned a unique sequential subject number by interactive response technology (IRT). The IRT
will be available 24 hours per day, 7 days a week. The subject number will consist of a unique 
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5 digit number which is assigned sequentially within a study (starting with 00001) by the IRT. 
This number will be used for identification throughout the study and will not be used for any 
other subject. Subjects screened for Part I, (Cohort 1) will be assigned sequential study numbers 
beginning with 00001, and subjects screened for Part II, (Cohort 2) will be assigned sequential 
study numbers beginning with 10001.
Randomization schedules will be generated by BMS and kept by the IRT vendor. Subjects who 
meet the inclusion/exclusion criteria will be randomly assigned by the IRT to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min) in a 1:1 ratio for Part I (Cohort 1) and 
placebo or 1 of the 2 active dose levels of BMS-986231 in a 1:1:1 ratio for Part II (Cohort 2).
Randomization will be stratified by region.
4.5
Selection and Timing of Dose for Each Subject
Subjects will be administered study medication as a continuous IV infusion over 48 hours.
Body weight measured at screening will be used for dose calculations.
Every effort must be made to initiate study drug administration promptly after 
randomization.
See Pharmacy Manual for additional dosing information.
4.5.1
Dose Reductions, Temporary Interruptions, and Permanent 
Discontinuations of Study Drug Due to Blood Pressure
Any decision to lower the dosage level of study drug or discontinue study drug should be based 
on the Investigators assessment of the subject’s overall clinical stability, in the context of 
appropriate ongoing monitoring of the subject’s condition. A 50% dosage adjustment downward 
maybe be achieved by decreasing the rate of study drug infusion.
In Part I (Cohort 1) subjects who require a dose reduction or temporary interruption during the 
first infusion period, hours 0 to 4 (dose of 3 μg/kg/min), will be permanently discontinued from 
study drug.
Study drug infusion rate may be reduced by 50%, temporarily interrupted, or permanently 
discontinued. See Figure 4.5.1-1 and the following sections for more detail.
Dose Reduction:

If the subject experiences SBP < 95 mm Hg, without symptoms related to hypotension, the 
measurement must be repeated within 15 minutes. If the SBP remains < 95 mm Hg, the dose 
reduction must occur

A 50% dosage adjustment downward may be achieved by decreasing the rate of study drug 
infusion by half

After a dose reduction, the dose cannot be increased again
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Temporary interruption:

If the systolic blood pressure reduces below < 85 mm Hg, and remains < 85 mm Hg during a 
repeated measure within 15 minutes, the study drug must be interrupted for at least 1 hour

For subjects that report symptoms consistent with hypotension (eg, dizziness, 
lightheadedness, etc.), and are related to hypotension, study drug must be interrupted for at 
least 1 hour
Resuming Study Drug

Study drug may be resumed at 50% of the dose after 1 hour interruption, if SBP rises to 
values 105 mm Hg and any symptoms of hypotension, if present, have resolved. 

If after 4 hours, the subject’s SBP remains below < 105 mm Hg, or if symptoms persist, then
study drug must be permanently discontinued

After a dose reduction, the dose cannot be increased again
Permanent discontinuation of the infusion:

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 subject’s best interest 
to continue to receive study drug

Study drug will be permanently discontinued after it has been down titrated once, and criteria 
for dose reduction or interruption has been met again.
Figure 4.5.1-1:
Guidance for Dose Reduction Based on Blood Pressure Measurements 
and/or Symptoms of low blood pressure
* Confirmed by a second measure within 15 min
**No need to wait for confirmatory measures within 15 min
§ But no more than 4 hours
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4.6
Blinding/Unblinding
4.6.1
Emergency Unblinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual subject in which knowledge of the 
investigational product is critical to the subject’s management, the blind for that subject may be 
broken by the investigator. The subject’s safety takes priority over any other considerations in 
determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual subject’s treatment, the investigator should determine 
that the unblinded information is necessary, ie, that it will alter the subject’s immediate 
management. In many cases, particularly when the emergency is clearly not related to the 
investigational product, the problem may be properly managed by assuming that the subject is 
receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the subject has been made.
For this study, the method of unblinding for emergency purposes is via the Interactive Response 
Technology (IRT) system. For information on how to unblind in an emergency, consult the IRT 
manual.
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind.
Any request to unblind a subject for non-emergency purposes should be discussed with the 
Medical Monitor.
4.6.2
Other Blinding and Unblinding
The Data Monitoring Committee (DMC; see Section 7) will assess safety on an ongoing basis, 
and will have access to unblinded treatment codes for individual subjects. An analysis team, 
including a reporting statistician and programming support, who are not involved with the 
conduct of the study, will provide analyses to the DMC.
Two interim analyses will be performed in this study.
The first unblinded interim analysis will be performed by the analysis team at the completion of 
the last visit at Hour 120 in Part I (Cohort 1). This analysis will be reviewed by the DMC and 
will be reviewed in parallel and by the executive committee (see Section 7) and Sponsor 
representatives.  The rationale for a fully unblinded review by the executive committee and 
Sponsor is to determine whether 12 μg/kg/min is an appropriate dose to study in Part II. 
The second interim analysis will be performed when 210 randomized subjects reach the last visit 
at Day 32 in Part II (Cohort 2). The study analysis team will then provide top-line results to the 
project team.
The follow-up to Day 182 and/or Day 32 for both Part I and Part II will be site-and-subject 
blinded. 
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Japanese subjects enrolled as part of the 210 subject global cohort (Part II, Cohort 2) will be site-
and-subject blinded until the end of the study in Japan.
The Bioanalytical Sciences section or its designate may be unblinded to the randomized 
treatment assignments in order to minimize unnecessary assays of samples from control group 
subjects. Likewise, the Biotransformation section or its designate may be unblinded, if 
metabolite profiling work is conducted.
In certain circumstances a pharmacokineticist or designates in Clinical Pharmacology and 
Pharmacometrics, biostatisticians and programmers 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 assignments.
The pharmacist at the site and/or its designate will be unblinded to the randomized treatment 
assignments in order to dispense treatment from bulk supplies, as needed. An unblinded Site 
Monitor, not involved with other study conduct, will be assigned exclusively to reconcile study 
medication and assure accountability.
Except as noted above, other members of BMS Research and Development personnel, as well as 
all vendors responsible for the conduct of the trial (protocol team) will remain blinded.
4.7
Treatment Compliance
Not applicable.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site.
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed 
after being inspected and reconciled by the responsible 
Study Monitor unless IP containers must be immediately 
destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics).
If IP will be returned, the return will be arranged by the 
responsible Study Monitor.
IP sourced by site, not supplied by BMS (or its 
vendors) (examples include IP sourced from the 
sites stock or commercial supply, or a specialty 
pharmacy)
It is the investigator’s or designee’s responsibility to 
dispose of all containers according to the institutional 
guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug
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
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced 
by the site, not supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Retained Samples for Bioavailability / Bioequivalence
Not Applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
Eligibility Assessments
Informed Consent
X
Review Inclusion/Exclusion Criteria
X
X
Medical History
X
Confirm administration of IV diuretic and time of 
administration
X
Safety Assessments
Complete Physical Examination
X
Body Weight
X
Height
X
Vital Signs: Blood Pressure and Heart Rate
X
X*
Perform Semi-Recumbent (at a 30º angle).
*Within 15 minutes prior to randomization
Respiratory Rate
X
X
Use of Oxygen Supplementation, Oxygen Saturation
X
X
Temperature
X
X*
*Within 15 minutes prior to randomization
Chest X-ray
X
As applicable, refer to section 3.3.1
X-ray obtained for the current episode of ADHF as part 
of standard of care may be used.
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Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
12-Lead ECG (Electrocardiogram)
X
Telemetry Monitoring 
X
Begin within 2 hours prior to start of study medication 
infusion
Holter Monitoring (Part II Cohort 2 Only)
X
For participating sites. 
Begin within 2 hours prior to start of study medication 
infusion
Investigator Assessment of Congestion
X
Physical exam to assess signs and symptoms of 
congestion will include symptom assessments (dyspnea 
on exertion, dyspnea at rest, orthopnea, paroxysmal 
nocturnal dyspnea, persistent coughing or wheezing, 
fatigue, and abdominal discomfort), and signs 
assessment (peripheral edema, pulmonary rales, 
tachypnea and/or oxygen desaturation, increased jugular 
venous pressure, hepatomegaly, ascites).
Serious Adverse Events Assessment
X
X
Begins at time subject signs ICF
Review concomitant medications/procedures
X
X
Local Laboratory Assessments
See Section 5.3.5.1 for Analytes
Hematology and Serum Chemistry
X
eGFR
X
Trough Serum Digoxin
X
If receiving digitalis glycosides
Hs Troponin T
X
Coagulation Tests 
X
Prothrombin Time (PT or PT-INR) 
NT-proBNP or BNP
X
As per site preference
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Table 5.1-1:
Screening Procedural Outline (CV013011)
Procedure
Screening Visit
(-18 for Part I 
Cohort 1 or -48 
for Part II 
Cohort 2, up to 
0 hours)
Pre-
Randomization 
Procedures
Notes
Pregnancy Test
X
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
Hs Troponin T
X
NT-proBNP, Serum Cystatin C, NGAL
X
CRP
X
Urinalysis
X
Urine creatinine, Na+, and K+
X
Efficacy Assessments
Resting Dyspnea measured by the Numerical Rating 
Scale (NRS)a
X
Other Assessments
Sensory Motor Survey
X
a If subject is receiving supplemental oxygen, perform NRS without removing oxygen
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Randomize Subject
X
Randomization must take place before 
Hour 0
Administer Study Medication
X
48 hour continuous infusion
*Study medication infusion begin
promptly after randomization*
Safety Assessments
Body Weight
X
X
X
X
X
Vital Signs: Blood Pressure and 
Heart Rated
X
X
X
X
X
X
Perform Semi-Recumbent (at a 30º 
angle) 
Day 1: Hours 0, 0.25 (15 min), 0.5 (30 
min), 0.75 (45 min), 1, 1.5, 2, 4, 5*, 6, 
8, 9*, 10, 12, 14, 16, 18, 20, 22 
Hours: 24, 28, 32, 36, 40, 44
Hours 48, 54, 60, 66
Hour 72
Hour 96
Hour 120
Perform measurements before IV bag 
change, when possible.
Repeats as per Section 5.3.1
Perform also if signs or symptoms of 
hypotension
*Part I (Cohort 1) only
Respiratory Rate
X
X
X
X
X
X
Day 1: Hours 6 and 12
Use of Oxygen Supplementation, 
X
X
X
X
X
X
Day 1: Hours 6 and 12
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Oxygen Saturation
Temperature
X
X
X
X
X
12-Lead ECG
X
X
X
X
Telemetry Monitoring
X
Continuous monitoring through 
Hour 50
Holter Monitoring (Part II Cohort 
2 Only)
X
For participating sites. 
Continuous monitoring through 
Hour 52. 12-lead ECGs will be 
extracted at 3 timepoints prior to the 
start of the infusion and at the same 
timepoints as PK determinations up to 
and including 48 hours post-dose (See 
section 5.5)
Subjects will be supinely resting in a 
semi-recumbent position for at least 10 
minutes prior to and 5 minutes after 
each timepoint for ECG extraction (Day 
1: Hour 0.75, 4*, 8*, 14, 48 and Hour 
52). When ECG extractions coincide 
with 12-lead safety ECGs, blood draws 
and other assessments, ECG extractions 
should, when feasible, be performed in 
said order.
Investigator Assessment of Signs 
of Congestion
X
X
X
X
X
Physical exam to assess signs and 
symptoms of congestion will include 
symptom assessments (dyspnea on 
exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea, 
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
persistent coughing or wheezing, 
fatigue, and abdominal discomfort), and 
signs assessment (peripheral edema, 
pulmonary rales, tachypnea and/or 
oxygen desaturation, increased jugular 
venous pressure, hepatomegaly, 
ascites).
Assessment of Hypotension
X
X
X
Assessment of signs and symptoms of 
hypotension.  
Serious Adverse Event Assessment
X
Adverse Events Assessment
X
From Hour 0 to Hour 120.
If subject is discharged before 
Hour 120, site asked to contact subject
at Hour 120 for final AE collection
Concomitant Medications
X
Local Laboratory Assessments
Cumulative Urinary Output 
(Volume) 
X
X
X
X
X
Provide daily volume
Pregnancy Test
X
X
WOCBP only
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
X
X
X
Hs Troponin T
X
X
X
X
NT-proBNP, Serum Cystatin C,
NGAL
X
X
X
X
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
CRP
X
X
Urinalysis
X
Urine creatinine, Na+ and K+
X
X
X
X
Pharmacokinetics
See Section 5.5
Pharmacokinetic Blood Samples
Collection and Preparation of 
Blood Samples 
X
X
X
Part I Cohort 1: Day 1: Hour 0.75, 4, 8, 
14
Hour 48
Hour 52
Part II Cohort 2: Day 1: Hour 0.75, 6, 
14
Hour 48
Hour 52
Perform measurements before IV bag 
change or stopping the infusion, 
whenever possible.
Collect sample when dose lowered due 
to a safety event and also at time of 
early discontinuation of study drug.
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Table 5.1-2:
Treatment and In-Hospital Follow-up (CV013011)
Procedure
Hour
0-23a
(Post 
Rand, 
Day 1)
Hour
24 2 
Hour
48 2 
Hour
72 2 
Hour
96 2
Hour
120 2 or 
Discharge b c
Notes
(Time is relative to start of dosing)
Efficacy Assessments
Resting Dyspnea measured by 
Numerical Rating Scale (NRS)e
X
X
X
X
X
Day 1: Hours 6 and 12
Resting Dyspnea measured by 
7-point Likert Scalee
X
X
X
X
X
Day 1: Hours 6 and 12
Patient Global Assessment
measured by 7-point Likert Scalee
X
X
X
X
X
Day 1: Hours 6 and 12
Assessments of Worsening Heart 
Failure
X
X
X
X
X
Documentation of Worsening Physical 
Signs and Symptoms of Heart Failure, 
and Documentation of Initiation or 
Increased dose of Parenteral Diuretic, 
Vasodilator and/or Inotropes, or Need 
for Mechanical interventions 
(mechanical ventilation, circulatory 
support, ultrafiltration or dialysis). 
Assessments to cover prior 24 hour 
period.
Wristworn Actigraphy monitoring
device (watch) (Part II Cohort 2)
X
X
X
X
For participating sites. 
Provide the device to subjects at the end 
of the 48 hours infusion or when the 
study drug has been permanently 
discontinued
Other Assessments
Sensory Motor Survey
X
a Hour 0 defined as start of study medication infusion
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b Visit to occur at Hour 120 2 or Discharge, whichever comes first. If subject is discharged after Hour 120, no further protocol in-hospital visits are completed
c Assessments required at Discharge Visit should not be repeated if performed within previous 12 hours
d  Vital signs should be taken within (0.25) 
e If subject is receiving supplemental oxygen, perform NRS without removing oxygen
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Table 5.1-3:
Outpatient Follow-up (CV013011)
Procedure
Day 32 
(2 Days)
Clinic Visita
Day 182 
(5 Days)
Phone Visitb
Notes
Safety Assessments
Vital Signs: Blood Pressure and Heart 
Rate
X
When possible, perform Semi-Recumbent (at a 30º angle)
Respiratory Rate
X
Body Weight
X
Temperature
X
Serious Adverse Events Assessment
X
Local Laboratory Assessments
Pregnancy Test
X
WOCBP only
Central Laboratory Assessments
See Section 5.3.5.2 for Analytes
Hematology and Serum Chemistry
X
NT-proBNP, Serum Cystatin C, NGAL
X
CRP
X
Urinalysis
X
Urine creatinine, Na+ and K+
X
Efficacy, Safety, and Other Assessments
Healthcare Utilization Assessment
X
Assessment of Mortality
X
X
Sensory Motor Survey
X
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Table 5.1-3:
Outpatient Follow-up (CV013011)
Procedure
Day 32 
(2 Days)
Clinic Visita
Day 182 
(5 Days)
Phone Visitb
Notes
Actigraphy monitoring watch (Part II 
Cohort 2)
X
For participating sites. 
One time complete transfer of data from the actigraphy device to a dedicated 
website via an electronic docking station to occur during or immediately
following the 32-days study visit
a Subjects in Japan who were enrolled after the end of global Part II enrollment will be followed for safety and rehospitalization 
endpoints through Day 32.
b Day 182 Phone Visit not applicable for Subjects in Japan who were enrolled after the end of global Part II enrollment, as they will 
be followed for safety and rehospitalization endpoints through Day 32 only.
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5.1.1
Retesting During Screening or Lead-in Period
All screening laboratory will be performed locally, and tests may be repeated at the discretion of 
the Investigator as per site policy.
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
In an effort to find all possible well-qualified subjects, subjects that have discontinued the study 
as a screen failure (have not been randomized) are eligible for re-screening upon presentation for 
a subsequent episode of ADHF at the discretion of the Investigator.
If re-screened, the subject must be re-consented and a new subject number will be assigned by 
the IRT. Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening 
Procedural Outline, must be repeated. The subject numbers and data will be linked in the clinical 
database.
5.1.2
Discharge
Discharge may occur as per institutions standard medical practice. It is recommended that 
subjects remain in the hospital for at least 24 hours after the completion of the 48-hour infusion 
of study drug for safety monitoring. 
Subjects discharged prior to Hour 120 should complete the Hour 120/Discharge visit. 
Assessments required at the Hour 120/Discharge Visit as per Table 5.1-1 should not be repeated 
if performed within the previous 12 hours. 
5.2
Study Materials

