Clinical trial NCT04318093
Conditions: Acute Decompensated Heart Failure
Keywords: Heart failure
Sponsor: Bristol-Myers Squibb
Start date: 2020-11-06; Completion date: 2021-07-19
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the safety of BMS-986259 in stable participants hospitalized for acute decompensated heart failure.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BMS-986259 intervention 2: Placebo
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days

Protocol documents:
Prot_SAP_000.pdf: 
Page:
1
Protocol Number:
CV019010
Date:
21-Jan-2020
Revised Date:
28-Oct-2020
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 146,110
EudraCT: 2019-004186-40
CLINICAL PROTOCOL CV019010
A Randomized, Double-Blinded, Placebo-Controlled, Study to Evaluate the Safety and 
Tolerability of BMS-986259 in Stabilized Patients Hospitalized for Acute Decompensated Heart 
Failure
Short Title:
Study of the safety of BMS-986259 post-acute decompensated heart failure
Revised Protocol Number: 01
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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, 
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Revised Protocol No.: 01
Date: 28-Oct-2020
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copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, 
amendments) that may be added to this document is also confidential and proprietary to 
BMS and must be kept in confidence in the same manner as the contents of this document. 
Any person who receives this document without due authorization from BMS is 
requested to return it to BMS or promptly destroy it. All other rights reserved. 
References to BMS in this protocol may apply to partners to which BMS has transferred 
obligations, eg, a Contract Research Organization (CRO).
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Revised Protocol No.: 01
Date: 28-Oct-2020
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
01
28-Oct-2020
This amendment adds safety measures in response to the coronavirus 
disease 2019 (COVID-19) pandemic and addresses health authority and 
ethics committee requests for clarifications, as follows:
•
An interim analysis has been added to occur when
approximately 50% of participants have completed the End of
Study Visit (Day 14).
•
The pharmacokinetic
 data collection was
simplified to minimize participant burden. Minor updates to the
study design schematic have also been made for clarity.
•
In response to the COVID-19 pandemic:
o
Related risks and risk mitigation measures are
discussed.
o
A negative reverse transcription polymerase chain
reaction or rapid antigen test for severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is
required at screening for inclusion in the study.
Original Protocol
21-Jan-2020
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 01:
This amendment adds safety measures in response to the coronavirus disease 2019 (COVID-19) 
pandemic and addresses 
 ethics committee requests for clarifications, as 
follows: 
•
An interim analysis has been added to occur when approximately 50% of participants have 
completed the End of Study Visit (Day 14). 
•
The pharmacokinetic (PK) 
 data collection was simplified to minimize 
participant burden. Minor updates to the study design schematic have also been made for 
clarity. 
•
In response to the COVID-19 pandemic:
−
Related risks and risk mitigation measures are discussed. 
−
A negative reverse transcription polymerase chain reaction (RT-PCR) or rapid antigen test 
for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required at 
screening for inclusion in the study. 
•
Additional revisions, including to sections of the Synopsis, have been made to align the 
protocol with respect to these changes. Minor formatting and typographical corrections have 
been made for accuracy and clarity throughout the document as well.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Title Page
Updated study director/medical 
monitor name and contact 
information.
Medical monitor was changed.
Section 2: 
Schedule of 
Activities;
Section 6.1: 
Inclusion Criteria
The following changes to Vital 
Signs were made:
•
In Table 2-1, Screening 
Procedural Outline (CV019010), 
clarified that:
o
Heart rate should be 
measured per standard of 
care (SOC).
o
Blood pressure should be 
measured while the 
participant is in a supine 
position (preferable).
•
In Table 2-2, On-Treatment and 
Follow-up Procedural Outline 
Updated text to clarify expectations for 
vital signs/blood pressure measurements 
and to ensure alignment with the 
primary endpoint.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
(CV019010), 
added 
text 
to 
describe expectations for at-home 
blood pressure measurements.
•
In Section 6.1, Inclusion Criteria, 
added text to criterion 2) b) v) 
that supine position for systolic 
blood 
pressure 
(SBP)
measurement is preferable, based 
on participant’s condition and 
comfort.
Section 2: 
Schedule of 
Activities
In Table 2-1, Screening Procedural 
Outline (CV019010):
•
Added a row for Urinalysis under 
Local Laboratory Assessments.
•
Changed 
footnote 
a 
to:
“Screening must occur at least 
24 hours post initial emergency 
room 
(ER)
presentation. 
Randomization 
must 
occur 
within 8 days post initial ER 
presentation.” 
In Table 2-2: On-Treatment and 
Follow-up Procedural Outline 
(CV019010):
•
Removed Urine PK & Metabolite 
Sampling.
•
Modified footnote d: “If needed, 
the study can be ended 1 day 
early, with the End of Study Visit 
taking place on Day 13 instead of 
Day 14.” Added footnote d to 
Day 13 column title.
Updated schedule of activities for clarity
and to align with protocol text.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
•
Added footnote e to Day 14: 
“Evaluations performed prior to 
study 
discharge, 
or 
for 
participants 
who 
prematurely 
discontinue treatment.”
•
Modified footnote f to: “Only 
performed at day of discharge 
(Day 6 or beyond). If study 
participant is not discharged on 
Day 6, delay assessments and 
sample collections until day of 
discharge.”
Section 2: 
Schedule of 
Activities; Section 
9.4.5.2: Central 
Laboratory 
Assessments (On 
Treatment)
•
In Table 2-2, On-Treatment and 
Follow-up Procedural Outline 
(CV019010), added footnote h to 
indicate that hematology, serum 
chemistry, and urinalysis samples 
should be collected predose.
•
In Section 9.4.5.2, before the list 
of central laboratory assessments,
added: “The following samples 
should be
collected predose: 
Hematology, 
Chemistry, 
and
Urinalysis.” 