11-item Numerical Rating Scale

7-point to Likert Scale

Sensory Motor Survey

Pharmacy Manual

Clinical Laboratory Manual

Subject education materials and other site support tools
5.3
Safety Assessments
Additional procedures and assessments may be performed as a part of the subject’s standard of 
care; however, data for these assessments will remain in the subject’s medical record and is not 
be provided to BMS, unless needed to support an AE, SAE report, or as specifically requested by 
the Sponsor.
5.3.1
Assessment of Blood Pressure and Symptoms for Hypotension
The primary endpoint of the study is the incidence of clinically relevant hypotension, defined by 
SBP < 90 mm Hg (confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up 
to 6 hours after the end of study drug infusion. Thus hypotension will be assessed by collection 
of symptoms and blood pressure measurements.
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Symptomatic hypotension is defined as the presence of both low SBP and significant and/or 
non-resolving symptoms due to low blood pressure (eg, lightheadedness, dizziness, etc.). 
Blood pressure measurements should be performed with the subject in a semi-recumbent (about 
a 30º angle) position, whenever possible. 
Blood pressure will be measured as indicated in Table 5.1-2, within (5 min in the first hour 
then 0.25 (15 min)) of the specified time points. In addition, sites may perform measurements 
at intervals defined by institutional standard of care for subjects receiving vasodilators, but no 
less than what is described in Table 5.1-2.
If the study drug dose is modified (decreased, interrupted, resumed or discontinued) the
frequency of blood pressure measurements will follow a more intensive schedule for up to 6 
hours following the dose modification (Table 5.3.1-1). Upon completion of the intensive 
schedule, measurements can be either resumed per the original schedule, or follow the 
discontinuation schedule if the drug is permanently discontinued. 
Table 5.3.1-1:
Schedule of Intensive Blood Pressure Collection Following a 
Dose Modification
30 minutes
post
1 hour
post
2 hours
Post
4 hours
post
6 hours
post
Dose reduction
X
X
X
X
X
Dose interruptiona
X
X
X
X
Dose resumptionb
X
X
X
X
X
Dose discontinuation
X
X
X
X
Xc
a dose must be resumed within 4 hours of dose interruption. If interruption last beyond 4 hours, dose must be 
discontinued and discontinuation schedule must be followed.
b If dose is restarted within 4 hours following interruption, follow schedule for dose resumption
c After 6 hours, continue collecting blood pressure measurement at a minimum of every 12 hours through hour 72 
or follow the local institutional standard of care protocol, whichever is more frequent.
In addition to assessments of blood pressure, the Investigator will be asked to collect and assess 
signs and symptoms of low blood pressure The details to be captured will include:

Onset date/time

Total duration of episode

Lowest blood pressure during the episode
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
Signs and symptoms associated with low blood pressure (such as confusion, dizziness,
fatigue, auditory disturbances (such as tinnitus), lightheadedness, chest pain, visual 
disturbances, vomiting, syncope, etc)
Events of clinically relevant hypotension will also be recorded as an Adverse Event (see 
Section 6)
Management of study drug (interruption, discontinuation, re-start) is detailed in Section 4.5.1.
Hypotension endpoints are defined in Section 8.3.
5.3.2
Physical Measurements
Height: Measurement of height should be performed with the subject’s shoes removed, if 
possible. The subject’s knees should be straightened, head held erect, and eyes forward.
Weight: Measurement of weight should be performed with the subject having pockets empty, 
shoes removed, and bladder empty, when possible.
5.3.3
Physical Examination
A complete physical examination should include general appearance, head, eyes, ears, nose, 
throat, neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, and 
musculoskeletal.
The individual performing the physical examinations must be licensed by state law 
(or applicable local law) to perform a physical examination.
5.3.4
Electrocardiogram
The Investigator should review and assess all ECGs for any clinically significant abnormalities, 
and initial and date the report.
The site should follow their standard practices for performing ECGs. Below is guidance to be 
used as a reference, if needed:
In preparation for the ECG, ensure there is minimal interference between the skin surface and the 
electrode. Use alcohol to prepare the skin at each electrode site. Thick chest hair should be 
shaved to ensure sufficient contact.
Before attaching electrodes to pick-up points, spread the electrode with electrode gel. Place the 
electrodes on bony areas, avoiding large muscle masses, to achieve better tracings as described 
below. The subject must be supine and should refrain from movement during the ECG recording.
Ensure that the subject and the electrodes (including the neutral electrode) are not exposed to 
conducting objects, even if grounded.

RL: On the right leg (inside calf, midway between knee and ankle)

LL: On the left leg (inside calf, midway between knee and ankle)

RA: Right arm (on the inside)

LA: Left arm (on the inside)

V1: 4th intercostal space, at right sternal margin

V2: 4th intercostal space, at left sternal margin
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
V3: Midway between V2 and V4

V4: 5th intercostal space at left midclavicular line

V5: Same transverse level at V4, at anterior axillary line

V6: Same transverse level at V4, at left midaxillary line
Keep one original ECG (print-out or electronic copy) in the medical chart and ensure a copy, 
assessed, initialed and dated by the Investigator, is maintained in the source documents for the 
study.
5.3.5
Laboratory Test Assessments
Subjects will have laboratory tests performed locally as necessary for treatment of ADHF 
following local practices. In addition, laboratory tests will be performed locally and centrally as 
described in the following sections.
5.3.5.1
Local Laboratory Assessments for Screening
The following local laboratory tests will be assessed as part of the screening evaluation. Local 
Laboratory results obtained for the current episode of heart failure as part of standard of care 
may be used. 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)

Alkaline Phosphatase

Total Bilirubin

Blood Urea Nitrogen (BUN)

Electrolytes

Sodium

Potassium

Serum Creatinine (Scr)
Other Assessments

eGFR, by locally used equation

Trough Serum Digoxin (if receiving digitalis glycosides)

Hs Troponin T (or other based on site’s available assays)

Coagulation Tests

Prothrombin Time (PT or PT-INR)
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
NT-ProBNP or BNP (as per site preference)
5.3.5.2
Central Laboratory Assessments 
The following laboratory tests will be performed and submitted to the Central Laboratory for 
analysis as per the Study Assessment and Procedures in Section 5.
Hematology

Hemoglobin

Hematocrit

White blood cell count and differential

Erythrocytes (RBC)

Erythrocyte mean corpuscular volume (MCV)*

Erythrocyte mean corpuscular hemoglobin (MCH)*

Erythrocyte mean corpuscular hemoglobin concentration (MCHC)*

Platelet count

Reticulocyte count*
*performed at baseline, Hour 120 or Discharge, whichever comes first, and Day 32
Serum chemistry

Aspartate Aminotransferase (AST, SGOT)

Alanine Aminotransferase (ALT, SGPT)

Alkaline Phosphatase

Creatine Kinase (Creatine Phosphokinase) (CK) (CPK)

Total Bilirubin

Uric Acid

Blood Urea Nitrogen (BUN)

Electrolytes

Sodium

Potassium

Chloride

Bicarbonate

Glucose

Anion gap

Magnesium

Total Protein

Albumin

Serum Creatinine (Scr)

Calcium*

Phosphorus*
*performed at baseline, Hour 24, Hour 48 and Hour 120 or Discharge, whichever comes first.
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Other Assessments

eGFR, by MDRD 

Trough Serum Digoxin (if receiving digitalis glycosides)

Hs Troponin T 

Coagulation Tests

Prothrombin Time (PT and PT-INR) 

Partial thromboplastin time (PTT) 

NT-ProBNP

Cystatin C

CRP

NGAL
Urinalysis

pH, protein, glucose, leukocyte esterase, blood by dipstick

Microalbumin

Albumin: creatinine ratio

Microscopy if dipstick positive for blood, leukocyte esterase or protein
The Central Laboratory and designated reference laboratories for this study will perform the
analysis of all scheduled laboratory tests and will provide reference ranges for these tests. Urine
dipstick testing for pregnancy (in WOCBP) at specified visits is to be done at the investigative
site. 
The detailed methods for specimen collection, handling, processing, shipping, and storage will
be supplied in the Investigator’s Laboratory Manual provided by the Central Laboratory.
5.3.6
Telemetry Monitoring
Telemetry monitoring will be performed to help monitor subject safety. The site will follow their 
normal operating procedures established for telemetry monitoring. Clinically significant findings 
from the telemetry monitoring will be recorded as AEs and SAEs per the Investigators decision.
5.3.7
Holter Recordings
Holter monitoring with extraction of serial ECGs will be performed in a sub-set of 51 patients in 
Part II Cohort 2 only, randomized 1:1:1 to placebo and the two active doses in Part II Cohort 2 of 
the study. The 12-lead Holter and ECG equipment will be supplied and supported by the sponsor 
and a core electrocardiographic laboratory. ECGs to be used in the analyses will be selected by 
pre-determined time points as defined in the Table of Assessments, and will be read centrally by
a core electrocardiographic laboratory. The analysis will be described in detail in a separate 
analysis plan.
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer-assisted and statistical process utilized by a 
core electrocardiographic laboratory. 
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At each protocol-specified timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG 
window” (typically, the last 5 minutes of the 15-minute period when the subject is maintained in 
a supine or semi-recumbent quiet position.  Subjects must be instructed to rest in a quiet position 
15 minutes before each PK draw.
5.3.8
Imaging Assessment for the Study
Not Applicable.
5.4
Efficacy Assessments
5.4.1
Assessments of Worsening Heart Failure
The Investigator will be asked to indicate if a subject has experienced worsening heart failure, to 
document the signs, and symptoms that led to the assessment of worsening heart failure, and to 
document the intensification of treatment implemented for worsening heart failure.  Assessment 
is to be done once daily covering the prior 24-hour period as per the scheduled times in Table 
5.1-2.
In this trial, worsening heart failure is defined as new or worsening signs and/or symptoms of 
heart failure that require:

Intensification of IV therapy for heart failure (such as initiation, restart or up-titration of IV 
diuretics, IV nitrates or other IV vasoactive drugs), and/or

Addition of a mechanical support, either:

Ventilatory (mechanical ventilation, noninvasive ventilation), 

Circulatory (Intra-Aortic Balloon Pump (IABP), ventricular assist device) or 

Use of ultrafiltration, hemofiltration or hemodialysis specifically for the management of 
WHF
The presence of WHF must be documented by the investigator recording the signs, symptoms, 
and/or laboratory assessments that led the conclusion that the subject had worsened.
Symptoms of heart failure may include: dyspnea on exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea, persistent coughing or wheezing, fatigue, and abdominal 
discomfort.
Signs of heart failure might include: pulmonary rales, tachypnea and/or oxygen desaturation, 
increased jugular venous pressure, hepatomegaly, peripheral edema, an increase in body weight, 
oliguria, and signs of hypo-perfusion such as mental confusion, hypotension, and cool skin
5.4.2
Investigator Assessment of Signs of Congestion
The Investigator will be asked to assess the subject’s signs of congestion using the following 
criteria:
1) Bilateral peripheral edema using a 4-point scale
a) 0 absent
b) 1+ Trace (Barely perceptible indent, skin rebounds quickly)
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c) 2+ Feet and ankles (Easily identifiable indent, skin rebounds in 15-30 sec, edema limited 
to feet and ankles)
d)
3+ Lower legs or thighs (Easily identifiable indent, skin rebounds in > 30 sec, edema 
extended to lower legs or thighs)
2) Bilateral pulmonary rales: Auscultation of the lungs applying a 3-point scale
a) 0 absent
b) 1+ < 1/3 up lung fields,
c) 2+ 1/3 up lung fields
3) Jugular venous distension (absent / present) 
4) Hepatic enlargement (absent / present)
5) Orthopnea: The subject should be observed after being in the lowest recumbent position for 
10-15 minutes
a) Absent – subject has no sensation of dyspnea in recumbent position
b) Present - dyspnea develops in the recumbent position and is relieved by elevation of the 
head with pillows
6) Ascites
a) Absent
b) Present
5.4.3
Physical activity monitoring using a wrist-worn actigraphy device
(watch)
Physical activity will be measured in a subset of approximately 100 patients in Part II of the trial 
only, using an actigraphy wearable device worn on the wrist (wristwatch) that utilizes an 
accelerometer to monitor the occurrence and degree of motion47.
All sites participating in the accelerometry sub-study will provide the device to subjects at the 
end of the 48 hours infusion or when the study drug has been permanently discontinued. Study 
participants accepting to participate in the sub-study will wear the device continuously during 30 
days follow-up period, with the exception of the charging period (battery life expected to be 
approximately 10-12 days), via a charger provided to the patient. Data collected by the device 
will be uploaded during the 32-days study visit via an electronic docking station at the site. 
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5.5
Pharmacokinetic Assessments
Blood samples will be collected for pharmacokinetic assessments as described in Table 5.5-1.
Table 5.5-1:
Pharmacokinetic Assessments
Time 
Relative to Dosing
Hour (window)
Time 
(Relative to Dosing)
Hour: Min
PK
Blood Sample
0.75 (0.25)
00:45
X
4 (0.5) 
04:00
X
8 (0.5) 
8:00
X
14 (4) 
14:00
X
48 (1) 
48:00
X
52 (1)
52:00
X
Dose lowered due to safety event (0.5)
Misc.
X
Early Discontinuation
Misc.
X
Collect the 4 and 8 hour PK samples immediately prior to the IV bag change whenever possible.
In addition, collect a PK sample from the subject 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.
 
 
 
 
 
 
 
 
 
 
 
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5.7
Outcomes Research Assessments
5.7.1
Dyspnea Assessments
The sensation of dyspnea is subjective, but dyspnea relief is important to subjects and has been 
long quantified in clinical trials using patient-reported outcome scales that have previously been 
used to assess the efficacy of other interventions in ADHF subjects.
In this trial, subjects are asked to report their absolute current severity of dyspnea on an 11-point 
numerical rating scale (NRS; range 0 to 10) and their current level of dyspnea relative to baseline 
using 7-level Likert scales.
5.7.1.1
Dyspnea Numerical Rating Scale
The numerical rating scale (NRS) will be used to assess the degree of dyspnea (breathlessness), 
measured using an 11-point scale provided by the Sponsor.
5.7.1.2
Dyspnea Likert Scale
Subject will be presented with the following question: “We would like to measure how you think 
your breathing is. Please circle the number next to the description that best indicates how you are 
breathing right now, compared to when you first started the study drug.”
3 = Markedly better
2 = Moderately better
1 = Minimally better
0 = No change
-1 = Minimally worse
-2 = Moderately worse
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-3 = Markedly worse
5.7.2
Healthcare Utilization
Following discharge from the index hospitalization, the occurrence of rehospitalizations and 
emergency department visits for heart failure and other causes of cardiovascular disease will be 
documented. Rehosptalizations will include subjects who are either under observation or 
admitted as an inpatient with a length of stay 24 hours. Emergency department visits will 
include urgent, unplanned visits in a monitored healthcare setting with a length of stay < 24 
hours. Only emergency department visits that do not result in a hospitalization will be counted as 
separate healthcare encounters.
In the event that the subject reports rehospitalizations or emergency department visits through 
Day 32 after the index hospitalization, the reason for the rehospitalization/ED visit will be 
recorded and, where possible, will be confirmed with the hospital or the subject’s physician. The 
investigator should make every effort to obtain a discharge summary. If the subject is currently 
hospitalized and unable to attend the visit, then the investigator should make every effort to 
reschedule the visit when medically appropriate and to obtain the discharge summary when 
available.
The primary reason for the rehospitalization/ED visit will be categorized by the investigator into 
1 of the following categories:

Heart failure related event involves a primary diagnosis of HF, where the subject has new or 
worsening symptoms, objective evidence of new or worsening HF, and receives new or 
intensification of treatment including an IV diuretic

Other cardiovascular, non-heart failure related event involves a primary diagnosis of 
cardiovascular disease other than HF including MI, resuscitate sudden cardiac death or other 
cardiovascular cause (eg, stroke)

Non-cardiovascular event involves primary diagnoses other than HF and CV disease
5.7.3
Mortality
Investigators will follow all subjects in global part II to Day 182 for mortality. Subjects in Japan
who were enrolled after the end of global Part II enrollment will be followed through Day 32.
Investigators will be asked to report deaths and categorize them as either cardiovascular or non-
cardiovascular death. All deaths will be assumed to be cardiovascular unless a non-
cardiovascular cause can be clearly provided. Below is guidance for Investigator classification:
Cardiovascular Death:
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden 
cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular 
(CV) procedures, death due to CV hemorrhage, and death due to other CV causes
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Non-cardiovascular Death:
This category includes all deaths due to a clearly documented non-cardiovascular cause, such as 
respiratory failure (excluding cardiogenic pulmonary edema), hemorrhage (other than 
intracranial or CV hemorrhage), infections/sepsis, neoplasm, and trauma (including suicide and 
homicide).
5.8
Other Assessments
5.8.1
Sensory Motor Survey  
Subject will be complete a 5 question interview relating to presence and degree of specified 
characteristics relating to sensory and motor function, with responses indicating either none, 
mild, moderate, or severe felt over the past 24 hours.
5.9
Additional Research Collection
Additional research collections and retention are mandatory for all subjects, except where 
prohibited by local laws or regulations.
This protocol will include residual sample storage for additional research (AR).
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health 
authority requests for analysis, and the advancement of pharmacodiagnostic development to 
better target drugs to the right patients. This may also include genetic/genomic exploration aimed 
at exploring disease pathways, progression and response to treatment etc.
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study Sponsor’s senior leaders in Research and Development to ensure the 
research supports appropriate and well-defined scientific research activities.