Updated on-treatment assessments to 
clarify that hematology, chemistry, and 
urinalysis samples are collected predose.
Section 2: 
Schedule of 
Activities
In Table 2-2, On-Treatment and 
Follow-Up Procedural Outline 
(CV019010), for 12-Lead 
Electrocardiogram (ECG) row, 
added the following note to specify 
timing of ECG measurements: “On 
Day 1, ECG will be collected 
pre-dose and at hours 2, 4, and 8. On 
Day 8 and Day 14, it will only be 
collected pre-dose.”
Added ECG time points in order to 
implement more robust safety 
monitoring on Day 1 of the study.
Section 2: 
Schedule of 
Activities; Section 
3.3.1: COVID-19-
related Risks and 
Risk Mitigation 
•
In 
Table 
2-1, 
Screening 
Procedural Outline (CV019010), 
SARS-CoV-2 testing (RT-PCR 
testing or rapid antigen test) was 
added.
Updates made to ensure participant and 
site safety and to maintain scientific 
integrity of the study in response to the 
COVID-19 pandemic.
Revised Protocol No: 01
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Measures Where 
Applicable;
Section 5.1: 
Overall Design; 
Section 6.2: 
Exclusion Criteria;
Section 7.2: 
Method of 
Treatment 
Assignment;
Section 8.1: 
Discontinuation 
from Study 
Treatment; Section 
9.4.5.1: Local 
Laboratory 
Assessments for 
Screening
•
In Table 2-2, On-Treatment and 
Follow-up Procedural Outline:
−
Footnote c was expanded to 
include an option for Day 8, 
Day 14, 
and 
Day 30 
ambulatory site visits to be 
done at home in cases where 
COVID-19 local regulations 
prevent in-person visits.
−
Footnote g was added to 
indicate that if the Targeted 
PE for Day 8 and Day 14 was 
not performed by the site due 
to 
COVID-19 
local 
regulations, 
a 
physical 
assessment will be done by 
the home nurse.
•
A new section, Section 3.3.1, 
COVID-19-related 
Risks 
and 
Risk Mitigation Measures Where 
Applicable, was added to address 
risk 
mitigation, 
including 
Investigational 
Product (IP)-related 
risk
(Section 3.3.1.1)
and 
general 
COVID-19-related 
risk 
mitigation 
measures
(Section 3.3.1.2). 
•
In Section 5.1, Overall Design,
text was added to describe:
−
The 
requirements
for 
SARS-CoV-2
testing 
(RT-PCR or rapid antigen 
test) at screening and a 
negative result in order to be 
randomized.
−
That, if the participant cannot 
return to the site because of 
COVID-19 local regulations
that prevent in-person visits 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
on Day 8, Day 14, and/or 
Day 30, then these visits can 
be done at home by the home 
nurse in discussion with the 
Principal 
Investigator 
(or 
designee).
•
In 
Section 
6.2, 
Exclusion 
Criteria, 
added 
exclusion 
criterion 
4) 
vii):
“Positive 
RT-PCR test or rapid antigen test
for 
SARS-CoV-2 
prior 
to 
randomization.”
•
In Section 7.2, Method of 
Treatment Assignment, updated 
that study treatment will be 
dispensed at the Day 1 visit, 
instead of at study visits listed in 
Schedule of Activities.
•
In Section 8.1, Discontinuation
from Study Treatment, added 
bullet: “Positive RT-PCR or 
rapid 
antigen 
test 
for 
SARS-CoV-2.”
•
In 
Section 
9.4.5.1, 
Local 
Laboratory 
Assessments 
for 
Screening, 
SARS-CoV-2
test
(RT-PCR or rapid antigen test)
was added to the list under Other 
Analyses.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 3.3: 
Benefit/Risk 
Assessment
The last sentence in the second 
paragraph was replaced with text 
describing hypotension as a risk 
associated with the use of 
BMS-986259 and the mitigation 
strategies implemented in the study. 
To clarify risk for study participation in 
regards to hypotension.
Section 4: 
Objectives and 
Endpoints
Secondary endpoint was updated to 
include Day 1 and to expand the PK 
parameters of BMS-986259 to 
include Cmax, Tmax, and 
AUC(TAU) on Day 1 and Day 5, 
and Ctrough. 
Updated secondary endpoint to 
characterize the PK after single dose and 
at steady state on Day 5.
Section 5.1: 
Overall Design
•
Added a bullet to clarify that 
“ADHF must be the main reason 
for hospitalization,
and other 
conditions with similar signs and 
symptoms must be excluded at 
screening.”
•
To the second bullet, added, 
“Randomization 
must 
occur 
within a maximum of 8 days 
Updated study design for clarity.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
since presentation to the ER and 
before hospital discharge.”
•
In Figure 5.1-1, the following 
updates were made:
−
Study Design was split into a 
Schematic portion and a 
Timeline portion.
−
Removed that participants in
the Sentinel Group must have 
SBP < 130 mmHg.
−
A box was added to specify 
the 
treatment 
initiation 
window compared to initial 
ER presentation for both 
groups.
−
Footnote b was added to 
indicate that “safety review of 
the sentinel group requires at 
least 
8 participants 
with 
systolic 
blood 
pressure
≥115 mmHg 
and < 130 mmHg.” 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 5.1: 
Overall Design
Updated first sentence in 
penultimate paragraph to: “In 
addition, if systolic BP is
< 85 mmHg or symptomatic 
hypotension occurs, the Principal 
Investigator (or designee; must be a 
medical doctor [MD]) must be 
contacted to make a decision as to 
whether an ambulatory unscheduled 
study visit or hospitalization is 
required based on overall clinical 
assessment. For example, 
asymptomatic study participants 
who can walk and have normal 
urination may not require 
hospitalization. BMS Study 
Director/Medical Monitor (or 
designee) must be notified.”