Residual plasma and serum samples from exploratory biomarker collections (see Table 5.6-1
and Table 5.9-1) will be retained for additional research purposes

Samples will be securely stored by the BMS Biorepository in Hopewell, NJ or at a BMS 
approved third party storage management facility

Samples will be stored in a coded fashion; and no researcher will have access to the key, 
which is securely held at the clinical site, so that there is no direct ability for a researcher to 
connect a sample to a specific individual

Additional research samples will be retained for 15 years or the maximum allowed by 
applicable law. No additional sampling is required for residual collections
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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Table 5.9-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be retained
Plasma exploratory biomarker
All
Serum exploratory biomarker
All
Urine
All
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and 
FDA Code of Federal Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect
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
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See 
Section 6.1.1 for reporting pregnancies).
Worsening heart failure, including hospital readmission is considered an SAE and should be 
reported as such.
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies:

a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 30 days of discontinuation of dosing.
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The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to Sponsor 
or designee within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the electronic case report form 
(eCRF). The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning. In this case, the paper forms are to be transmitted via 
email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission,
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact: (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to Sponsor or 
designee using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
BMS will be reporting adverse events to regulatory authorities and ethics committees according 
to local applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious Adverse 
Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities and 
investigators following local and global guidelines and requirements.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug and 
continue through Hour 120.
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AEs will be collected from Hour 0 to Hour 120. If a subject is discharged prior to Hour 120, the 
site is asked to follow-up with the subject at Hour 120 to complete AE collection.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic).
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE 
eCRF page or SAE Report Form electronic) as appropriate. Paper forms are only intended as a 
back-up option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the Sponsor or 
designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). Please call the Sponsor or designee within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours of awareness of 
the event and in accordance with SAE reporting procedures described in Section 6.1.1.
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for BMS to collect any pregnancy surveillance information from 
the female partner, the female partner must sign an informed consent form for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
6.5
Overdose
Include any project specific definition of overdose in addition to the following mandatory 
statement as the last sentence:
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 intravenous 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 heart failure 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 heart failure subjects. If marked hypotension occurs, appropriate treatment, 
including intravenous pressor agents may be required to support blood pressure. All occurrences 
of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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Potential drug induced liver injury is defined as:
Aminotransaminases (ALT or AST) elevation > 3 times upper limit of normal (ULN) if baseline 
values are within the normal range, or > 2 times the baseline values in case of baseline values 
above the upper limit of normal (ULN) AND Total bilirubin > 2 times ULN, without initial 
findings of cholestasis (elevated serum alkaline phosphatase)
AND No other immediately apparent possible causes of aminotransaminases (AT) elevation and 
hyperbilirubinemia, including, but not limited to, worsening heart failure, viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other drug(s), herbal medications 
or substances known to be hepatotoxic
Given the short treatment course, baseline liver enzyme testing will be performed at Pre-
randomization and post-treatment liver enzyme testing will be performed at Hour 120 and Day 
32.
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.1.1 for reporting details).
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Data Monitoring Committee
An independent DMC will review safety data to ensure subjects safety. The full role of the DMC 
will be defined in the DMC charter. The DMC will review unblinded accumulating data on a 
regular basis and make recommendations to BMS and the Executive Committee regarding 
subjects currently enrolled and yet to be enrolled in the trial. The DMC may recommend 
suspension of enrolment or early termination of the trial, for safety reasons. See Section 8.5 for 
additional information.
The DMC will consider available endpoint information, in addition to safety events, before 
making any study stopping recommendations to the Executive Committee and Sponsor, as per 
guidelines set forth in the DMC charter.
7.2
Executive Committee
The executive committee will be a small body comprised of academic leaders. The executive 
committee will provide advice on overall design, study endpoints and recommendations for 
study sites, and will review results from interim and final analyses with Sponsor.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
For Part I (Cohort 1), approximately 50 subjects per group will be randomized to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min). Under a sample decision rule 
(eg, observed doubling with more than a 4% difference) and assuming clinically relevant 
hypotension incidences of 5% or 10% in the placebo group, the posterior probabilities of 
detecting an increase of 4-fold or 3-fold in incidence, respectively, are 86% and 80%, 
respectively. If there is no increase in clinically relevant hypotension, then the posterior 
probabilities of falsely detecting an increase are 11-12%.
For Part II (Cohort 2), approximately 70 subjects per group will be randomized to placebo or one 
of the two active dose levels of BMS-986231. Under a sample decision rule (eg, observed 
1.8-fold increase with more than a 3% difference) and assuming clinically relevant hypotension 
incidences of 5% or 10% in the placebo group, the posterior probabilities of detecting an increase 
of 3-fold or 2.5-fold in incidence, respectively, are 82% and 80%, respectively. If there is no 
increase in clinically relevant hypotension, then the posterior probabilities of falsely detecting an 
increase are 13-15%. These probabilities do not reflect multiple comparison.
While the enrollment in the main study protocol will continue until 210 patients have been 
randomized globally in Part II (Cohort 2), enrollment may continue further only in Japan until 
approximately 18 total Japanese subjects are randomized
With regards to overall performance for selection of a maximally tolerated dose, a sample size of 
50 per group for Part I (Cohort 1), along with 70 per group for Part II (Cohort 2) will identify a 
maximally tolerated dose approximately 50-70%, based on detecting an increase of 3-fold or 
2.5-fold in incidence, and using sample decision rules that are consistent with above. Also, the
design will provide an option to select a titrated 12 μg/kg/min dose approximately 60% of the 
time when that dose is tolerated, but a non-titrated 12 μg/kg/min dose is not tolerated. 
Conversely, the study design will not identify a maximally tolerated dose from Part II (Cohort 2) 
approximately 80%-85% of the time when no maximally tolerated dose exists
8.2
Populations for Analyses

The Enrolled Subjects Data Set will consist of all subjects who sign informed consent

The Randomized Subjects Data Set will consist of all randomized subjects who have started 
study drug infusion. This is also known as the Intent to Treat (ITT) population. Data in this 
data set will be analyzed based on randomized treatment group

The Treated Subjects Data Set will consist of all subjects who receive any study drug 
infusion. This will be the primary safety data set. Data in this data set will be analyzed based 
on randomized treatment, except in the following cases:
o
If a subject received the same incorrect treatment throughout the 48 hours study drug 
infusion or until discontinuation of the study drug, then the subject will be analyzed 
based on the treatment received
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o
If a subject received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
subject will be analyzed based on the first treatment received

The Pharmacokinetic analysis dataset will consist of all subjects who receive BMS-986231 
and have at least one post dose PK sample
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint is the incidence of clinically relevant hypotension, defined by SBP 
< 90 mm Hg (confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up to 
6 hours after the end of study drug infusion.
8.3.2
Secondary Endpoints

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes 
first), and at Day 32

Change in patient-reported resting dyspnea from baseline through Hour 72, as measured by 
the area under the curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at
baseline, and Hours 6, 12, 24, 48, and 72
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3.4
Safety Endpoints.
Safety endpoints consist of the following:

The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion

The incidence of SBP < 90 mm Hg (confirmed by a repeated value)

Change in Troponin T from baseline to Hour 24, 48, and 72

Percentage of subjects who have died (all- cause and CV related) 
Additionally, the percentage of subjects with discontinuation due to symptomatic hypotension, as
well as percentage of subjects with down-titrations, interruptions or discontinuations as a result 
of low blood pressure, either protocol specified clinically relevant hypotension, or asymptomatic 
decreases will be assessed. Other safety endpoints include the incidence of Adverse Events and 
Marked Laboratory Abnormalities, changes from baseline in vital signs, ECGs, physical 
measurements and laboratory assessments through Hour 120 or discharge, whichever comes 
first. The incidence of Serious Adverse Events will be assessed though Day 32.
8.4
Analyses
Results from Part I (Cohort 1) and Part II (Cohort 2) will be presented separately.
Subjects in Japan who started treatment after last patient randomization date of subjects who 
were enrolled before closure of the 210 subject global enrollment will not be part of the main 
global part II Day 32 interim analysis or the main global part II Day 182 analysis. Details will be 
provided in the statistical analysis plan
For analyses involving baseline, the baseline value is defined by the last value prior to the start of 
infusion, unless otherwise noted.
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8.4.1
Demographics and Baseline Characteristics
Frequency distributions and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined. Demographic variables to be 
summarized include: age, gender, race, and geographic region.
Baseline variables to be summarized include physical measurements (height, body weight, body 
mass index), vital signs (systolic blood pressure, diastolic blood pressure, and heart rate), disease 
characteristics (New York Heart Association Class prior to admission, ejection fraction, heart 
failure etiology, number of heart failure hospitalizations in past year, time since original HF 
diagnosis and since first diuretic use in the current episode of decompensation to first treatment, 
commorbities, including history of coronary artery disease, hypertension, or diabetes, and 
presence of atrial fibrillation), important laboratory variables (including NT-proBNP, serum 
sodium and eGFR), and current heart failure medications.
8.4.2
Primary, Secondary, and Exploratory Endpoints Analyses
8.4.2.1
Primary Endpoint Analysis
The incidence of clinically relevant hypotension from the start to 6 hours after the end of study 
drug infusion will be summarized by treatment. Point estimates and 95% CIs for event rates will 
be presented by treatment, together with point estimates and 95% CIs for the risk difference and 
relative risk between each BMS-986231 arm and placebo.
8.4.2.2
Secondary Endpoint Analyses
NT-proBNP will be summarized descriptively by treatment for each time point, as well as 
change from baseline.
Analyses for changes from baseline in the resting dyspnea as measured by the 11-point NRS will 
be done using a longitudinal repeated measures model, with baseline value and region as 
covariates. A trapezoidal rule will be applied to calculate AUC using model-estimated values 
from the time points. Missing values for the dyspnea NRS will not be imputed, except if a NRS 
cannot be obtained because the subject has died or is physically unable to complete the form. In 
these cases, a worst score imputation will be used for that time point. 
 
 
 
 
 
n 
 
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8.4.3
Safety Analyses
Troponin T will be summarized descriptively by treatment for each time point, as well as change 
from baseline.
Percentage of subjects who have died (all- cause and CV related) will be summarized 
descriptively by treatment.
All recorded adverse events 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.
Percentage of subjects with discontinuations due to symptomatic hypotension, as well as 
percentage of subjects with down-titrations or interruptions or discontinuations as a result of 
hypotension, either protocol specified clinically relevant hypotension, or asymptomatic decreases 
will be summarized descriptively by treatment.
In addition, the final infusion dose at the completion of 48 hours infusion will be summarized 
descriptively by treatment. The subjects who discontinued prematurely from infusion would be 
counted as having a final infusion dose of 0 g/kg/min. 
8.4.4
Pharmacokinetic Analyses
Blood samples will be collected from all subjects at 0.75, 4, 8, 14, and 48 hours during infusion 
and 4 hours after end of infusion and plasma concentrations will be measured using LC-MS. 
Pharmacokinetic parameters for BMS-986231 and BMT-284730 and other metabolites 
(eg, BMT-279554 & CAR-000463) will be estimated as appropriate. The plasma concentration 
may also be used to conduct population pharmacokinetic analysis and exposure-response 
analysis with select efficacy and safety endpoints. Results of the population pharmacokinetic and 
exposure-response analysis will be reported in a separate report.
 
 
 
 
 
 
8.4.6
Outcomes Research Analyses
Healthcare utilization is defined as the percentage of subjects with rehospitalizations and 
emergency department visits will be summarized descriptively by treatment group for HF or 
other cardiovascular disease separately.
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8.4.7
Other Analyses
Not applicable.
8.5
Interim Analyses
Two interim analyses will be performed for this study. An interim analysis will be performed 
following the completion of the last visit at Hour 120 in Part I (Cohort 1). The analysis will 
include data for all Cohort 1 subjects through at least Hour 120. The DMC, Executive 
Committee and representatives from the Sponsor will assess hypotension, as well as additional 
safety information, in addition to any available endpoint events. The outcome will determine 
whether 12 μg/kg/min is a sufficiently tolerated dose to be used in Part II (Cohort 2). The dose 
selection decision for Part II will be made by the Sponsor in collaboration with the Executive 
Committee, with input from the DMC. The doses for Part II (Cohort 2) will be determined based 
on general guiding principles and considered in the context of the totality of the data. For 
example, some of the critical information that will be considered evaluating the suitability 12 
μg/kg/min for Part II will include the percentage of subjects completing the 48 hour infusion, 
percentage of subjects with temporary interruptions or permanent discontinuation of study drug, 
percentage of subjects with clinically relevant hypotension, percentage of subjects with 
symptomatic hypotension, and other key safety endpoints of interest (eg, renal function). 
The second interim analysis will be performed when 210 randomized subjects reach the last visit 
at Day 32 in Part II (Cohort 2) in order to facilitate drug development decisions. The study 
analysis team will then provide top-line results to the project team.
After each DMC review, the Sponsor will be advised by the DMC Chair as to whether the study 
is safe to proceed as written, that the study should be modified, or that the study should be 
stopped. In addition to these periodic reviews, the DMC will review the unblinded data from Part 
I in parallel with the review by the executive committee and the Sponsor. A similar 
recommendation will be provided to the Sponsor, that the study is to proceed as written, or 
should be modified or stopped.  
Analyses will consist of summaries of the available data. No formal inferences requiring any 
adjustment to statistical significance level will be performed
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. If a deviation or change to a protocol is implemented to eliminate an 
immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the deviation or 
change will be submitted as soon as possible to:

IRB/IEC 
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
Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
In addition, the study may be evaluated by BMS or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS or designee.
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original.
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9.2
Records
9.2.1
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 or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee.
9.2.2
Study Drug Records 
Records for IP and Non-IMP (whether supplied by BMS, its vendors, or the site) must 
substantiate IP integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If...
Then...
Supplied by BMS (or its vendors):
Records or logs must comply with applicable regulations and guidelines 
and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique 
subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

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.
These records should include:

label identification number or batch number 

amount dispensed to and returned by each subject, including unique 
subject identifiers

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
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BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which 
will be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor of designee.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a subinvestigator and who is delegated this task on 
the Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF 
approval task. For electronic CRFs, review and approval/signature is completed electronically 
through the BMS, or designee, electronic data capture tool. The investigator must retain a copy 
of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to 
other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report.
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator

Study Steering Committee chair or their designee
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
Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
BMS or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. This also means that 
abstinence is the preferred and usual lifestyle of the patient. This does not mean 
periodic abstinence (eg, calendar, ovulation, symptothermal, profession of abstinence 
for entry into a clinical trial, post-ovulation methods) and withdrawal, which are not 
acceptable methods of contraception. Women must continue to have pregnancy tests.
Acceptable alternate methods of highly or less effective contraception’s must be 
discussed in the event that the subject chooses to forego complete abstinence.
Presentation
First dose of IV diuretic for the current episode
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11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ADHF
acute decompensated heart failure
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AT
Aminotransaminases
AUC
area under the concentration-time curve
BiPAP
bilevel positive airway pressure
BMS
Bristol-Myers Squibb
BNP
brain natriuretic peptide
BP
blood pressure
bpm
Beats per minute
BUN
blood urea nitrogen
C
Celsius
CCU
coronary care unit
CFR
Code of Federal Regulations 
CI
cardiac index
CPAP
continuous positive airway pressure
CRF
Case Report Form, paper or electronic
CVA
cerebral vascular accident
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
ESR
Expedited Safety Report
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
H
Hour
HF
heart failure
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Term
Definition
HFrEF
heart failure with reduced ejection fraction
HNO
Nitroxyl
HRT
hormone replacement therapy
Hs
high sensitivity
IABP
Intra-Aortic Balloon Pump 
ICH
International Conference on Harmonisation 
ICU
intensive care unit
Ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
K3EDTA
potassium ethylenediaminetetraacetic acid
Kg
Kilogram
LVEF
left ventricular ejection fraction
mg
Milligram
min
Minute
Mm Hg
millimeters of mercury
MS
mass spectrometry
MUGA
multigated acquisition
g
Microgram
Na+
Sodium
NIMP
non-investigational medicinal products 
NO
nitric oxide
NRS
numerical rating scale
NT-proBNP
N-terminal prohormone of brain natriuretic peptide
PADP
Pulmonary Artery Diastolic Pressure
PC
peripheral capillary wedge pressure
PDE3
phosphodiesterase 3
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Term
Definition
PDE5
phosphodiesterase type 5
PK
pharmacokinetics
PT
prothrombin time
PTT
partial thromboplastin time
RBC
red blood cell
SAE
serious adverse event
TIA
transient ischemic attack
WOCBP
women of childbearing potential
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APPENDIX 1
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels.