Clarified that primary investigator 
makes decisions on hospitalization for 
hypotension based on clinical 
judgement.
Section 5.5: 
Justification for 
Dose
Removed last paragraph and added 
text earlier in Section 5.5 to clarify 
dosing: “The observed mean 
exposures at steady state with 
repeated 3 mg QD dosing 
(AUC[TAU]) of 9,070 ng·h/mL 
remain under the mean exposure 
(AUC[INF]) of 38,200 ng·h/mL 
observed after a single 15 mg dose 
that was determined to be safe and 
well tolerated in a healthy 
participants study (Table 5.5-1).”
Provided further clarification on doses 
and exposures.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 6.1: 
Inclusion Criteria
•
Inclusion 
criterion 
3) 
was 
modified to delete the text: “The 
investigator shall evaluate the 
effectiveness of the contraceptive 
method in relationship to the first 
dose of study intervention.”
•
Removed statement in criterion 3) to 
ensure that the protocol specifies 
definitive 
requirements 
for 
contraception.
•
Added notes (1) and (2) to 
inclusion criteria 3) b) ii) and 
3) b) v). Note (1) in each criterion 
indicates that, respectively, for 
males who are sexually active 
with WOCBP and for female 
partners of males participating in 
the study, “less than highly 
effective 
methods 
of 
contraception and unacceptable 
methods of contraception are not 
permitted.” Note (2) in both 
criteria indicates that “Hormonal 
contraception 
is 
also 
not 
permitted.”
•
Added notes to criteria 3) b) ii) and 
3) b) v) to clarify contraception 
requirements for the study.
Section 6.1: 
Inclusion Criteria; 
Appendix 7: 
Country Specific 
Requirements/ 
Differences
•
In Section 6.1, added notes to 
criteria 
3) a) i) 
and 
3) b) i) 
referencing 
Appendix 
7 
for 
maximum age limit where locally 
mandated.
•
Added Appendix 7 to provide 
Czech 
Republic 
specific 
language. For inclusion criteria 
3) a) i) and 3) b) i), for females 
and males, respectively, added a 
maximum age of 75 years.
Added Czech Republic specific 
inclusion criteria for maximum age 
limits 
 
Section 6.2:
Exclusion Criteria
•
Expanded 
upon 
exclusion 
criterion 3) a) by listing out 
restrictions 
and 
prohibited 
treatments 
(phosphodiesterase 
type 5 [PDE5] inhibitors used for 
erectile dysfunction, continuous 
infusion of IV diuretics, inotropes 
and vasodilators), which are also 
provided in Section 7.7.
•
Added details on restrictions and 
prohibited 
treatments 
for 
clarification.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
•
Exclusion criterion 4) a) iv) was 
removed
and 
deemed 
“Not 
applicable per Revised Protocol 
01,”
and a new replacement 
criterion 4) a) vi) was added to 
modify 
the 
previous 
total 
bilirubin 
and 
liver 
enzyme 
requirements 
to
“Liver 
abnormalities 
including 
total 
bilirubin > 1.5 ×
ULN or 
significant elevation of liver 
enzymes 
(AST 
or 
ALT > 3 × ULN).”
•
Exclusion criterion was modified for 
clarity and to ensure appropriate level 
of liver enzymes is used for the study 
population.
Section 7.3: 
Blinding
Modified the last 2 paragraphs to:
•
Add that the Safety Review 
Committee is independent from 
the study team.
• Update unblinding procedures.
Clarified role of internal Safety Review 
Committee and unblinding for 
conducting the assessment of blood
pressure data in the Sentinel Group, and 
the planned interim analysis.
Section 7.5:
Preparation/ 
Handling/Storage/ 
Accountability
Removed text: “Study medication 
will be prepared by an unblinded 
pharmacist (or appropriate designee) 
at time of randomization.”
Clarified that unblinded pharmacist is 
not required, as the study will have 
matching placebo.
Section 7.7.1: 
Prohibited and/or 
Restricted 
Treatments
Revised the required window for 
reporting medications taken in 
hospital prior to study drug 
administration from 1 week to 
8 days.
Since screening period can be up to 
8 days after presentation at ER, text was 
updated to clarify that it needs to be 
ensured that all medications 
administered at the hospital are 
recorded.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 9.5: 
Pharmacokinetics;
 
 
 
 
 
In Section 9.5, Pharmacokinetics:
•
Removed AUC(INF) from the list 
of PK parameters.
•
Removed AUC(INF), as it cannot be 
calculated for steady state dosing at 
Day 5 for multiple dosing regimen.
•
Added text:
“When multiple 
procedures are required at a time 
point, prioritize that
the PK 
samples are collected as close to 
the
scheduled time point
as 
possible.”
•
Clarified
PK 
sample 
collection 
instruction at the time of multiple 
procedures.
•
In Table 9.5-1, Pharmacokinetic 
 Sampling 
Schedule for All Participants:
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
−
Removed the following PK 
sampling time points: Day 1 
1:00, 5:00, 7:00, 9:00, 11:00, 
12:00, and 16:00 postdose, 
Day 4 predose, Day 5 5:00 
and 15:00 postdose, and 
Day 7, 9, 10, 12, and 13 
predose. Added the following 
PK sampling time points: 
Day 5 3:00, 6:00, 8:00, 14:00 
post 
dose, 
and 
Day 14 
predose.
•
Optimized PK sampling to better 
characterize the PK on Day 1 and 
Day 5, 
and 
for 
participant 
convenience.
−
Removed 
urine 
and 
metabolite 
sample 
collections.
•
Removed 
urine 
and 
metabolite 
sample collections because it was 
already 
shown 
in 
previous 
nonclinical and clinical studies that 
there is minimal renal excretion of 
BMS-986259.