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH level
is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
At a minimum, subjects must agree to use one highly effective method of contraception as listed 
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use 
one of the highly effective methods of contraception listed below. Male subjects must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as follows:
1. Nonhormonal IUDs, such as ParaGard
2. Bilateral tubal occlusion
3. Vasectomised partner with documented azoospermia 90 days after procedure
a.
Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success
4. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual 
intercourse (refer to Glossary of Terms)
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b. Complete abstinence is an acceptable form of contraception for all study drugs and 
must be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days)
c.
It is not necessary to use any other method of contraception when complete 
abstinence is elected
d. Subjects who choose complete abstinence must continue to have pregnancy tests, 
as specified in Section 5
e.
Acceptable alternate methods of highly effective contraception must be discussed 
in the event that the subject chooses to forego complete abstinence
f.
The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject
UNACCEPTABLE METHODS OF CONTRACEPTION
A. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
B. Withdrawal (coitus interruptus)
C. Spermicide only
D. Lactation amenorrhea method (LAM)
E. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
F. Withdrawal (coitus interruptus)
G. Spermicide only
H. Lactation amenorrhea method (LAM)
I.
Progestogen only hormonal contraception associated with inhibition of ovulation or where 
inhibition of ovulation is not the primary mode of action
J.
Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena
K. Intrauterine hormone-releasing system (IUS)
L. Diaphragm with spermicide
M. Cervical cap with spermicide
N. Vaginal sponge with spermicide
O. Male or female condom with or without spermicide*
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APPENDIX 2
CORE AND EXTENDED ADME GENE LIST
Core ADME Gene List:
Gene 
Symbol
Full Gene Name
Class
ABCB1
ATP-binding cassette, sub-family B (MDR/TAP), member 1
Transporter
ABCC2
ATP-binding cassette, sub-family C (CFTR/MRP), member 2
Transporter
ABCG2
ATP-binding cassette, sub-family G (WHITE), member 2
Transporter
CYP1A1
cytochrome P450, family 1, subfamily A, polypeptide 1
Phase I
CYP1A2
cytochrome P450, family 1, subfamily A, polypeptide 2
Phase I
CYP2A6
cytochrome P450, family 2, subfamily A, polypeptide 6
Phase I
CYP2B6
cytochrome P450, family 2, subfamily B, polypeptide 6
Phase I
CYP2C19
cytochrome P450, family 2, subfamily C, polypeptide 19
Phase I
CYP2C8
cytochrome P450, family 2, subfamily C, polypeptide 8
Phase I
CYP2C9
cytochrome P450, family 2, subfamily C, polypeptide 9
Phase I
CYP2D6
cytochrome P450, family 2, subfamily D, polypeptide 6
Phase I
CYP2E1
cytochrome P450, family 2, subfamily E, polypeptide 1
Phase I
CYP3A4
cytochrome P450, family 3, subfamily A, polypeptide 4
Phase I
CYP3A5
cytochrome P450, family 3, subfamily A, polypeptide 5
Phase I
DPYD
dihydropyrimidine dehydrogenase
Phase I
GSTM1
glutathione S-transferase M1
Phase II
GSTP1
glutathione S-transferase pi
Phase II
GSTT1
glutathione S-transferase theta 1
Phase II
NAT1
N-acetyltransferase 1 (arylamine N-acetyltransferase)
Phase II
NAT2
N-acetyltransferase 2 (arylamine N-acetyltransferase)
Phase II
SLC15A2
solute carrier family 15 (H+/peptide transporter), member 2
Transporter
SLC22A1
solute carrier family 22 (organic cation transporter), member 1
Transporter
SLC22A2
solute carrier family 22 (organic cation transporter), member 2
Transporter
SLC22A6
solute carrier family 22 (organic anion transporter), member 6
Transporter
SLCO1B1
solute carrier organic anion transporter family, member 1B1
Transporter
SLCO1B3
solute carrier organic anion transporter family, member 1B3
Transporter
SULT1A1
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1
Phase II
TPMT
thiopurine S-methyltransferase,
Phase II
UGT1A1
UDP glucuronosyltransferase 1 family, polypeptide A1
Phase II
UGT2B15
UDP glucuronosyltransferase 2 family, polypeptide B15
Phase II
UGT2B17
UDP glucuronosyltransferase 2 family, polypeptide B17
Phase II
UGT2B7
UDP glucuronosyltransferase 2 family, polypeptide B7
Phase II
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Extended ADME Gene List:
Gene 
Symbol
Full Gene Name
Class
ABCB8
ATP-binding cassette, sub-family B (MDR/TAP), member 8
Transporter
ABCC12
ATP-binding cassette, sub-family C (CFTR/MRP), member 12
Transporter
ABCC3
ATP-binding cassette, sub-family C (CFTR/MRP), member 3
Transporter
ABCC4
ATP-binding cassette, sub-family C (CFTR/MRP), member 4
Transporter
AHR
aryl hydrocarbon receptor
Modifier
ALDH4A1
aldehyde dehydrogenase 4 family, member A1
Phase I
ALDH5A1
aldehyde dehydrogenase 5 family, member A1
Phase I
ALDH6A1
aldehyde dehydrogenase 6 family, member A1
Phase I
CES1
carboxylesterase 1 (monocyte/macrophage serine esterase 1)
Phase I
CES2
carboxylesterase 2 (intestine, liver)
Phase I
CYP7A1
cytochrome P450, family 7, subfamily A, polypeptide 1
Phase I
EPHX1
epoxide hydrolase 1, microsomal (xenobiotic)
Phase I
FMO3
flavin containing monooxygenase 3
Phase I
GSTA1
glutathione S-transferase A1
Phase II
GSTA2
glutathione S-transferase A2
Phase II
GSTA3
glutathione S-transferase A3
Phase II
GSTA4
glutathione S-transferase A4
Phase II
GSTA5
glutathione S-transferase A5
Phase II
GSTM2
glutathione S-transferase M2 (muscle),glutathione S-transferase M4
Phase II
GSTM3
glutathione S-transferase M3 (brain)
Phase II
GSTM4
glutathione S-transferase M4
Phase II
GSTO1
glutathione S-transferase omega 1,glutathione S-transferase omega 
2
Phase II
GSTO2
glutathione S-transferase omega 2
Phase II
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Gene 
Symbol
Full Gene Name
Class
GSTT2
glutathione S-transferase theta 2
Phase II
SLC10A1
solute carrier family 10 (sodium/bile acid cotransporter family), 
member 1
Transporter
SLC15A1
solute carrier family 15 (oligopeptide transporter), member 1
Transporter
SLC22A11
solute carrier family 22 (organic anion/cation transporter), member 11
Transporter
SLC22A8
solute carrier family 22 (organic anion transporter), member 8
Transporter
SLC7A5
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 5
Transporter
SLCO1A2
solute carrier organic anion transporter family, member 1A2
Transporter
SLCO2B1
solute carrier organic anion transporter family, member 2B1
Transporter
SULT1A2
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 2
Phase II
SULT1A3
sulfotransferase family, cytosolic, 1A, phenol-preferring, member 3
Phase II
SULT1B1
sulfotransferase family, cytosolic, 1B, member 1
Phase II
UGT1A3
UDP glucuronosyltransferase 1 family, polypeptide A3
Phase II
UGT1A6
UDP glucuronosyltransferase 1 family, polypeptide A6
Phase II
UGT1A7
UDP glucuronosyltransferase 1 family, polypeptide A7
Phase II
UGT1A8
UDP glucuronosyltransferase 1 family, polypeptide A8
Phase II
UGT1A9
UDP glucuronosyltransferase 1 family, polypeptide A9
Phase II
UGT2A1
UDP glucuronosyltransferase 2 family, polypeptide A1
Phase II
UGT2B11
UDP glucuronosyltransferase 2 family, polypeptide B11
Phase II
UGT2B28
UDP glucuronosyltransferase 2 family, polypeptide B28
Phase II
UGT2B4
UDP glucuronosyltransferase 2 family, polypeptide B4
Phase II
ABCA1
ATP-binding cassette, sub-family A (ABC1), member 1
Transporter
ABCA4
ATP-binding cassette, sub-family A (ABC1), member 4
Transporter
ABCB11
ATP-binding cassette, sub-family B (MDR/TAP), member 11
Transporter
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Gene 
Symbol
Full Gene Name
Class
ABCB4
ATP-binding cassette, sub-family B (MDR/TAP), member 4
Transporter
ABCB5
ATP-binding cassette, sub-family B (MDR/TAP), member 5
Transporter
ABCB6
ATP-binding cassette, sub-family B (MDR/TAP), member 6
Transporter
ABCB7
ATP-binding cassette, sub-family B (MDR/TAP), member 7
Transporter
ABCC1
ATP-binding cassette, sub-family C (CFTR/MRP), member 1
Transporter
ABCC10
ATP-binding cassette, sub-family C (CFTR/MRP), member 10
Transporter
ABCC11
ATP-binding cassette, sub-family C (CFTR/MRP), member 11
Transporter
ABCC5
ATP-binding cassette, sub-family C (CFTR/MRP), member 5
Transporter
ABCC6
ATP-binding cassette, sub-family C (CFTR/MRP), member 6
Transporter
ABCC8
ATP-binding cassette, sub-family C (CFTR/MRP), member 8
Transporter
ABCC9
ATP-binding cassette, sub-family C (CFTR/MRP), member 9
Transporter
ABCG1
ATP-binding cassette, sub-family G (WHITE), member 1
Transporter
ADH1A
alcohol dehydrogenase 1A (class I), alpha polypeptide
Phase I
ADH1B
alcohol dehydrogenase IB (class I), beta polypeptide
Phase I
ADH1C
alcohol dehydrogenase 1C (class I), gamma polypeptide
Phase I
ADH4
alcohol dehydrogenase 4 (class II), pi polypeptide
Phase I
ADH5
alcohol dehydrogenase 5 (class III), chi polypeptide,methionyl 
aminopeptidase 1
Phase I
ADH6
alcohol dehydrogenase 6 (class V)
Phase I
ADH7
alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide
Phase I
ALDH1A1
aldehyde dehydrogenase 1 family, member A1
Phase I
ALDH1A2
aldehyde dehydrogenase 1 family, member A2
Phase I
ALDH1A3
aldehyde dehydrogenase 1 family, member A3
Phase I
ALDH1B1
aldehyde dehydrogenase 1 family, member B1
Phase I
Revised Protocol No.: 02c
Date: 24-Sep-2019
101
5.0
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
ALDH2
aldehyde dehydrogenase 2 family (mitochondrial)
Phase I
ALDH3A1
aldehyde dehydrogenase 3 family, memberA1
Phase I
ALDH3A2
aldehyde dehydrogenase 3 family, member A2
Phase I
ALDH3B1
aldehyde dehydrogenase 3 family, member B1
Phase I
ALDH3B2
aldehyde dehydrogenase 3 family, member B2
Phase I
ALDH7A1
aldehyde dehydrogenase 7 family, member A1
Phase I
ALDH8A1
aldehyde dehydrogenase 8 family, member A1
Phase I
ALDH9A1
aldehyde dehydrogenase 9 family, member A1
Phase I
AOX1
aldehyde oxidase 1
Phase I
ARNT
aryl hydrocarbon receptor nuclear translocator
Modifier
CBR1
carbonyl reductase 1
Phase I
CBR3
carbonyl reductase 3
Phase I
CDA
cytidine deaminase
Modifier
CYB5R3
cytochrome b5 reductase 3
Phase I
CYP11A1
cytochrome P450, family 11, subfamily A, polypeptide 1
Phase I
CYP11B1
cytochrome P450, family 11, subfamily B, polypeptide 1
Phase I
CYP11B2
cytochrome P450, family 11, subfamily B, polypeptide 2
Phase I
CYP17A1
cytochrome P450, family 17, subfamily A, polypeptide 1
Phase I
CYP1B1
cytochrome P450, family 1, subfamily B, polypeptide 1
Phase I
CYP20A1
cytochrome P450, family 20, subfamily A, polypeptide 1
Phase I
CYP20A1
cytochrome P450, family 20, subfamily A, polypeptide 1
Phase I
CYP21A2
cytochrome P450, family 21, subfamily A, polypeptide 2
Phase I
CYP24A1
cytochrome P450, family 24, subfamily A, polypeptide 1
Phase I
Revised Protocol No.: 02c
Date: 24-Sep-2019
102
5.0
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
CYP26A1
cytochrome P450, family 26, subfamily A, polypeptide 1
Phase I
CYP27A1
cytochrome P450, family 27, subfamily A, polypeptide 1
Phase I
CYP2A13
cytochrome P450, family 2, subfamily A, polypeptide 13
Phase I
CYP2A7
cytochrome P450, family 2, subfamily A, polypeptide 7
Phase I
CYP2C18
cytochrome P450, family 2, subfamily C, polypeptide 18
Phase I
CYP2F1
cytochrome P450, family 2, subfamily F, polypeptide 1
Phase I
CYP2J2
cytochrome P450, family 2, subfamily J, polypeptide 2
Phase I
CYP39A1
cytochrome P450, family 39, subfamily A, polypeptide 1
Phase I
CYP3A43
cytochrome P450, family 3, subfamily A, polypeptide 43
Phase I
CYP3A7
cytochrome P450, family 3, subfamily A, polypeptide 7
Phase I
CYP4B1
cytochrome P450, family 4, subfamily B, polypeptide 1
Phase I
CYP4F11
cytochrome P450, family 4, subfamily F, polypeptide 11
Phase I
CYP51A1
cytochrome P450, family 51, subfamily A, polypeptide 1
Phase I
EPHX2
epoxide hydrolase 2, cytoplasmic
Phase I
FMO1
flavin containing monooxygenase 1
Phase I
FMO2
flavin containing monooxygenase 2
Phase I
FMO4
flavin containing monooxygenase 4
Phase I
FMO5
flavin containing monooxygenase 5
Phase I
GPX2
glutathione peroxidase 2 (gastrointestinal)
Phase I
GPX3
glutathione peroxidase 3 (plasma)
Phase I
GPX7
glutathione peroxidase 7
Phase I
GSR
glutathione reductase
Phase I
GSTK1
glutathione S-transferase kappa 1
Phase II
Revised Protocol No.: 02c
Date: 24-Sep-2019
103
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
GSTM5
glutathione S-transferase M5
Phase II
GSTZ1
glutathione transferase zeta 1 (maleylacetoacetate isomerase)
Phase II
NNMT
nicotinamide N-methyltransferase
Phase II
NR1I2
nuclear receptor subfamily 1, group I, member 2
Modifier
NR1I3
nuclear receptor subfamily 1, group I, member 3
Modifier
PNMT
phenylethanolamine N-methyltransferase
Phase II
PON1
paraoxonase 1
Phase I
PON2
paraoxonase 2
Phase I
PON3
paraoxonase 3
Phase I
POR
P450 (cytochrome) oxidoreductase
Modifier
PPARD
peroxisome proliferative activated receptor, delta
Modifier
PPARG
peroxisome proliferative activated receptor, gamma
Modifier
RXRA
retinoid X receptor, alpha
Modifier
SLC10A2
solute carrier family 10 (sodium/bile acid cotransporter family), 
member 2
Transporter
SLC13A1
solute carrier family 13 (sodium/sulfate symporters), member 1
Transporter
SLC13A2
solute carrier family 13 (sodium-dependent dicarboxylate 
transporter), member 2
Transporter
SLC13A3
solute carrier family 13 (sodium-dependent dicarboxylate 
transporter), member 3
Transporter
SLC16A1
solute carrier family 16 (monocarboxylic acid Transporter), member 1
Transporter
SLC19A1
solute carrier family 19 (folate transporter), member 1
Transporter
SLC22A10
solute carrier family 22 (organic anion/cation transporter), member 10
Transporter
SLC22A12
solute carrier family 22 (organic anion/cation transporter), member 12
Transporter
SLC22A13
solute carrier family 22 (organic cation transporter), member 13
Transporter
SLC22A14
solute carrier family 22 (organic cation transporter), member 14
Transporter
Revised Protocol No.: 02c
Date: 24-Sep-2019
104
5.0
Approved
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4.0
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
SLC22A15
solute carrier family 22 (organic cation transporter), member 15
Transporter
SLC22A16
solute carrier family 22 (organic cation transporter), member 16
Transporter
SLC22A17
solute carrier family 22 (organic cation transporter), member 17
Transporter
SLC22A18
solute carrier family 22 (organic cation transporter), member 18
Transporter
SLC22A18AS
solute carrier family 22 (organic cation transporter), member 18 
antisense
Transporter
SLC22A3
solute carrier family 22 (extraneuronal monoamine transporter), 
member 3
Transporter
SLC22A4
solute carrier family 22 (organic cation transporter), member 4
Transporter
SLC22A5
solute carrier family 22 (organic cation transporter), member 5
Transporter
SLC22A7
solute carrier family 22 (organic anion transporter), member 7
Transporter
SLC22A9
solute carrier family 22 (organic anion/cation transporter), member 9
Transporter
SLC27A1