−
Added footnote a: “All the 
PK 
samples 
should 
be 
collected as close to the 
scheduled 
time 
point 
as 
clinically feasible.”
•
Clarified
PK 
sample 
collection
instruction.
−
Added footnote b to clarify 
timing of predose sample 
collection in relation to the 
injection time and in the event 
of a dose delay.
•
Clarified 
PK 
predose 
sample 
collection instruction.
Revised Protocol No: 01
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
−
Added footnote c to indicate 
that if End of Study Visit 
takes place
on Day 13, 
indicated Day 14 PK samples 
should be collected on Day 
13.
•
Clarified End of Study Visit PK 
sample collection.
−
Updated footnotes d. e, f, and 
g to detail the timing and 
applicability of 
follow-up 
visits.
•
Clarified 
follow-up 
timing 
and 
applicability.
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 10.3.2: 
Safety Analyses
The endpoint description of Adverse 
Events, Vital Signs, Laboratory Test 
Results, ECGs, and Physical 
Examination was moved into the 
Primary row. The matching 
statistical methods for these items 
were also moved into the Primary 
row. 
Updated endpoints, safety analyses, and 
statistical analysis methods for accuracy 
to match the study objectives and 
endpoints.
Section 10.3.5: 
Interim Analyses
Replaced “Not Applicable” with a 
description of the planned interim 
analysis.
Added description for an interim 
analysis to formally evaluate safety 
during the study half-way point.
Appendix 1: 
Abbreviations
Definitions for new in-text 
abbreviations were added.
Updated for accuracy and completeness.
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3.3.1 COVID-19-related Risks and Risk Mitigation Measures Where 
Applicable ................................................................................................... 
3.3.1.1 Investigational Product-related Risk .............................................. 
3.3.1.2 General COVID-19-related Risk Mitigation Measures .................. 
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8.1.1 Post Study Treatment Study Follow-up.................................................... 
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9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
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9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
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9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Electrocardiograms ................................................................................. 
9.4.5 Clinical Safety Laboratory Assessments .................................................. 
9.4.5.1 Local Laboratory Assessments for Screening ................................. 
9.4.5.2 Central Laboratory Assessments (On Treatment) .......................... 
9.4.6 Imaging Safety Assessment ...................................................................... 
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10.3.2 Safety Analyses....................................................................................... 
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Clinical Protocol
CV019010
BMS-986259
FA-Relaxin
1
SYNOPSIS
Protocol Title:
A Randomized, Double-Blinded, Placebo-Controlled, Study to Evaluate the Safety and 
Tolerability of BMS-986259 in Stabilized Patients Hospitalized for Acute Decompensated Heart 
Failure
Short Title: Study of the safety of BMS-986259 post-acute decompensated heart failure
Study Phase: 2A 
Rationale:
The main purpose of this trial is to evaluate the effect of BMS-986259 on blood pressure (BP)
events defined as symptomatic hypotension or hypotension requiring study drug discontinuation, 
in hospitalized heart failure (HF) patients stabilized after an admission for acute decompensated 
HF (ADHF). The study is designed to provide data on the range of BP in which BMS-986259 is 
safe and well tolerated in the context of the current hospitalization for ADHF. It also aims to 
provide additional rationale for future development, future clinical use and to inform the design of 
the next Phase 2-3 studies. In addition, this study will provide initial data on the pharmacokinetics
(PK) of BMS-986259 in HF participants. 
Standard of care in the treatment of ADHF involves the use of intravenous (IV) loop diuretics and 
vasodilators, which may predispose participants to hypotension, with or without symptoms.
Current guidance also recommends continuing Guidelines Directed Medical Therapy (GDMT)
including angiotensin-converting enzymes (ACE), Beta-Blockers, mineralocorticoid receptor 
antagonists (MRA)/mineralocorticoid 
receptor 
inhibitors (MRI), 
and 
angiotensin 
receptor-neprilysin inhibitors (ARNI), which may also lower BP. In the Serelaxin ADHF study, 
RELAX-AHF, greater reductions from baseline in systolic blood pressure (SBP) were observed 
during IV infusion up to 48 hours in the serelaxin group (-16.5 mmHg ± 17.2) compared with 
placebo (-12.3 mmHg ± 17.2). Also, more participants on serelaxin than on placebo had protocol 
required BP-related dose reduction (29% vs 18%) or drug discontinuation (19% vs 12%). In 
contrast, in the chronic stable HF population of the RELAX REPEAT study, SBP in the serelaxin 
group did not differ from placebo. There are no data on the effect of relaxin on BP in the population 
of HF patients admitted for ADHF, but not yet discharged, already medically stabilized and 
weaned from IV vasodilators or inotropes. 
Study Population:
Male and females, at least 18 years of age or local age of majority, currently hospitalized for 
ADHF, regardless of left ventricular ejection fraction (LVEF).
Revised Protocol No: 01
Date: 28-Oct-2020
22
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
CV019010
BMS-986259
FA-Relaxin
Objectives and Endpoints:
Objective
Endpoint
Primary
•
To establish safety & tolerability of 
BMS-986259 when initiated 
in-hospital in participants stabilized
after an admission for ADHF
•
Incidence of clinically relevant hypotension, defined as:
−
Supine SBP < 85 mmHg (confirmed by repeat 
measurement within 30 minutes), regardless of symptoms 
of hypotension 
OR
−
Supine SBP < 90 mmHg (confirmed by repeat measurement 
within 30 minutes) AND symptoms of hypotension.
Secondary
•
To evaluate serum PK parameters in 
participants with HF 
•
PK parameters of BMS-986259:
−
Cmax, Tmax, and AUC(TAU) on Day 1 and Day 5
−
Ctrough
Abbreviations: ADHF = acute decompensated heart failure; AUC(TAU) = area under the concentration-time curve in 
one dosing interval; BMS = Bristol-Myers Squibb; Cmax = maximum observed concentration; Ctrough = trough 
concentration; HF = heart failure; PK = pharmacokinetic; SBP = systolic blood pressure; Tmax = time of maximum 
observed concentration.
Overall Design:
This is a Phase 2A randomized, double-blind, placebo-controlled study of BMS-986259 in 
hemodynamically stabilized patients currently hospitalized for ADHF. The study is designed to 
establish if BMS-986259 is safe and well tolerated in this population with regards to clinically 
significant hypotension.
•
ADHF must be the main reason for hospitalization, and other conditions with similar signs and 
symptoms must be excluded at screening.
•
at least 24 hours after presentation to Emergency Room (ER) and no later than 8 days after 
presentation to ER. Time of the presentation is defined as the time of the first dose of IV 
diuretic in the hospital. Randomization must occur within a maximum of 8 days since 
presentation to ER and before hospital discharge.
•
at least 12 hours since last dose change of IV loop diuretics and at least 24 hours since last 
dose of positive inotropes and ≥ 12 hours since the last dose of IV vasodilators.
•
Prior to randomization, participants will also be tested for severe acute respiratory syndrome 
coronavirus 2 by reverse transcription polymerase chain reaction or rapid antigen test. Only 
participants with a negative test result are eligible for randomization.
Participants will be randomized 1:1 to receive BMS-986259 3 mg or placebo. Treatment will be 
administered subcutaneously once daily for 14 days and follow-up will last until Day 30 (± 2 days). 
 
Revised Protocol No: 01
Date: 28-Oct-2020
23
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
CV019010
BMS-986259
FA-Relaxin
A minimum hospital stay of 5 days from randomization/first dose of investigational product (IP)
is required. If participants are discharged home before the end of active study treatment, study 
visits will be performed daily either as an outpatient clinic visit or by a home nurse or healthcare 
provider (per local regulations/requirements) who will be responsible to measure pre-dose BP, 
draw PK sample(s), administer the IP subcutaneously
 
when appropriate per study schedule.
Participants will return for up to three ambulatory visits at the site on Day 8, Day 14, Day 30 
(follow-up). If the participant cannot return to the site because of coronavirus disease 2019 
(COVID-19) local regulations that prevent visits in-person, these visits can be done at home by 
the home nurse in discussion with the Principal Investigator (or designee). In addition, at discharge, 
participants will receive BP measuring device and will be instructed to measure BP if symptoms 
consistent with hypotension occur. If systolic BP falls below 85 mmHg (on 2 repeated 
measurements within 30 minutes) and symptoms of hypotension persist, participants will be 
instructed to report to the study site or another healthcare provider if the study site cannot be 
reached.
Initially participants with SBP ≥115 mmHg will qualify to be randomized 1:1 to receive 3 mg 
subcutaneous BMS-986259 once daily (QD) or placebo. After approximately 8 participants with 
SBP ≥115 and < 130 mmHg have completed the treatment period, the Safety Review Committee 
will review the safety data from this sentinel group and ensure it is safe to proceed with the 
Main Group, ie., open the recruitment for participants with SBP less than 115 mmHg (but at least 
100 mmHg).
The Main Group will include participants with SBP ≥100 mmHg, randomized 1:1 to BMS-986259 
or placebo. The proportion of participants with SBP > 125 mmHg will be capped at 48 participants.
Study drug may be down-titrated to 1 mg or discontinued according to the criteria described in 
dose modification.
In addition, if systolic BP is < 85 mmHg or symptomatic hypotension occurs, the Principal 
Investigator (or designee; must be a medical doctor [MD]) must be contacted to make a decision 
as to whether an ambulatory unscheduled study visit or hospitalization is required based on overall 
clinical assessment. For example, asymptomatic study participants who can walk and have normal 
urination may not require hospitalization. BMS Study Director/Medical Monitor (or designee) 
must be notified. A blinded clinical contact will be available 24/7 to answer questions and guide 
the home nurse as needed.
The study design schematic is presented in Figure 1.
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Figure 1:
Study Design Schematic
Abbreviations:
 D = day; ER = emergency room; 
QD = once 
daily; R = randomization; SBP = systolic blood pressure.
a May be down-titrated to 1 mg or discontinued according to the dosage modification criteria described in the 
protocol.
b Safety review of the sentinel group requires at least 8 participants with blood pressure < 130 mmHg.
c If participant is discharged before the end of active study treatment, study visits will be performed daily either as 
an outpatient clinic visit or by a home nurse or healthcare provider.
Number of Participants: 
It is estimated that a total of approximately 72 participants will be randomized with 1:1 ratio
assigned to either BMS-986259 subcutaneous QD or Placebo to have at least 60 completers by the 
end of the study.
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Treatment Arms and Duration:
Study treatment: 
Study Drug for CV019010
Medication 
Potency 
IP/Non-IP 
BMS-986259 injection 
for SC administration
5 mg/vial (5 mg/mL)
Dose level 3 mg and 1 mg
BMS-986259 will be diluted to administer a 3 mg or 1 mg dose as 
a 1 mL SC injection. Details of preparation and administration are 
provided in the pharmacy manual
IP
Placebo injection for SC 
administration
N/A
IP
Abbreviations: IP = investigational product; N/A = not applicable; SC = subcutaneous.
Safety Review Committee: Yes
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CV019010)
Procedure
Screening
Notes
Visita
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed consent 
is signed.
Inclusion/Exclusion Criteria
X
Note: ≥12 hours since the last dose change of IV loop diuretics, and ≥24 hours 
since last dose of positive inotropes and ≥12 hours since the last dose of IV 
vasodilators. See Section 6.1 and Section 6.2. 