solute carrier family 27 (fatty acid transporter), member 1
Transporter
SLC28A1
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 1
Transporter
SLC28A2
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 2
Transporter
SLC28A3
solute carrier family 28 (sodium-coupled nucleoside transporter), 
member 3
Transporter
SLC29A1
solute carrier family 29 (nucleoside Transporter), member 1
Transporter
SLC29A2
solute carrier family 29 (nucleoside Transporter), member 2
Transporter
SLC2A4
solute carrier family 2 (facilitated glucose transporter), member 4
Transporter
SLC2A5
solute carrier family 2 (facilitated glucose/fructose transporter), 
member 5
Transporter
SLC5A6
solute carrier family 5 (sodium-dependent vitamin transporter)
Transporter
SLC6A6
solute carrier family 6 (neurotransmitter transporter, taurine), member 
6
Transporter
SLC7A8
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 8
Transporter
SLCO1C1
solute carrier organic anion transporter family, member 1C1
Transporter
SLCO2A1
solute carrier organic anion transporter family, member 2A1
Transporter
Revised Protocol No.: 02c
Date: 24-Sep-2019
105
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
SLCO3A1
solute carrier organic anion transporter family, member 3A1
Transporter
SLCO4A1
solute carrier organic anion transporter family, member 4A1
Transporter
SLCO4C1
solute carrier organic anion transporter family, member 4C1
Transporter
SLCO5A1
solute carrier organic anion transporter family, member 5A1
Transporter
SLCO6A1
solute carrier organic anion transporter family, member 6A1
Transporter
SULT1C1
sulfotransferase family, cytosolic, 1C, member 1
Phase II
SULT1C2
sulfotransferase family, cytosolic, 1C, member 2
Phase II
SULT1E1
sulfotransferase family 1E, estrogen-preferring, member 1
Phase II
SULT2A1
sulfotransferase family, cytosolic, 2A, DHEA preferring, member 1
Phase II
SULT2B1
sulfotransferase family, cytosolic, 2B, member 1
Phase II
TAP1
transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)
Transporter
UGT1A10
UDP glucuronosyltransferase 1 family, polypeptide A10
Phase II
UGT1A4
UDP glucuronosyltransferase 1 family, polypeptide A4
Phase II
UGT1A5
UDP glucuronosyltransferase 1 family, polypeptide A5
Phase II
UGT2B10
UDP glucuronosyltransferase 2 family, polypeptide B10
Phase II
ABCC13
ATP-binding cassette, sub-family C (CFTR/MRP), member 13
Transporter
ARSA
arylsulfatase A
Modifier
CAT
catalase
Modifier
CHST8
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 8
Phase II
CYP19A1
cytochrome P450, family 19, subfamily A, polypeptide 1
Phase I
CYP26C1
cytochrome P450, family 26, subfamily C, polypeptide 1
Phase I
CYP27B1
cytochrome P450, family 27, subfamily B, polypeptide 1
Phase I
CYP2R1
cytochrome P450, family 2, subfamily R, polypeptide 1
Phase I
Revised Protocol No.: 02c
Date: 24-Sep-2019
106
5.0
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
CYP2S1
cytochrome P450, family 2, subfamily S, polypeptide 1
Phase I
CYP46A1
cytochrome P450, family 46, subfamily A, polypeptide 1
Phase I
CYP4A11
cytochrome P450, family 4, subfamily A, polypeptide 11
Phase I
CYP4F12
cytochrome P450, family 4, subfamily F, polypeptide 12
Phase I
CYP4F2
cytochrome P450, family 4, subfamily F, polypeptide 2
Phase I
CYP4F3
cytochrome P450, family 4, subfamily F, polypeptide 3
Phase I
CYP4F8
cytochrome P450, family 4, subfamily F, polypeptide 8
Phase I
CYP4Z1
cytochrome P450, family 4, subfamily Z, polypeptide 1
Phase I
CYP7B1
cytochrome P450, family 7, subfamily B, polypeptide 1
Phase I
CYP8B1
cytochrome P450, family 8, subfamily B, polypeptide 1
Phase I
DHRS13
dehydrogenase/reductase (SDR family) member 13
Phase I
DHRS2
dehydrogenase/reductase (SDR family) member 2
Phase I
GPX1
glutathione peroxidase 1
Phase I
GPX4
glutathione peroxidase 4 (phospholipid hydroperoxidase)
Phase I
GPX5
glutathione peroxidase 5 (epididymal androgen-related protein)
Phase I
GPX6
glutathione peroxidase 6 (olfactory)
Phase I
GSS
glutathione synthetase
Phase I
GSTCD
glutathione S-transferase, C-terminal domain containing
Phase II
HNF4A
hepatocyte nuclear factor 4, alpha
Modifier
HNMT
histamine N-methyltransferase
Phase II
HSD11B1
hydroxysteroid (17-beta) dehydrogenase 11
Phase I
HSD17B11
hydroxysteroid (17-beta) dehydrogenase 11
Phase I
HSD17B14
hydroxysteroid (17-beta) dehydrogenase 14
Phase I
Revised Protocol No.: 02c
Date: 24-Sep-2019
107
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
LOC731356
similar to dehydrogenase/reductase (SDR family) member 4 like 2
Phase I
MGST1
microsomal glutathione S-transferase 1
Phase II
MGST2
microsomal glutathione S-transferase 2
Phase II
MGST3
microsomal glutathione S-transferase 3
Phase II
MPO
myeloperoxidase
Modifier
NOS1
nitric oxide synthase 1 (neuronal)
Phase I
NOS2A
nitric oxide synthase 2A (inducible, hepatocytes)
Phase I
NOS3
nitric oxide synthase 3 (endothelial cell)
Phase I
PPARA
peroxisome proliferator-activated receptor alpha
Modifier
SERPINA7
serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, 
antitrypsin), member 7
Modifier
SLC7A7
solute carrier family 7 (cationic amino acid transporter, y+ system), 
member 7
Transporter
SOD1
superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 
(adult))
Modifier
SOD2
superoxide dismutase 2, mitochondrial
Modifier
SOD3
superoxide dismutase 3, extracellular precursor
Modifier
SULF1
sulfatase 1
Phase I
SULT4A1
sulfotransferase family 4A, member 1
Phase II
TAP2
transporter 2, ATP-binding cassette, sub-family B (MDR/TAP)
Transporter
UGT8
UDP glycosyltransferase 8 (UDP-galactose ceramide 
galactosyltransferase)
Phase II
XDH
xanthine dehydrogenase
Phase I
ADHFE1
alcohol dehydrogenase, iron containing, 1
Phase I
CHST1
carbohydrate (keratan sulfate Gal-6) sulfotransferase 1
Phase II
CHST10
carbohydrate sulfotransferase 10
Phase II
CHST11
carbohydrate (chondroitin 4) sulfotransferase 11
Phase II
Revised Protocol No.: 02c
Date: 24-Sep-2019
108
5.0
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
CHST12
carbohydrate (chondroitin 4) sulfotransferase 12
Phase II
CHST13
carbohydrate (chondroitin 4) sulfotransferase 13
Phase II
CHST2
carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2
Phase II
CHST3
carbohydrate (chondroitin 6) sulfotransferase 3
Phase II
CHST4
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 4
Phase II
CHST5
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 5
Phase II
CHST6
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 6
Phase II
CHST7
carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7
Phase II
CHST9
carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9
Phase II
CYP2D7P1
cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 1
Phase I
DDO
D-aspartate oxidase
Phase I
DHRS1
dehydrogenase/reductase (SDR family) member 1
Phase I
DHRS12
dehydrogenase/reductase (SDR family) member 12
Phase I
DHRS3
dehydrogenase/reductase (SDR family) member 3
Phase I
DHRS4
dehydrogenase/reductase (SDR family) member 4
Phase I
DHRS4L1
dehydrogenase/reductase (SDR family) member 4 like 1
Phase I
DHRS4L2
dehydrogenase/reductase (SDR family) member 4 like 2
Phase I
DHRS7
dehydrogenase/reductase (SDR family) member 7
Phase I
DHRS7B
dehydrogenase/reductase (SDR family) member 7B
Phase I
DHRS7C
dehydrogenase/reductase (SDR family) member 7C
Phase I
DHRS9
dehydrogenase/reductase (SDR family) member 9
Phase I
DHRSX
dehydrogenase/reductase (SDR family) X-linked
Phase I
DPEP1
dipeptidase 1 (renal)
Phase I
Revised Protocol No.: 02c
Date: 24-Sep-2019
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Clinical Protocol
CV013011
BMS-986231
HNO donor
Gene 
Symbol
Full Gene Name
Class
FMO6P
flavin containing monooxygenase 6
Phase I
HAGH
hydroxyacylglutathione hydrolase
Phase I
IAPP
islet amyloid polypeptide
Modifier
KCNJ11
potassium inwardly-rectifying channel, subfamily J, member 11
Modifier
LOC728667
similar to dehydrogenase/reductase (SDR family) member 2 isoform 
1
Phase I
LOC731931
similar to dehydrogenase/reductase (SDR family) member 2 isoform 
1
Phase I
MAT1A
methionine adenosyltransferase I, alpha
Modifier
METAP1
methionyl aminopeptidase 1
Phase I
PDE3A
phosphodiesterase 3A, cGMP-inhibited
Phase I
PDE3B
phosphodiesterase 3B, cGMP-inhibited
Phase I
PLGLB1
plasminogen-like B1
Phase I
ATP7A
ATPase, Cu++ transporting, alpha polypeptide (Menkes syndrome)
Modifier
ATP7B
ATPase, Cu++ transporting, beta polypeptide
Modifier
CFTR
cystic fibrosis transmembrane conductance regulator 
Modifier
Revised Protocol No.: 02c
Date: 24-Sep-2019
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CV013011
BMS-986231
HNO donor
APPENDIX 3
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 02b, 30-May-2019
The below changes are due to a DMC recommendation to increase oversight of patients at the 
initiation of the infusion.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02B
Section 
Number & 
Title
Description of Change
Brief Rationale
Table 5.1-2: 
Treatment and
In-Hospital 
Follow-up 
(CV013011)
Additional Blood Pressure and 
Heart Rate Measurements at: 15 
minutes, 45 minutes, and 1.5 
hours.  
Section 5.3.1: 
Assessment of 
Blood 
Pressure and 
Symptoms for 
Hypotension
Clarification that blood pressure 
measurements within 5 min in 
the first hour, then 15 min of the 
specified timepoints in 
Table 5.1-2. 
Overall Rationale for the Revised Protocol 02a, 13-Mar-2019
These changes serve to clarify the milestone, timing of enrollment and inclusion/exclusion criteria 
of the Japanese population. While the enrollment in the main study protocol will continue until 
210 patients have been randomized globally in Part II (Cohort 2), enrollment in Japan may continue 
further only in Japan until approximately 18 total Japanese subjects are randomized.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02A
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 3.1: 
Study Design 
and Duration; 
Synopsis
Section modified to add: while the 
enrollment in the main study 
protocol will continue until 210 
patients have been randomized 
globally in Part II (Cohort 2), 
enrollment in Japan may continue 
further only in Japan until 
approximately 18 total Japanese 
subjects are randomized. 
Revised Protocol No.: 02c
Date: 24-Sep-2019
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CV013011
BMS-986231
HNO donor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02A
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 3.3.1: 
Inclusion 
Criteria; 
Synopsis
Inclusion criteria # 2G) was 
modified to decrease the 
minimum allowable BNP levels 
from 400 pg/mL (116 pmol/L) 
to 350 pg/mL (101 pmol/L) and 
NT-proBNP levels from 
1600 pg/mL (189 pmol/L) to 
1400 pg/mL (166 pmol/L)
Section 3.3.1: 
Inclusion 
Criteria; 
Synopsis
Inclusion criteria # 2H) was 
modified to decrease the 
minimum allowable body weight 
from 50 kg to 40 kg
Section 3.3.2: 
Exclusion 
Criteria; 
Synopsis
Exclusion Criteria # 4D) was 
modified to: 
Subjects treated with oral 
phosphodiesterase type 5 (PDE5) 
inhibitor sildenafil, vardenafil or 
avanafil within 24 hours of 
screening or treated with tadalafil 
within 4 days of screening, oral 
inotropic agents (eg, pimobendan) 
or oral vasopressin V2 receptor 
antagonist (eg, tolvaptan) initiated 
for the current ADHF episode. 
NOTE: chronic use of tolvaptan is 
not exclusionary.
Section 4.6.2 
Other 
Blinding and 
Unblinding
Section was modified to include:
The second interim analysis will 
be performed when 210 
randomized subjects reach the last 
visit at Day 32 in Part II (Cohort 
2). The study analysis team will
then provide top-line results to the 
project team.
Revised Protocol No.: 02c
Date: 24-Sep-2019
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Clinical Protocol
CV013011
BMS-986231
HNO donor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02A
Section 
Number & 
Title
Description of Change
Brief Rationale
The follow-up to Day 182 for both 
Part I and Part II will be site-and-
subject blinded.
Japanese subjects enrolled as part 
of the 210 subject global cohort 
(Part II, Cohort 2) will be site-
and-subject blinded until the end 
of the study in Japan.
Section 8.1: 
Sample Size 
Determination
Section was modified to add: 
While the enrollment in the main 
study protocol will continue until 
210 patients have been 
randomized globally in Part II 
(Cohort 2), enrollment may 
continue further only in Japan 
until approximately 18 total 
Japanese subjects are randomized
Section 8.4: 
Analyses
Section was modified to add: 
Subjects in Japan who started 
treatment after last patient 
randomization date of subjects 
who were enrolled before closure 
of the 210 subject global 
enrollment will not be part of the 
main global Part II Day 32 interim 
analysis. Details will be provided 
in the statistical analysis plan
Section 8.5: 
Interim 
Analyses
Section was modified to add: 
The second interim analysis will 
be performed when 210 
randomized subjects reach the last 
visit at Day 32 in Part II (Cohort 
2) in order to facilitate drug 
development decisions. The study 
analysis team will then provide 
Revised Protocol No.: 02c
Date: 24-Sep-2019
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Clinical Protocol
CV013011
BMS-986231
HNO donor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02A
Section 
Number & 
Title
Description of Change
Brief Rationale
top-line results to the project 
team.
An additional interim analysis 
may be performed following 
completion of the last visit at Day 
32 of the last enrolled Japanese 
subject. 
Overall Rationale for the Revised Protocol 02, 09-Apr-2018
These changes serve to clarify procedures for Part II Cohort 2 of the study. Part I Cohort 1 of the 
study is not impacted. Changes include: 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Section 3.3.2 
Exclusion 
Criteria
Exclusion criteria # 2b was 
modified to clarify: 
Suspected acute lung disease (eg, 
pneumonia or asthma) or severe 
chronic lung disease (eg, severe 
chronic obstructive pulmonary 
disease, pulmonary fibrosis, 
patients with hypercapnia or 
requiring home oxygen therapy or 
chronic oral steroids.)
Revised Protocol No.: 02c
Date: 24-Sep-2019
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Clinical Protocol
CV013011
BMS-986231
HNO donor
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 02
Section 
Number & 
Title
Description of Change
Brief Rationale
Section 3.1 
Study Design 
and Duration
Changed to:
Study Medication infusion must 
start within 18 hours of 
presentation (or 48 hours in Part II 
Cohort 2 of the trial), with 
presentation defined as the first 
dose of diuretic for current 
episode
Section 5.1.2 
Treatment and 
In-Hospital 
Follow-up
Addition of window to collect 
vital signs within .25 hours of 
specified time points. 
All
Minor formatting and 
typographical corrections
Revised Protocol No.: 02c
Date: 24-Sep-2019
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SAP_001.pdf: 
Official Title of Study: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, 
Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of 
BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function 
 
NCT Number: NCT03016325 
Document Date (Date in which document was last revised): June 21, 2017 


STATISTICAL ANALYSIS PLAN
FOR
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-
Ranging, Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous 
Infusions of   BMS-986231 in Hospitalized Patients with Heart Failure and Impaired 
Systolic Function
PROTOCOL(S) CV013011
VERSION # 1
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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................2
2
STUDY DESCRIPTION ..........................................................................................6
2.1
Study Design ............................................................................................................6
2.2
Treatment Assignment..............................................................................................9
2.3
Blinding and Unblinding...........................................................................................9
2.4
Protocol Amendments.............................................................................................10
2.5
Data Monitoring Committee and Other External Committees .................................10
2.5.1
Data Monitoring Committee ...................................................................................10
2.5.2
Executive Committees.............................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary...................................................................................................................10
3.2
Secondary...............................................................................................................10
3.3
Safety.....................................................................................................................10
4
ENDPOINTS..........................................................................................................11
4.1
Efficacy Endpoints .................................................................................................11
4.1.1
Primary Efficacy Endpoint......................................................................................11
4.1.2
Secondary Efficacy Endpoints.................................................................................12
4.2
Safety Endpoints.....................................................................................................12
4.2.1
Primary Safety Endpoint.........................................................................................12
4.2.2
Other Safety Endpoints...........................................................................................12
5
SAMPLE SIZE AND POWER...............................................................................13
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................14
6.1
Study Periods..........................................................................................................14
6.2
Treatment Regimens...............................................................................................14
6.3
Populations for Analyses ........................................................................................14
7
STATISTICAL ANALYSES..................................................................................15
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7.1
General Methods ....................................................................................................15
7.2
Study Conduct........................................................................................................15
7.3
Study Population ....................................................................................................16
7.4
Extent of Exposure .................................................................................................17
7.5
Efficacy..................................................................................................................18
7.5.1
Primary Efficacy Analysis.......................................................................................18
7.5.2
Secondary Efficacy Analysis ...................................................................................18
7.6
Safety.....................................................................................................................19
7.6.1
Primary Safety Analysis..........................................................................................19
7.6.2
Other Safety Analyses.............................................................................................19
7.6.2.1
Deaths ....................................................................................................................19
7.6.2.2
Serious Adverse Events...........................................................................................19
7.6.2.3
Adverse Events .......................................................................................................20
7.6.2.4
Clinical Laboratory Evaluations.............................................................................21
7.6.2.5
ECG .......................................................................................................................24
7.6.2.6
Vital Signs ..............................................................................................................24
7.6.2.7
Physical Examination Findings...............................................................................24
7.6.2.8
Daily Urinary Output .............................................................................................25
7.6.2.9
Oxygen Saturation..................................................................................................25
7.7.1
7-Point Likert Scale................................................................................................25
7.7.2
Worsening Heart Failure and Worsening Renal Function.......................................25
7.7.3
Congestive Heart Failure .......................................................................................26
7.7.4
Sensory and Motor Function...................................................................................26
7.8
Pharmacokinetics....................................................................................................26
7.10
Outcomes Research ................................................................................................27
7.11
Interim Analyses.....................................................................................................27
8
CONVENTIONS....................................................................................................28
8.1
Safety Data Conventions.........................................................................................28
8.2
Baseline Measurements ..........................................................................................29
8.3
Hour Ranges for Analysis of Time Points ...............................................................29
8.4
Multiple Measurements ..........................................................................................30
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8.5
Pharmacokinetic Summaries...................................................................................31
9
CONTENT OF REPORTS .....................................................................................31
LIST OF TABLES
Table 7.3-1:
Demographics and Baseline Characteristics............................................16
Table 7.6.2.4-1:
Laboratory MA Criteria..........................................................................21
Table 8.3-1:
Hour Ranges for Analyses of  Dyspnea Measured by 11-point NRS 
and 7-point Likert Scale and PGA Measured by 7-point Likert 
Scale.......................................................................................................29
Table 8.3-2:
Hour Ranges for Analyses of  Laboratory Measurements........................29
Table 8.3-3:
Hour Ranges for Analyses of  ECG ........................................................30
Table 8.3-4:
Hour Ranges for Analyses of  Respiratory Rate and Temperature...........30
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2
STUDY DESCRIPTION
2.1
Study Design
This is a multi-center, randomized, placebo-controlled, double-blind study of continuous 48-hour 
intravenous (IV) infusions of BMS-986231 in hospitalized HFrEF subjects with ADHF. The trial 
was designed to identify the doses of BMS-986231 that are safe and tolerated with regard to 
clinically relevant hypotension. 
The study consists of 2 parts, each with a unique cohort of subjects. 
Subjects that are randomized in Part I of the study will not be allowed to participate in Part II. 
In Part I (Cohort 1) of the study, approximately 100 subjects will be randomized in a 1:1 ratio to 
placebo or an escalating dose of BMS-986231 (3 g/kg/min for 4 hours, then 6 g/kg/min for 
another 4 hours, then 12 g/kg/min for the remaining 40 hours). 
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In Part II (Cohort 2) of the study, the 2 highest planned doses of BMS-986231 in Cohort 1, BMS-
986231 6 g/kg/min and BMS-986231 12 g/kg/min, will be administered. Approximately 210 
subjects will be randomized in a 1:1:1 ratio to one of the 2 active doses of BMS-986231 or placebo.
If BMS-986231 12 g/kg/min is not considered to be a tolerated dose in Part I, then BMS-986231 
3 g/kg/min and BMS-986231 6 g/kg/min will be evaluated in Part II. In the event that neither 6 
g/kg/min nor 12 g/kg/min are tolerated, the protocol will require modification.
The study design schematic is presented in Figure 2.1-1 for Part I (Cohort 1) and Figure 2.1-2 for 
Part II (Cohort 2).
Figure 2.1-1: Study Design Schematic Part I (Cohort 1)
a Every effort should be made to initiate study drug administration promptly after randomization 
b Study Medication infusion must start within 18 hours of presentation, defined as the first dose of diuretic for 
current episode, but not within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours after 
the initiation or an increase in the dose of an IV  diuretic administered by continuous infusion
c Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital 
for at least 24 hours after the completion of the 48-hour infusion of study drug for safety monitoring
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Figure 2.1-2: Study Design Schematic Part II (Cohort 2)
a 3 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
b 6 µg/kg/min if 12 µg/kg/min is not tolerated in Part I
c Every effort should be made to initiate study drug administration promptly after randomization 
d Study Medication infusion must start within 18 hours of presentation, defined as the first dose of diuretic for current episode, but not 
within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or an increase in the dose of an IV  
diuretic administered by continuous infusion
e Discharge may occur as per standard medical practice. It is recommended that subjects remain in the hospital for at least 24 hours after 
the completion of the 48-hour infusion of study drug for safety monitoring.
Subjects must be randomized and treated within 18 hours of presentation, defined as the first dose 
of IV diuretic for the current episode of ADHF. In addition, subjects must not be randomized 
within 2 hours following an IV bolus dose of diuretic, or within 2 hours after the initiation or an 
increase in the dose of an IV diuretic administered by continuous infusion. It is recommended that 
subjects remain in the hospital for at least 24 hours after the completion of the 48-hour infusion of 
study drug for safety monitoring.
Every effort must be made to initiate study drug administration promptly after 
randomization.
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The inpatient period will end in conjunction with the final inpatient assessment at Hour 120 or 
discharge. All subjects will be followed for safety and rehospitalization endpoints through Day 32 
and mortality through Day 182.
The start of the trial is defined as the first subject screened. End of trial is defined as the last Day 
182 follow-up visit, or withdrawal date (for subjects who withdraw prematurely from the study) 
by any patient, whichever comes later.
2.2
Treatment Assignment
At the time of screening for both Part I (Cohort 1) and Part II (Cohort 2), each subject will be 
assigned a unique sequential subject number by interactive response technology (IRT). The IRT 
will be available 24 hours per day, 7 days a week. The subject number will consist of a unique 
5 digit number which is assigned sequentially within a study (starting with 00001) by the IRT. 
This number will be used for identification throughout the study and will not be used for any other 
subject. Subjects screened for Part I, (Cohort 1) will be assigned sequential study numbers 
beginning with 00001, and subjects screened for Part II, (Cohort 2) will be assigned sequential 
study numbers beginning with 10001.
Randomization schedules will be generated by BMS and kept by the IRT vendor. Subjects who 
meets the inclusion/exclusion criteria will be randomly assigned by the IRT to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min) in a 1:1 ratio for Part I (Cohort 1) and 
placebo or 1 of the 2 active dose levels of BMS-986231 in a 1:1:1 ratio for Part II (Cohort 2).
Randomization will be stratified by the following regions: North America, Europe, and Latin 
America (Argentina only).
2.3
Blinding and Unblinding
The Data Monitoring Committee (DMC; see Section 2.5.1) will assess safety on an ongoing basis, 
and will have access to unblinded treatment codes for individual subjects. An analysis team, 
including a reporting statistician and programming support, who are not involved with the conduct 
of the study, will provide analyses to the DMC.
Two interim analyses will be performed in this study (see section 7.11).
The first unblinded interim analysis will be performed by the analysis team at the completion of 
the last visit at Hour 120 in Part I (Cohort 1). This analysis will be reviewed by the DMC and will 
be reviewed in parallel and by the executive committee (see Section 2.5) and Sponsor 
representatives. The rationale for a fully unblinded review by the executive committee and Sponsor 
is to determine whether 12 μg/kg/min is an appropriate dose to study in Part II.
The second interim analysis will be performed following completion of the last visit at Day 32 in 
Part II (Cohort 2). The study analysis team will then provide top-line results to the project team.
The follow-up to Day 182 for both Part I and Part II will be site-and-subject blinded. 
In certain circumstances a pharmacokineticist or designates in Clinical Pharmacology and 
Pharmacometrics, biostatisticians and programmers at BMS, or designee, may be unblinded in 
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order to prepare preliminary summaries of pharmacokinetics (PK) and safety data, as needed. 
These summaries will not reveal individual subjects’ treatment assignments.
2.4
Protocol Amendments
This statistical analysis plan (SAP) is based on the revised protocol version 01 which incorporates 
Amendment 01, dated 11-Oct-2016.
2.5
Data Monitoring Committee and Other External Committees
2.5.1
Data Monitoring Committee
An independent DMC will review safety data to ensure safety of subjects in the trial. The full role 
of the DMC will be defined in a separate DMC charter. The DMC will review unblinded 
accumulating data on a regular basis and make recommendations to BMS and the Executive 
Committee regarding subjects currently enrolled and yet to be enrolled in the trial. The DMC may 
recommend suspension of enrolment or early termination of the trial for safety reasons. See Section 
7.11 for additional information.
The DMC will consider available endpoint information, in addition to safety events, before making 
any study stopping recommendations to the Executive Committee and Sponsor, as per guidelines 
set forth in the DMC charter.
2.5.2
Executive Committees
The executive committee will be a small body comprised of academic leaders. The executive 
committee will provide advice on overall design, study endpoints and recommendations for study 
sites, and will review results from interim and final analyses with Sponsor. 
3
OBJECTIVES
3.1
Primary
The primary objective is to evaluate the effects of various doses of BMS-986231 compared to 
placebo on clinically relevant hypotension (defined by SBP < 90 mm Hg or symptoms of 
hypotension)
3.2
Secondary
Secondary objectives include the following:

Assess the effect of BMS-986231 on NT-proBNP

Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 
11-point Numerical Rating Scale (NRS)
3.3
Safety
Safety objectives include the following:

Evaluate the effect of BMS-986231 on the incidence of symptomatic hypotension

Evaluate the effect of BMS-986231 on the incidence of SBP < 90 mm Hg
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
Evaluate the incidence of dose reductions, temporary interruptions, and permanent 
discontinuation of BMS-98623 infusions

Evaluate the safety and tolerability of a continuous 48-hour infusion of BMS-986231 in 
hospitalized HFrEF subjects with ADHF

Evaluate the effect of BMS-986231 on high sensitivity (Hs) Troponin T

Assess the effect of BMS-986231 on mortality at Day 182
 
 
 
 
 
 
 
 
 
 
 
4
ENDPOINTS
4.1
Efficacy Endpoints
4.1.1
Primary Efficacy Endpoint
There is no primary efficacy endpoint. The primary safety endpoint is discussed in Section 4.2.1.
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4.1.2
Secondary Efficacy Endpoints
Secondary endpoints include the following:

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes 
first), and at Day 32

Change in patient-reported resting dyspnea from baseline through Hour 72, as measured by the 
area under the curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at 
baseline, and Hours 6, 12, 24, 48, and 72
4.2
Safety Endpoints
4.2.1
Primary Safety Endpoint
The primary safety endpoint is the incidence of clinically relevant hypotension, defined by SBP 
< 90 mm Hg (confirmed by a repeated value < 90 mm Hg, see Section 8.1) or symptoms of 
hypotension, up to 6 hours after the end of study drug infusion.
4.2.2
Other Safety Endpoints 
Other safety endpoints include the following:

The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion

The incidence of SBP < 90 mm Hg (confirmed by a repeated value, see Section 8.1) up to 6 
hours after the end of study drug infusion

Change in Troponin T from baseline to Hour 24, 48, and 72

Percentage of subjects who have died (all- cause and CV(cardiovascular) related) through Day 
182
Additionally, the percentage of subjects with discontinuation due to symptomatic hypotension, as 
well as percentage of subjects with down-titrations, interruptions or discontinuations as a result of 
low blood pressure, either protocol specified clinically relevant hypotension, or asymptomatic 
decreases will be assessed. Other safety endpoints include the incidence of Adverse Events and 
Marked Laboratory Abnormalities, changes from baseline in vital signs, ECGs, physical 
measurements and laboratory assessments through Hour 120 or discharge, whichever comes first. 
The incidence of Serious Adverse Events will be assessed though Day 32.
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
For Part I (Cohort 1), approximately 50 subjects per group will be randomized to placebo or an 
incremental dose of BMS-986231 (3 - 6 - 12 μg/kg/min). Under a sample decision rule (eg, 
observed doubling with more than a 4% difference) and assuming clinically relevant hypotension 
incidences of 5% or 10% in the placebo group, the posterior probabilities of detecting an increase 
of 4-fold or 3-fold in incidence, respectively, are 86% and 80%, respectively. If there is no increase 
in clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase 
are 11-12%.
For Part II (Cohort 2), approximately 70 subjects per group will be randomized to placebo or one 
of the two active dose levels of BMS-986231. Under a sample decision rule (eg, observed 1.8-fold 
increase with more than a 3% difference) and assuming clinically relevant hypotension incidences 
of 5% or 10% in the placebo group, the posterior probabilities of detecting an increase of 3-fold 
or 2.5-fold in incidence, respectively, are 82% and 80%, respectively. If there is no increase in 
clinically relevant hypotension, then the posterior probabilities of falsely detecting an increase are 
13-15%. These probabilities do not reflect multiple comparison.
With regards to overall performance for selection of a maximally tolerated dose, a sample size of 
50 per group for Part I (Cohort 1), along with 70 per group for Part II (Cohort 2) will identify a 
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maximally tolerated dose approximately 50-70%, based on detecting an increase of 3-fold or 2.5-
fold in incidence, and using sample decision rules that are consistent with above. Also, the design 
will provide an option to select a titrated 12 μg/kg/min dose approximately 60% of the time when 
that dose is tolerated, but a non-titrated 12 μg/kg/min dose is not tolerated. Conversely, the study 
design will not identify a maximally tolerated dose is established from Part II (Cohort 2) 
approximately 80%-85% of the time when no maximally tolerated dose exists.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
Screening period starts from 18 hours prior to start of study drug infusion to Hour 0 (the start of 
study drug infusion). In-hospital follow-up starts from the end of study drug infusion to Hour 120 
or discharge, whichever comes first. Day 32 follow-up occurs 32 days after the start of study drug 
infusion. Day 182 follow-up occurs 182 days after the start of study drug infusion.
Please see the study design (Section 2.1) for the details on study periods.
6.2
Treatment Regimens
BMS will provide Investigational drug product BMS-986231 for infusion (active pharmaceutical 
ingredient BMS-986231 formulated with Captisol®) to all sites. In addition, Potassium acetate is 
to be locally sourced by sites within the US and will supplied to all ex-US sites.
Subjects will be administered study medication as a continuous IV infusion over 48 hours.
Body weight measured at screening will be used for dose calculations.
See Pharmacy Manual for additional dosing information.
6.3
Populations for Analyses
The following populations will be used for the analyses:

The Enrolled Subjects Data Set will consist of all subjects who sign informed consent

The Randomized Subjects Data Set will consist of all randomized subjects who have started 
study drug infusion. This is also known as the Intent to Treat (ITT) population. Data in this 
data set will be analyzed based on randomized treatment group

The Treated Subjects Data Set will consist of all subjects who receive any study drug infusion. 
This will be the primary safety data set. Data in this data set will be analyzed based on 
randomized treatment, except in the following cases:

If a subject received the same incorrect treatment throughout the 48 hours study drug 
infusion or until discontinuation of the study drug, then the subject will be analyzed based 
on the treatment received

If a subject received study drug from more than one treatment group, and none of the 
administrations were consistent with the assigned randomized treatment group, then the 
subject will be analyzed based on the first treatment received
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
The Pharmacokinetic analysis dataset (PK Population) will consist of all subjects who receive 
BMS-986231 and have at least one post dose PK sample. Additionally, the Evaluable PK 
Population is defined as subjects who have adequate PK profiles.
7
STATISTICAL ANALYSES
SAS® version 9.2 or higher will be used for statistical analyses, tabulations and graphical 
presentations. S-Plus® may be also used for graphical presentations. 
7.1
General Methods
Results from Part I (Cohort 1) and Part II (Cohort 2) will be presented separately, unless otherwise 
noted.
Except as noted otherwise, descriptive summaries will be presented for continuous variables using 
number of subjects (N), mean, standard deviation (SD), median, minimum and maximum. 
Descriptive summaries for categorical variables will utilize counts and percentages. Several 
analyses noted in subsequent sections will present 95% confidence intervals (CIs), but no pre-
specified significance testing will be included.
Adverse events and medical history will be coded according to the most recent Medical Dictionary 
for Regulatory Activities (MedDRA) version. Previous and concomitant medications will be coded 
using the WHO Drug Dictionary.
7.2
Study Conduct
Protocol deviations identified as significant will be captured in a trial management system and 
reported in the CSR. Relevant protocol deviations are those that are programmable and could 
potentially affect the interpretability of the study results. The following protocol deviations will 
be defined as relevant protocol deviations and listed:

Error in treatment assignment resulting in a subject being dosed with an incorrect treatment

Subject not treated within 24 hours of first dose of intravenous diuretic (the time difference 
between start of infusion and first dose of intravenous diuretic > 24 hours)

Systolic blood pressure (SBP) < 105 mm Hg at screening or Hour 0

Violation of inclusion criterion 2 (b): Subjects not hospitalized for ADHF

Violation of inclusion criterion 2 (g): Not having at least 2 of the following at time of screening:
i) evidence for pulmonary congestion on chest x-ray
ii) rales by chest auscultation,
iii) edema ≥2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in
15-30 seconds)
iv) presence of jugular venous distention

Violation of inclusion criterion 2 (h): Have no elevated NT-proBNP 1600 pg/mL 
(516 pmol/L) or BNP 400 pg/mL (116 pmol/L) as determined at the local laboratory within 
18 hours prior to the start of study drug infusion. For subjects with atrial fibrillation: no NT-
proBNP 2400 pg/ml or BNP 600 pg/ml
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
Violation of exclusion criterion 4 (a): Subjects administered IV or transdermal nitrate therapy 
prior to randomization, when at least one of the following criteria are not met:
i)
Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg 
AND
ii) The IV nitroglycerin dose is < 100 g/min (or isosorbide dinitrate < 3 mg/hour), AND
iii) The infusion rate and dose has been unchanged for > 2 hours