Medical History
X
Include any toxicities or allergy related to previous treatments.
Safety Assessments
Physical Examination (PE)
X
If the Screening PE is performed within 24 hours prior to dosing on Day 1 then a 
single exam may count as both the Screening and pre-dose evaluation.
Physical Measurements
X
Includes height, weight, and body mass index (BMI).
Vital Signs
X
Includes body temperature, respiratory rate, blood pressure, and heart rate. Heart 
rate should be measured per standard of care (SOC). Blood pressure should be 
measured while the participant is in a supine position (preferable, based on 
participant’s condition and comfort). Consider alternate position(s) for vital sign 
collection.
Assessment of Signs and Symptoms (NYHA class)
X
Refer to Appendix 6.
Concomitant Medication Use
X
See Section 7.7.
12-Lead Electrocardiogram (ECGs)
X
ECGs should be recorded after the participant has been supine for at least 5 minutes. 
Central Laboratory Assessments
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Table 2-1:
Screening Procedural Outline (CV019010)
Procedure
Screening
Notes
Visita
Local Laboratory Assessments
Includes blood and urine samples for chemistry, CBC, hematology, and urinalysis 
(dipstick and full microscopic evaluation if dipstick positive). See Section 9.4.5.
SARS-CoV-2 Testing
X
RT-PCR testing or rapid antigen test must be performed prior to randomization. 
Potential participants found to test positive for SARS-CoV-2 will be treated 
according to site standard practice and in accordance with local and national 
regulations.
Hematology and Serum Chemistry
X
See Section 9.4.5.
Serology (Hepatitis and HIV)
X
See Section 9.4.5.
Urinalysis
X
See Section 9.4.5.
NT-proBNP or BNP
X
Local lab value for NT-proBNP or BNP can be used for eligibility. 
FSH Test
X
For women < 55 years.
Monitor for Serious Adverse Events (SAEs)
X
All SAEs must be collected from the date of participant’s written consent until 
30 days post discontinuation of dosing or participant’s participation in the study if 
the last scheduled visit occurs at a later time.
Abbreviations: BMI = body mass index; BNP = brain natriuretic peptide; CBC = complete blood count; ECG = electrocardiogram; ER = emergency room; 
FSH = follicle stimulating hormone; HIV = human immunodeficiency virus; IV = intravenous; NT-proBNP = N-terminal pro-brain natriuretic peptide; 
NYHA = New York Heart Association; PE = physical examination; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; SAE = serious adverse event; SOC = standard of care.
a Screening must occur at least 24 hours post initial emergency room (ER) presentation. Randomization must occur within 8 days post initial ER presentation.
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Safety Assessments
Targeted PE
Xf
Xg
Xg
Complete before 
discharge.
Injection site 
evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site 
evaluation 
performed daily 
pre-dose and in the 
evening. 
Post-discharge, a 
home nurse (or 
site personnel) will 
evaluate injection 
site prior to study 
drug 
administration.
Physical 
Measurements 
X
X
X
X
X
Xf
X
X
In hospital weight 
measurements 
daily until 
discharge.
Day 1 pre-dose.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre-dose BP 
measurement on
Day 1 at 0 hour; at
2, 4, 8, 12, 16, 20, 
24 hours post 
dose.
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Pre-dose BP 
measurement on 
Day 2 at 0 hour, at 
2, 4, 8, and 
12 hours post 
dose.
Then 4 times a day 
on following days 
until discharge, 0, 
4, 8, 12 hours. 
Once participant is 
discharged home, 
BP to be measured 
pre-dose by home 
nurse. Participant 
should be in 
supine position
(preferable, based 
on participant’s 
condition and 
comfort) and using 
non-dominant arm
for home 
measurements.
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Assessment of Sign 
and Symptoms 
(NYHA class)
X
Xf
X
X
12-Lead ECG
X
X
X
ECGs should be 
recorded after the 
participant has 
been supine for at 
least 5 minutes.
On Day 1, ECG 
will be collected 
pre-dose and at 
hours 2, 4, and 8. 
On Day 8 and 
Day 14, it will 
only be collected 
pre-dose.
Concomitant 
Medication Use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central Laboratory Assessments  
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Hematology and 
Serum Chemistryh
X
X
X
Xf
X
X
X
See Section 9.4.5.
Urinalysish
X
X
X
Xf
X
X
X
See Section 9.4.5.
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Adverse Event Reporting
Monitor for 
Non-Serious 
Adverse Events & 
Serious Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic (PK) Assessments
Blood PK Sampling
See Table 9.5-1 for sampling schedule
See Section 9.5.
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Table 2-2:
On-Treatment and Follow-up Procedural Outline (CV019010)
Procedure
Randomization
D1a
D
2
D
3
D
4
D
5
D
6
D
7b
D
8
Visitc
D
9b
D
10
D
11b
D
12
D
13d
D14
End 
of 
Study 
Visit
c,d,e
D30
(± 2 
days)
Follow 
-Up
Visitc
Notes
Clinical Drug Supplies
Randomize
X
Study Drug 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP is administered 
subcutaneously 
once daily.
Abbreviations:
 BP = blood pressure; COVID-19 = coronavirus disease 2019; 
D = Day; 
ECG = electrocardiogram; HF = heart failure; ICF = informed consent form; IMP = investigational medicinal product;
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IP = investigational product; IV = intravenous; 
NYHA = New York Heart 
Association; PE = physical examination; PK = pharmacokinetic
.
a If screening and randomization are on the same day all evaluations can be performed only once.
b Study coordinator calls participants post-discharge to ensure investigational medicinal product (IMP) storage compliance.
c Participants will return to site for up to three ambulatory visits. (Day 8, Day 14, Day 30). If the participant cannot return to the site because of COVID-19 local 
regulations that prevent visits in-person, these visits can be done at home by the home nurse in discussion with the Principal Investigator (or designee).
d If needed, the study can be ended 1 day early, with the End of Study Visit taking place on Day 13 instead of Day 14.
e Evaluations performed prior to study discharge, or for participants who prematurely discontinue treatment.
f Only performed at day of discharge (Day 6 or beyond). If study participant is not discharged on Day 6, delay assessments and sample collections until day of 
discharge.
g If the physical examination was not completed by the site because of COVID-19 local regulations, a physical assessment will be done by the home nurse.
h These samples should be collected predose.