Violation of exclusion criterion 4 (d): Subjects treated with oral phosphodiesterase type 5 
(PDE5) inhibitor sildenafil, vardenafil or avanafil within 24 hours of screening or treated with 
tadalafil within 4 days prior to the start of screening

Initiation of PDE5 inhibitors during study drug infusion 
7.3
Study Population
7.3.1 Subject Disposition
Subject disposition will be listed. Summary tables reflecting the number of subjects who are 
enrolled, who are randomized, and reasons for not being randomized, will be presented as overall. 
The number of subjects who do not complete the treatment of 48 hours infusion, both overall and 
according to reasons for discontinuation from the treatment, will be summarized for all treated 
subjects, as overall and by treatment. Subjects who have temporary interruption or down-titration
of study drug but do not discontinue permanently will be treated as completing the treatment. The 
number of subjects who do not complete the study phase, both overall and according to reasons 
for not completing, will be summarized for all treated subjects, as overall and by treatment.
Summary tables will be presented for study phases ending at Hour 120 (or discharge, whichever 
comes first), Day 32, and Day 182.
7.3.2 Demographics and Baseline Characteristics
Frequency distributions and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined for all treated subjects. Demographic 
variables to be summarized include: age, gender, race, and geographic region. See Table 7.3-1 for 
countries in each region.
Table 7.3-1:
Demographics and Baseline Characteristics
Region
Country
North America
Canada and United States
Europe
Czech Republic, France, Germany, Greece, Italy, 
Netherlands, Poland, Spain, and United Kingdom
Latin America
Argentina
Baseline variables to be summarized include the following:
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
Physical measurements (height, body weight, body mass index) 

Vital signs (systolic blood pressure, diastolic blood pressure, and heart rate)

Disease characteristics 

New York Heart Association Class prior to admission

Ejection fraction (%)

Heart failure etiology (as collected in the CRF Hear Failure Etiology page at screening)

Number of heart failure hospitalizations in past year

Time since original HF diagnosis to first treatment of study drug

Time since first diuretic use in the current episode of decompensation to first treatment of 
study drug

Comorbidities listed in “Specific Disease History” CRF page, including but not limited to 
coronary artery disease, hypertension, diabetes, and presence of atrial fibrillation

Important laboratory variables (including NT-proBNP, serum sodium and eGFR)

Current heart failure medications 
Start time of first diuretic use will be obtained from “Previous and Concomitant Intravenous 
Medications” CRF page.
Current heart failure medications will be taken from CRF previous and concomitant IV and non-
IV medications pages with Use of “Heart Failure” and start date prior to first treatment of study 
drug. The CRF pages collect IV medications administered starting from one week prior to 
randomization.
7.3.3 Physical Measurements
Physical measurements such as body weight and height will be summarized by nominal visit for 
all treated subjects, as overall and by treatment. Measurements will also be listed for all treated 
subjects.
7.3.4 Medical History and Previous Medications
Medical history and previous medications taken prior to dosing will be listed for all treated 
subjects. 
7.4
Extent of Exposure
Study drug administration and randomization schedule will be documented as per subject listings. 
Any non-study medications taken by subjects, any conducted non-study medical treatment 
procedures, and any utilized non-study diagnostic procedures will also be listed.
Percentage of subjects with discontinuation due to symptomatic hypotension, as well as percentage 
of subjects with down-titrations or discontinuations as a result of low blood pressure, either 
protocol specified clinically relevant hypotension, or asymptomatic decreases will be analyzed and 
presented in the same manner as the primary endpoint.
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The final infusion dose at the completion of 48 hours infusion will be summarized descriptively 
by treatment. The subjects who discontinue prematurely from infusion will be counted as having 
a final infusion dose of 0 µg/kg/min. Subjects who are down-titrated and complete the 48 hours 
infusion will be counted as having a final infusion dose of 1/2 of the scheduled dose at time of 
down-titration. For example, the final dose will be 3 µg/kg/min if down-titration occurs when 
6 µg/kg/min is administered for a subject in Part I (Cohort 1) and the subject otherwise complete 
dosing after the down-titration.
7.5
Efficacy
7.5.1
Primary Efficacy Analysis
There is no primary efficacy analysis for this study. The primary safety analysis is discussed in 
Section 7.6.1.
7.5.2
Secondary Efficacy Analysis
NT-proBNP will be summarized descriptively for all treated subjects by treatment for each time 
point, as well as change from baseline. Geometric mean and coefficient of variation (%CV) will 
also be presented for the original values and percent of baseline.
The NRS is an ordinal scale of 0 to 10. A score of 0 represents “I am not breathless at all” and 10 
represents “I am the most breathless I can possibly imagine”.
To incorporate the correlations among NRS assessments at different time points and an appropriate 
representation of effect of baseline assessments, the change from baseline at time point t (Hour  
24, 48, and 72) in NRS assessments will be analyzed using a longitudinal repeated measures 
method. The model will include treatment, region and time as fixed effects and baseline value as 
covariate. Furthermore, interaction terms of time by treatment, time by region and time by baseline 
value will be included. An unstructured variance-covariance matrix for the NRS assessments 
within same subject will be used (Autoregressive structure will be used if the model does not 
converge with unstructured matrix.). The SAS® procedure PROC MIXED will be used.
After obtaining the estimates of mean change from baseline at time point t in NRS assessments, 
the mean change in AUC within a treatment group or difference in mean change in AUC between 
treatment groups will be estimated within the framework of the mixed model, using the formula 
based on the Trapezoidal rule:
where yti is the estimate of mean change from baseline at target time ti in a treatment group for 
estimation of mean change in AUC within treatment group, and for estimation of difference in 
change in AUC between treatment groups, yti is the estimate of mean difference between treatment 
groups in change from baseline at target time ti . The variability of ∆AUC will also be estimated







3
1
1
2
)
(
1
i
i
t
t
i
i
iy
y
t
t
∆AUC
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within the framework of the mixed model in SAS using variability from terms used in the 
ESTIMATE statement.
Missing values for the dyspnea NRS will only be imputed if a NRS cannot be obtained because 
the subject has died or is physically unable to complete the form. In these cases, a worst score (i.e. 
10) imputation will be used for that time point. Missing values for subjects who are discharged 
prior to Hour 120 will not be imputed.
7.6
Safety
All safety presentations will be based on the Treated Subject Data Set.
7.6.1
Primary Safety Analysis
The incidence of clinically relevant hypotension from the start to 6 hours after the end of study 
drug infusion will be summarized by treatment. Point estimates and 95% confidence interval (CIs)
for event rates will be presented by treatment, together with point estimates and 95% CIs for the 
risk difference and relative risk between each BMS-986231 arm and placebo. The confidence 
intervals will be calculated using an exact method. The 95% confidence intervals for the relative 
risk and risk difference will be obtained using an exact procedure that inverted the 2-sided test 
statistics (Agresti and Min, 2001)1.
The event rate is calculated as the number of subjects experiencing at least one clinically relevant 
hypotension from the start to 6 hours after the end of study drug infusion, divided by the total 
number of subjects receiving study treatment.
The incidence of symptomatic hypotension up to 6 hours after the end of study drug infusion, as 
well as the incidence of SBP < 90 mm Hg (confirmed by a repeated measure) will be analyzed and 
presented in the same manner as the primary endpoint.
7.6.2
Other Safety Analyses
7.6.2.1
Deaths
All reported deaths after a subject is enrolled (i.e., has signed the informed consent) will be listed 
separately by subject.
Percentage of subjects who have died (all- cause and CV related) through Day 32 and Day 182, 
and percentage of subjects who have heart failure hospitalizations or CV mortality through Day 
32 will be analyzed and presented in the same manner as the primary endpoint, respectively.
7.6.2.2
Serious Adverse Events
All reported serious adverse events (SAEs) will be listed by System Organ Class (SOCs) and 
Preferred Terms (PTs) for all enrolled subjects. SAEs with onset time from the start of study 
treatment, up to and including 32 days after the start of study treatment will be included in the 
summary tables. SAEs will be coded and grouped into PT by SOC (see section 7.6.2.3).
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7.6.2.3
Adverse Events
All AEs will be coded and grouped into PT by SOC, using current version of Medical Dictionary 
for Regulatory Activities (MedDRA). All AEs will be summarized and listed by SOCs and PTs.
Non-serious AEs with onset time from the start of study treatment, up to and including 120 hours 
after the start of study treatment will be included in the summary tables. Events will be assigned 
to the study treatment administered to the subject. The proportion of subjects having an adverse 
event will be calculated as the number of subjects experiencing the event, divided by the total 
number of subjects receiving study treatment.
All AE listings will indicate the unique subject identifier, age, gender, current treatment, the date 
and time of onset, the date and time of resolution, day of onset relative to the start of treatment, 
action taken, investigator’s assessment of severity and relationship to study drug. Additional 
listings will be provided for adverse events leading to discontinuation and adverse events without 
recorded resolution. Summaries of adverse events will include adverse events, adverse events by 
intensity and adverse events by relationship.  
Where a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the subject will only be counted once at the preferred terminology 
level in adverse event frequency tables.
Where a subject has multiple adverse events within the same system organ class in a single analysis 
period, the subject will only be counted once at the system organ class level in adverse event 
frequency tables.
When a subject has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:

Relationship to study medication

Intensity of event

Onset date and time
When reporting adverse events by intensity, in addition to providing a summary table based on the 
event selection criteria detailed above, summary tables will also be provided based on the most 
intense event during the analysis period - independent of relationship to study medication. For 
these tables, the following criteria, in order of precedence, will be used to select the event to be 
included in summary tables:

Intensity of event

Onset date and time
Subjects will only be counted once in the ‘Total’ at their maximum intensity, regardless of SOC 
or PT.
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7.6.2.4
Clinical Laboratory Evaluations
The results of all protocol-specified clinical laboratory tests will be listed. Scheduled laboratory 
measurements and corresponding change from baseline values will be summarized by treatment 
and scheduled time points for each laboratory test.
The criteria used for classifying laboratory test results as markedly abnormal will be listed. 
Laboratory results for subjects with any marked laboratory abnormality (scheduled and 
unscheduled) will be listed. This listing will include all observations for the specific laboratory 
test and subject, not only the marked laboratory abnormalities. The frequency of subjects with any 
marked laboratory abnormality as well as hematology, serum chemistry, and urinalysis marked 
abnormalities, based on pre-specified criteria (see Table 7.6.2.4-1), will be presented. 
Troponin T will be summarized descriptively by treatment for each time point, as well as change 
from baseline. Geometric mean and coefficient of variation (%CV) will also be presented for the 
original values and percent of baseline.
Table 7.6.2.4-1:
Laboratory MA Criteria
Parameter
Test 
Code
Direction 
of Change
MA Criteria in US Standard Units 
(apply to labs collected after baseline 
only)
MA Criteria in SI Units
(apply to labs collected after baseline 
only)
HEMATOLOGY
Hemoglobin
HB
Low only
> 2 g/dl decrease compared to pre-dose or  
Value 8 g/dl 
> 20 g/l decrease compared to pre-dose or  
Value 80 g/l 
Hematocrit
HCT
Low only
< 0.75 pre-dose 
< 0.75 pre-dose 
Erythrocytes
RBC
Low only
< 0.75 pre-dose 
< 0.75 pre-dose 
Platelet Count
PLAT
Low Only
< 100,000/mm3 (or < 100109 cells/L) 
< 100109 cells/L 
Leukocytes
WBC
Low/High
< 0.75 LLN or > 1.25 ULN, or
if pre-dose < LLN then use < 0.8 pre-
dose or > ULN
if pre-dose > ULN then use > 1.2 pre-
dose or < LLN
< 0.75 LLN or > 1.25 ULN, or
if pre-dose < LLN then use < 0.8 pre-
dose or > ULN
if pre-dose > ULN then use > 1.2 pre-
dose or < LLN
Neutrophils 
(absolute)
NEUTA
Low Only
< 1.0 103 cells/L
< 1.0 109 cells/L
LIVER/KIDNEY
Alkaline 
Phosphatase 
ALP
High only
> 2 ULN
> 2 ULN
Aspartate 
Aminotransferase
AST
High only
> 3 ULN, > 5 ULN, > 10 ULN
> 3 ULN, > 5 ULN, > 10 ULN
Alanine 
Aminotransferase
ALT
High only
> 3 ULN, > 5 ULN, > 10 ULN
> 3 ULN, > 5 ULN, > 10 ULN
Bilirubin, Total
TBILI
High only
> 2 ULN
> 2 ULN
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Table 7.6.2.4-1:
Laboratory MA Criteria
Parameter
Test 
Code
Direction 
of Change
MA Criteria in US Standard Units 
(apply to labs collected after baseline 
only)
MA Criteria in SI Units
(apply to labs collected after baseline 
only)
Blood Urea 
Nitrogen
BUN
High only
>2 ULN 
>2 ULN 
ELECTROLYTES
Sodium, Serum
NA
Low/High
< 0.95 LLN or > 1.05ULN, or
if pre-dose < LLN then use < 0.95 pre-
dose or >ULN
if pre-dose > ULN then use > 1.05 pre-
dose or < LLN
< 0.95 LLN or > 1.05ULN, or
if pre-dose < LLN then use < 0.95 pre-
dose or >ULN
if pre-dose > ULN then use > 1.05 pre-
dose or < LLN
Potassium, Serum
K
Low/High
< 0.9LLN or > 1.1ULN, or
if pre-dose < LLN then use < 0.9 pre-
dose or > ULN
if pre-dose > ULN then use > 1.1 pre-
dose or < LLN
< 0.9LLN or > 1.1ULN, or
if pre-dose < LLN then use < 0.9 pre-
dose or > ULN
if pre-dose > ULN then use > 1.1 pre-
dose or < LLN
Chloride, Serum
CL
Low/High
< 0.9 LLN OR > 1.1 ULN, or
if pre-dose < LLN then use < 0.9 pre-
dose or > ULN
if pre-dose > ULN then use > 1.1 pre-
dose or < LLN
< 0.9 LLN OR > 1.1 ULN, or
if pre-dose < LLN then use < 0.9 pre-
dose or > ULN
if pre-dose > ULN then use > 1.1 pre-
dose or < LLN
Calcium, Total
CA
Low/High
< 0.8 LLN or > 1.2 ULN, or
if pre-dose < LLN then use < 0.75 pre-
dose or > ULN
if pre-dose > ULN then use > 1.25 pre-
dose or < LLN
< 0.8 LLN or > 1.2 ULN, or
if pre-dose < LLN then use < 0.75 pre-
dose or > ULN
if pre-dose > ULN then use > 1.25 pre-
dose or < LLN
Bicarbonate
HCO3
Low/High
< 0.75 LLN or > 1.25 ULN, or
if pre-dose < LLN then use < 0.75 pre-
dose or > ULN
if pre-dose > ULN then use > 1.25 pre-
dose or < LLN
< 0.75 LLN or > 1.25 ULN, or
if pre-dose < LLN then use < 0.75 pre-
dose or > ULN
if pre-dose > ULN then use > 1.25 pre-
dose or < LLN
OTHER CHEMISTRY
Creatine Kinase
CK
High only
> 5 ULN
> 5 ULN
Total Protein
TPRO
Low/High
< 0.9 LLN or > 1.1 ULN, or
if pre-dose < LLN then use 0.9 pre-dose 
or > ULN
if pre-dose > ULN then use 1.1   pre-dose 
or < LLN
< 0.9 LLN or > 1.1 ULN, or
if pre-dose < LLN then use 0.9 pre-dose 
or > ULN
if pre-dose > ULN then use 1.1   pre-dose 
or < LLN
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Table 7.6.2.4-1:
Laboratory MA Criteria
Parameter
Test 
Code
Direction 
of Change
MA Criteria in US Standard Units 
(apply to labs collected after baseline 
only)
MA Criteria in SI Units
(apply to labs collected after baseline 
only)
Glucose, 
Serum 
Fasting
GLUCF
Low/High
< 0.8 LLN or > 1.5 ULN, or
if pre-dose < LLN then use < 0.8 pre-
dose or > ULN
if pre-dose > ULN then use > 2.0 pre-
dose or <LLN
< 0.8 LLN or > 1.5 ULN, or
if pre-dose < LLN then use < 0.8 pre-
dose or > ULN
if pre-dose > ULN then use > 2.0 pre-
dose or <LLN
Uric Acid
URIC
High only
> 1.5 ULN, or
if pre-dose > ULN then use > 2 pre-dose
> 1.5 ULN, or
if pre-dose > ULN then use > 2 pre-dose
Albumin
Low only
≤ 2 g/dL 
≤ 20 g/L 
URINALYSIS
Protein, Urine
UPRO
High only
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Blood, Urine
UBLD
High only
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
Leukocyte 
Esterase, Urine
ULEUK
High only
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
RBC, Urine
URBC
High only
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
If missing pre-dose then use 2, or
if value 4, or
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
WBC, Urine
UWBC
High only
If missing pre-dose then use 2, or
if value 4, or
If missing pre-dose then use 2, or
if value 4, or
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Table 7.6.2.4-1:
Laboratory MA Criteria
Parameter
Test 
Code
Direction 
of Change
MA Criteria in US Standard Units 
(apply to labs collected after baseline 
only)
MA Criteria in SI Units
(apply to labs collected after baseline 
only)
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
if pre-dose = 0 or 0.5 then use 2, or
if pre-dose = 1 then use 3, or
if pre-dose = 2 or 3 then use 4
7.6.2.5
ECG
All recorded ECGs (heart rate (HR), QT (QT, Bazett’s corrected QT [QTcB], Fridericia's corrected 
QT [QTcF]), PR and QRS intervals) will be listed.
Summaries of ECG parameters (heart rate (HR), QT (QT, QTcF), PR and QRS intervals) will be 
tabulated by time point and treatment. Summaries of ECG parameters will include change from 
baseline at list of time points.
If QTcF is not available in the database, QTcF will be calculated using the reported uncorrected 
QT Interval and Heart Rate, and the following formula: 


3
/
1
60
RATE
HEART
QT
QTcF 
Subjects with ECG intervals outside of a pre-specified range will also be listed.
The following criteria will be used to determine ECG results that are outside of a pre-specified 
range:
PR (msec):
Value > 200
QRS (msec):
Value > 120
QT (msec):
Value > 500 or change from baseline > 30
QTcF (msec):
Value > 450 or change from baseline > 30
7.6.2.6
Vital Signs
Values and changes from baseline for vital sign measurements will be summarized by treatment 
group at each scheduled time point using descriptive statistics.
7.6.2.7
Physical Examination Findings
All physical examination abnormal findings will be listed per subject.
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7.6.2.8
Daily Urinary Output
Cumulative urinary output is collected daily at Hour 24, 48, 72, 96 and 120. Daily urinary output 
will be summarized descriptively for all treated subjects by treatment for each time point. 
7.6.2.9
Oxygen Saturation
Oxygen Saturation will be summarized descriptively for all treated subjects by treatment for each 
time point as well as change from baseline. 
7.7.1
7-Point Likert Scale
Both the percentage of subjects reporting moderate or markedly improved resting dyspnea and 
percentage of subjects reporting moderate or marked improvement using the patient global 
assessment on a 7-point Likert scale will be analyzed and presented in the same manner as the 
primary endpoint at Hours 6, 12, and 24. Missing values for the Likert scale at Hours 6, 12, and 
24 will only be imputed, if a score cannot be obtained because the subject has died or is physically 
unable to complete the form. In these cases, a worst score imputation (i.e. -3) will be used for that 
time point.  
7.7.2
Worsening Heart Failure and Worsening Renal Function
The Investigator will be asked to indicate if a subject has experienced worsening heart failure, to 
document the signs, and symptoms that led to the assessment of worsening heart failure, and to 
document the intensification of treatment implemented for worsening heart failure.  Assessment 
is to be done once daily covering the prior 24-hour period as per the scheduled times. Worsening 
heart failure is defined as new or worsening signs and/or symptoms of heart failure that require:

Intensification of IV therapy for heart failure (such as initiation, restart, or up-titration of IV 
diuretics, IV nitrates or other IV vasoactive drugs), and/or

Addition of a mechanical support, either:

Ventilatory (mechanical ventilation, noninvasive ventilation),

Circulatory (Intra-Aortic Balloon Pump (IABP), ventricular assist device) or

Use of ultrafiltration, hemofiltration or hemodialysis specifically for the management of
WHF
Supportive evidences (new or worsening signs or symptoms, intensification of IV heart failure 
medications, and/or addition of mechanical support) for worsening heart failure collected in CRF 
page will be tabulated. Signs and symptoms of worsening heart failure and IV heart failure 
medications for subjects experiencing worsening heart failure will be listed.
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The percentage of subjects reporting with an episode of worsening heart failure and percentage of 
subjects reporting worsening renal function will be analyzed and presented in the same manner as 
the primary endpoint.
7.7.3
Congestive Heart Failure
Shift analysis will be performed for changes in physical signs of congestive heart failure through 
Hour 120 to evaluate qualitative changes that occurred through Hour 120. A shift table will be 
generated for each physical sign to tabulate per-subject changes between the categories at baseline 
and at each study time point.
7.7.4
Sensory and Motor Function
Shift analysis will be performed for changes from baseline in items related to patient assessed 
peripheral sensory and motor function. A shift table will be generated for each item to tabulate 
per-subject changes between the scores at baseline and at each study time point.
7.8
Pharmacokinetics
Blood samples will be collected from all subjects at 0.75, 4, 8, 14, and 48 hours during infusion 
and 4 hours after end of infusion and plasma concentrations will be measured using LC-MS. In 
addition, a PK sample will be collected from the subject when the dose is lowered due to a safety 
event and also at time of early discontinuation of study drug. Pharmacokinetic parameters for 
BMS-986231 and BMT-284730 and other metabolites (e.g., BMT-279554 and CAR-000463) will 
be estimated as appropriate. The plasma concentration data will also be used to conduct population 
pharmacokinetic analysis and exposure-response analysis with select efficacy and safety 
endpoints. Results of the population pharmacokinetic and exposure-response analysis will be 
reported in a separate report.
The PK population will be used for all listings. Evaluable PK population will be used for 
summaries and statistical analyses. Geometric mean and coefficient of variation (%CV) will also 
be presented for sample plasma concentration-time data. Analysis will include all analyte data in 
the PK dataset for BMS-986231 and metabolites of BMS-986231.
Subject plasma concentration-time profiles will be listed and summarized by treatment and 
nominal collection time for each analyte. Plots of mean (+SD) plasma concentration profiles versus
time will be presented for each analyte, and all treatments will be superimposed on the same plot.
Concentration at the end of infusion will also be summarized by treatment, which is the 
concentration at hour 48 for subjects completing 48 hours infusion and the concentration collected 
at early discontinuation for subjects not completing 48 hours infusion. The PK samples collected 
when the dose is lowered due to a safety event will be listed.
 
 
 
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7.10
Outcomes Research
For the index hospitalization, length of stay from start of infusion to discharge and length of stay 
in the ICU/CCU will be summarized descriptively (see section 7.1, including the first and third 
quartiles) for all treated subjects by treatment.
Following discharge from the index hospitalization,
the percentage of subjects with 
rehospitalizations and emergency department visits will be summarized descriptively by treatment 
group for heart failure or other cardiovascular disease separately through Day 32 and will be 
analyzed and presented in the same manner as the primary endpoint.
Rehospitalizations will include subjects who are either under observation or admitted as an 
inpatient with a length of stay ≥ 24 hours. Emergency department visits will include urgent, 
unplanned visits in a monitored healthcare setting with a length of stay < 24 hours. Only emergency 
department visits that do not result in a hospitalization will be counted as separate healthcare 
encounters. Number of days alive and out of the hospital will also be summarized for all treated 
subjects by treatment.
7.11
Interim Analyses
Two interim analyses will be performed for this study. An interim analysis will be performed 
following the completion of the last visit at Hour 120 in Part I (Cohort 1). The analysis will include 
data for all Cohort 1 subjects through at least Hour 120. The DMC, Executive Committee and 
representatives from the Sponsor will assess hypotension, as well as additional safety information, 
in addition to any available endpoint events. The outcome will determine whether 12 μg/kg/min is 
a sufficiently tolerated dose to be used in Part II (Cohort 2). The dose selection decision for Part 
II will be made by the Sponsor in collaboration with the Executive Committee, with input from 
the DMC.
The doses for Part II (Cohort 2) will be determined based on general guiding principles and 
considered in the context of the totality of the data. For example, some of the critical information 
that will be considered evaluating the suitability 12 μg/kg/min for Part II will include the 
percentage of subjects completing the 48 hour infusion, percentage of subjects with temporary 
interruptions or permanent discontinuation of study drug, percentage of subjects with clinically 
relevant hypotension, percentage of subjects with symptomatic hypotension, and other key safety 
endpoints of interest (e.g. renal function).
The second interim analysis will be performed following completion of the last visit at Day 32 in 
Part II (Cohort 2) in order to facilitate drug development decisions. The study analysis team will 
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then provide top-line results to the project team. In addition to the two interim analyses, safety 
reviews after 20 patients in Part I (Cohort 1) and after 50 patients in each part will be performed. 
No adjustments to confidence limits will be made as a result of interim analyses.
8
CONVENTIONS
8.1
Safety Data Conventions
Except as noted in Section 7.6, safety data will be handled according to the BMS safety data 
conventions. This document includes descriptions on how to analyze AE data as well as how to 
handle partial dates, missing dates, and unknown end dates when analyzing safety data. If onset 
time of AEs is missing or incomplete, the onset date of AEs will be used to determine if the AEs 
will be included in the AE summary tables as follows.

Non-serious AEs will be included in summary tables if the onset date is on or after the start 
date of study treatment and not later than the date of Hour 120.

Serious AEs will be included in summary tables if the onset date is on or after the start date of 
study treatment and not later than the date of Day 32.
Clinically relevant hypotension defined in the primary endpoint consists of two components which 
are further clarified as follow:

The component of “SBP < 90 mm Hg (confirmed by a repeated value < 90 mm Hg)” will be 
identified by a SBP measurement < 90 mm Hg with confirmatory SBP measurement < 90 mm 
Hg within 30 minutes after the initial qualifying value. If a confirmatory SBP is missing, the 
initial SBP will be treated as confirmed if no SBP measurement ≥ 90 mm Hg within 30 minutes 
exists. The assessment time of the initial SBP < 90 mm Hg will include time from start of 
infusion, up to and including 6 hours after end of infusion.
The confirmatory measurement should be within 15 minutes; however, a window of up to 30 
minutes will be applied, to determine if a qualifying confirmatory value is obtained.

The component of “symptoms of hypotension” will be identified by at least one symptom 
(other than “low blood pressure”) from the CRF page collecting signs and symptoms of low 
blood pressure with onset time from start of infusion, up to and including 6 hours after end of 
infusion
This clarification is also applied to the safety endpoints “The incidence of symptomatic 
hypotension up to 6 hours after the end of study drug infusion, as well as the incidence of SBP 
< 90 mm Hg (confirmed by a repeated value)”.
Subjects counted in the endpoint “Percentage of subjects with discontinuation due to symptomatic 
hypotension” are those who have “Hypotension” as the reason for discontinuation and have a 
symptom (other than “low blood pressure”) from the CRF page collecting signs and symptoms of 
low blood pressure with onset time on or before the time of dose discontinuation. 
Subjects counted in the endpoint “Percentage of subjects with down-titrations, interruptions or 
discontinuations as a result of low blood pressure, either protocol specified clinically relevant 
hypotension, or asymptomatic decreases” are those who have ‘Hypotension’ as the reason for rate 
reduction, infusion interruption or discontinuation.
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8.2
Baseline Measurements
For analyses involving baseline, the baseline value is defined by the last value prior to the start of 
infusion, unless otherwise noted.
When there is a missing baseline assessment it will not be imputed, thus, subjects are excluded 
from any changes from baseline analysis for which they have a missing baseline value.
8.3
Hour Ranges for Analysis of Time Points
Subjects do not always adhere strictly to the visit schedule timing in the protocol. The hour ranges 
for the analyses of dyspnea measured by 11-point NRS and 7-point Likert scale and patient global 
assessment (PGA) measured by 7-point Likert scale are defined in Table 8.3-1. The hour ranges 
for the analyses of laboratory ECG are defined in Table 8.3-2 and 8.3-3, respectively. The hour 
ranges for the analyses of assessments measured at Hour 24, 48, 72, 96, and 120 (including 
respiratory rate and temperature) are defined in Table 8.3.4.
Table 8.3-1:
Hour Ranges for Analyses of  Dyspnea Measured by 11-point NRS 
and 7-point Likert Scale and PGA Measured by 7-point Likert 
Scale
Nominal Visit
Target Hour
Hour Ranges
Baseline
Pre-dose
Randomization to ≤ Hour 0
Hour 6
Start of infusion + 6
≥Hour 3 to < Hour 9
Hour 12
Start of infusion + 12
≥ Hour 9 to < Hour 18
Hour 24
Start of infusion + 24
≥ Hour 18 to < Hour 36
Hour 48
Start of infusion + 48
≥ Hour 36 to < Hour 60
Hour 72
Start of infusion + 72
≥ Hour 60 to < Hour 96
Hour 120
Start of infusion + 120
≥ Hour 96 to ≤ Hour 132
Table 8.3-2:
Hour Ranges for Analyses of  Laboratory Measurements
Nominal Visit
Target Hour
Hour Ranges
Baseline
Pre-dose
Randomization to ≤ Hour 0
Hour 24
Start of infusion + 24
≥Hour 12 to < Hour 36
Hour 48
Start of infusion + 48
≥ Hour 36 to < Hour 60
Hour 72
Start of infusion + 72
≥ Hour 60 to < Hour 96
Hour 120
Start of infusion + 120
≥ Hour 96 to ≤ Hour 132
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Table 8.3-3:
Hour Ranges for Analyses of  ECG
Nominal Visit
Target Hour
Hour Ranges
Baseline
Pre-dose
Randomization to ≤ Hour 0
Hour 48
Start of infusion + 48
≥Hour 24 to < Hour 60
Hour 72
Start of infusion + 72
≥ Hour 60 to < Hour 96
Hour 120
Start of infusion + 120
≥ Hour 96 to ≤ Hour 132
Table 8.3-4:
Hour Ranges for Analyses of  Respiratory Rate and Temperature
Nominal Visit
Target Hour
Hour Ranges
Baseline
Pre-dose
Randomization to ≤ Hour 0
Hour 24
Start of infusion + 24
≥Hour 12 to < Hour 36
Hour 48
Start of infusion + 48
≥ Hour 36 to < Hour 60
Hour 72
Start of infusion + 72
≥ Hour 60 to < Hour 84
Hour 96
Start of infusion + 96
≥ Hour 84 to < Hour 108
Hour 120
Start of infusion + 120
≥ Hour 108 to ≤ Hour 132
Vital signs (blood pressure and heart rate) are assessed at Hours 0, 0.5, 1, 2, 4, 5 (for Part I only), 
6, 8, 9 (for Part I only), 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 54, 60, 66, 72, 96, 
120, and Day 32. The hour ranges for the analyses of vital signs are defined in the same manner
as in Table 8.3-1 to Table 8.3-4. The hour ranges around planned measurement times are based on 
the midpoint between planned measurement times, for example, Hour Ranges for Hour 24 is ≥ 
Hour 23 to < Hour 26. Hour Ranges for Hour 120 are ≥ Hour 108 to ≤ Hour 132. The value
collected at the Day 32 visit will be used for the Day 32 time regardless of time ranges.
The hour ranges for the analyses of oxygen saturation are defined in the same manner as in Table 
8.3-1 for Baseline, Hours 6, 12, 24, 48, and Table 8.3-4 for Hours 72, 96, and 120. 
8.4
Multiple Measurements
For longitudinal summaries of data, if there are multiple records within the same Hour ranges, then 
the value closest to the time of the planned time points is selected unless specified otherwise. 
Laboratory Measurements
For tabulations of changes from baseline or shift analyses, if multiple laboratory measurements 
are obtained within the same nominal visit, then the measurement obtained on the day closest to 
the target day for that nominal visit will be used; in the case of a tie, the measurement obtained on 
the earlier day will be used in the analyses.
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For tabulations of incidence of marked abnormalities (e.g. ALT > 3xULN), if multiple laboratory 
measurements are obtained within the same nominal visit, then the worst measurement within the 
nominal visit window nominal visit will be used.
Vital Signs and ECGs
If multiple vital sign or ECG measurements are obtained within the same nominal visit, then the 
measurement obtained on the day closest to the target day for that nominal visit will be used; in 
the case of a tie, the measurement obtained on the earlier day will be used in the analyses.
8.5
Pharmacokinetic Summaries
In-text Tables
For in-text pharmacokinetic tables, coefficient of variation (%CV) will be reported as integers. For 
other statistics except for standard deviations, values of 100 or higher will be presented as integers, 
values of 10 - <100 will be displayed to one decimal place, and values of 1 - < 10 will be displayed 
to two decimal places. Values less than 1 will be displayed to three decimal places.  Ratios will 
also be displayed to three decimal places. Standard deviations will be reported to a precision of 1 
decimal place more than the mean.
Handling of Non-Quantifiable Concentrations
For the summaries of plasma concentration-time data, concentrations that are less than the lower 
limit of quantification (LLOQ) should be displayed as “< LLOQ” in the listings and be treated as 
missing in summary tables and plots.  
All available plasma concentration-time data will be included in the PK data set and listed 
accordingly.
Treatment of Outliers
Individual plasma concentrations, if deemed to be anomalous, may be excluded from the analysis 
following a review of available documentation (e.g., bioanalytical report, clinical data). Any such 
exclusion will be clearly listed in the study report along with justification for exclusion.
Entire plasma concentration-time profiles for a subject may be excluded following review of 
available documentation (e.g., bioanalytical report, clinical data). However, results of analysis with 
and without the excluded profiles may be presented in the study report. Any such exclusion will 
be clearly listed in the study report along with justification for exclusion.
PK Exclusions2
PK Analysis, Reporting, and Exclusion criteria should follow the BMS PK Harmonization 
document Version 3.0. 
9
CONTENT OF REPORTS
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Details of the tables, listings, and figures to be prepared for interim analyses 
and the final CSR will be included in a study-specific Data Presentation Plan (DPP).
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