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In the event multiple procedures are required at a single time point, the following is a list of 
procedures from highest priority to low:
•
Vital signs
•
Pharmacokinetic (PK) Sampling
•
Safety (clinical labs)
•
Safety (electrocardiogram [ECG])
3
INTRODUCTION
Heart failure (HF) is a clinical syndrome that results from insufficient supply of blood to maintain 
normal tissue function due to any structural or functional impairment of ventricular filling or 
ejection of blood from the heart. The cardinal manifestations of HF are dyspnea and fatigue, which 
may limit exercise tolerance and promote fluid retention, leading to pulmonary and/or splanchnic 
congestion and/or peripheral edema.1 The global burden of HF is substantial with an estimated 
global prevalence of 26 million. In the United States alone, an estimated 6.5 million people suffer 
from HF, a number that is projected to increase ~ 46% by the year 2030.2,3 Current treatment 
guidelines categorize HF patients based on ejection fraction (EF): 1) heart failure with reduced 
ejection fraction (HFrEF) with an EF ≤40%, 2) heart failure with a mid-range (intermediate) 
ejection fraction (HFmrEF) of 41% to 49%, and 3) heart failure with preserved ejection fraction 
(HFpEF) with an EF ≥50%.1 The pathophysiology of HF is highly complex and diverse in 
etiology, especially with regard to the biological pathways that lead to either HFrEF or HFpEF.4,5,6
Although therapeutics which target the neurohormonal axis (eg, beta-blockers, angiotensin 
converting enzyme inhibitors and other renin angiotensin-aldosterone system (RAAS) inhibitors, 
as well as mineralocorticoid receptor antagonists [MRAs]) have led to a decrease in mortality rates 
in HFrEF patients, unmet medical need remains very high.7 No therapy has yet been proven in a 
placebo-controlled clinical trial to reduce mortality rates in HFpEF patients.7
HF is commonly accompanied by multiple comorbidities including hypertension, diabetes 
mellitus, and chronic kidney disease (CKD).5 The majority of HF patients have CKD, defined as 
an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2.8 A large meta-analyses of 
80,098 hospitalized and non-hospitalized HF patients revealed that the presence of CKD is highly 
prognostic of worsening HF.9 Furthermore, worsening renal function (WRF) during the 1-year 
period following hospital discharge for acute decompensated HF (ADHF) was a strong predictor 
of all-cause mortality.10 These types of associative data combined with biological plausibility, in 
that renal impairment can lead to a feedback response of neurohormonal and RAAS activation, 
have led some investigators to suggest that CKD may play a causal role in HF.9 However, whether 
or not CKD is truly on the causal pathway to worsening HF is unknown. 
Human relaxin (H2-relaxin) is a peptide hormone believed to be, at least in part, responsible for 
the many physiological adaptations that occur during human pregnancy.11 These changes include 
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an ~ 30% increase in global arterial compliance which is important to maintain efficient 
ventricular-arterial coupling, an ~ 30% decrease in total systemic vascular resistance (SVR), and 
up to an 80% and 50% increase in renal blood flow (RBF) and glomerular filtration rate (GFR), 
respectively.12,13,14 As discussed in detail below, clinical studies in which serelaxin was 
administered intravenously (IV) to either normal healthy volunteers (NHV) or HF patients 
provided pharmacological evidence that H2-relaxin is involved, at least in part, in mediating these 
adaptive maternal changes. Because H2-relaxin activates both relaxin/insulin-like family peptide 
receptor 1 (RXFP1) and relaxin/insulin-like family peptide receptor 2 (RXFP2) it has been difficult 
to precisely define the individual roles of each receptor during mammalian pregnancy. However, 
several lines of evidence, including the noted receptor potency differential in relationship to low 
endogenous blood levels of H2-relaxin during human pregnancy, tissue expression patterns, and 
arterial compliance experiments in vessels that express RXFP1, but not RXFP2, all suggest that 
RXFP1 plays the larger role of the 2 receptors.15,16 There are no reports in the literature describing 
loss-of-function mutations in humans for either the H2-relaxin or the RXFP1 gene. In contrast, 
missense mutations in either the human insulin-like peptide 3 (INSL3) or the RXFP2 gene are 
associated with cryptorchidism, indicating that activation of RXFP2 plays a critical role in 
testicular descent, which normally occurs at gestational week 24 through 34 in humans.17 The 
physiological effect, if any, of RXFP2 activation in the adult human is unknown.
A short-acting recombinant form of H2-relaxin, serelaxin- (Novartis), administered IV, was 
demonstrated to have vasodilatory properties and to enhance both RBF and eGFR in patients with 
HF.18,19,20 Serelaxin also demonstrated anti-fibrotic activity in cell-based and in preclinical models 
of fibrosis.21,22 In a large Phase 3 clinical trial (RELAX-AHF-2), serelaxin, when administered as 
a short-term 48-hour continuous IV infusion, failed to improve long-term clinical outcomes 
compared with placebo in patients with ADHF.23 Although this failure represents a setback for the 
advancement of novel therapeutics to treat HF, learnings from the multitude of serelaxin clinical 
trials, indicate that chronic administration of a therapeutic with H2-relaxin-like activity (ie, beyond 
48 hours) could potentially benefit HF patients. More specifically, serelaxin was demonstrated to 
increase both RBF and eGFR in NHV and HF patients.18,19,20,24,25 In a non-placebo-controlled 
trial, when serelaxin- was administered IV to NHV over a 5-hour period at a dose resulting in 
blood concentrations that closely mimicked the peak human pregnancy blood concentration of 
H2-relaxin (1.0 ng/mL), a 47% increase, relative to baseline, in RBF was observed, although GFR 
remained unchanged.24 Changes in RBF were similar between males and females. In a separate 
double-blind, placebo-controlled, dose-ranging study in NHV of Japanese descent, serelaxin was 
given as a continuous 48-hour IV infusion at doses of 10, 30, or 100 μg/kg/day.25 Mean blood 
concentrations of serelaxin at the 48-hour time point were 3.49 ng/mL, 9.82 ng/mL, and 
29.2 ng/mL, respectively. Statistically significant increases in eGFR were observed for all doses 
of serelaxin, but not for placebo. Changes in RBF were not evaluated in this study. In a 
double-blind and placebo-controlled study in chronic HF patients, when compared to placebo, 
statistically significant increases in renal plasma flow were observed for serelaxin when given as 
a continuous 24-hour IV infusion at a dose of 30 μg/kg/day.18 Changes in GFR were minimal and 
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not significantly different from placebo. In a separate double-blind and placebo -controlled study 
in which serelaxin was given to chronic HF patients as a continuous 48-hour IV infusion at the 
dose of 30 μg/kg/day, when compared to placebo, statistically significant increases in eGFR 
(difference of 4.7, 5.9 and 5.7 ml/min/1.73m2 vs placebo, at 2, 4 and 8 weeks; p<0.001) were 
observed for serelaxin.19 Plasma concentrations of aldosterone were decreased in the serelaxin 
treatment group, but not in the placebo treatment group indicating that enhancement of renal 
function in chronic HF patients may lead to attenuation of RAAS activation.
Hemodynamic effects of serelaxin were also studied in a double-blind, placebo-controlled trial in 
patients hospitalized for ADHF. When serelaxin was given as a 20-hour IV infusion at a dose of 
30 μg/kg/day, hemodynamic effects were detected early (within 30 minutes), and were 
characterized by statistically significant reductions (versus placebo) in pulmonary capillary wedge 
pressure (PCWP) and pulmonary arterial pressure (PAP), with a concomitant decrease in SVR.20
Serelaxin administration also improved renal function and decreased circulating levels of 
N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of cardiac stress. 
Several investigators, through the use of subcutaneous (SC) osmotic mini-pumps which 
continuously deliver drug at a defined rate, demonstrated that treatment with H2-relaxin decreased 
fibrosis in various rodent models of cardiac, kidney, lung and liver fibrosis.21 In a cell-based model 
of TGF-β-treated rat cardiac fibroblasts, serelaxin significantly decreased expression of the pro-
fibrotic genes smooth muscle alpha-actin and collagen type I.22 Changes in levels of protein 
phosphorylation indicated that the reduction in pro-fibrotic gene expression was the result of 
serelaxin-dependent suppression of activin-like kinase 5 (ALK5)/Mothers against decapentaplegic 
homolog 2 (SMAD2) signaling, a well-studied signaling pathway induced by TGF-β.
The ability of H2-relaxin/serelaxin to positively impact both systemic and renal hemodynamics, 
improve renal function, and possibly decrease cardiac fibrosis, makes H2-relaxin an attractive 
candidate as a chronic therapy for HF patients. However, the short-acting PK profile of H2-relaxin 
essentially precludes its use as a chronic therapeutic. In contrast, with a PK profile (non-clinical 
studies and preliminary clinical data) that supports once daily (QD) dosing and H2-relaxin-like 
activity, BMS-986259 represents an opportunity to provide HF patients with the therapeutic 
benefits anticipated for H2-relaxin when dosed chronically.
3.1
Study Rationale
The main purpose of this trial is to evaluate the effect of BMS-986259 on blood pressure (BP)
events defined as symptomatic hypotension or hypotension requiring study drug discontinuation, 
in hospitalized HF patients stabilized after an admission for ADHF. The study is designed to 
provide data on the range of BP in which BMS-986259 is safe and well tolerated in the context of 
the current hospitalization for ADHF. It also aims to provide additional rationale for future 
development, future clinical use and to inform the design of the next Phase 2-3 studies. In addition,
this study will provide initial data on the pharmacokinetics of BMS-986259 in HF participants. 
Standard of care in the treatment of ADHF involves the use of IV loop diuretics and vasodilators, 
which may predispose participants to hypotension, with or without symptoms. Current guidance 
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also recommends continuing Guidelines Directed Medical Therapy (GDMT)
including 
angiotensin-converting enzymes (ACE), beta-blockers, MRAs/mineralocorticoid receptor 
inhibitors (MRI), and angiotensin receptor-neprilysin inhibitors (ARNI), which may also lower 
BP. In the Serelaxin ADHF study, RELAX-AHF, greater reductions from baseline in SBP were 
observed during IV infusion up to 48 hours in the serelaxin group (-16.5 mmHg ± 17.2) compared 
with placebo (-12.3 mmHg ± 17.2). Also, more participants on serelaxin than on placebo had 
protocol required blood pressure-related dose reduction (29% vs 18%) or drug discontinuation 
(19% vs 12%).26 In contrast, in the chronic stable HF population of the RELAX REPEAT study,
SBP in the serelaxin group did not differ from placebo.19 There are no data on the effect of relaxin
on BP in the population of HF patients admitted for ADHF, but not yet discharged, already 
medically stabilized and weaned from IV vasodilators or inotropes. 
3.2
Background
Over the last several decades, the improvements in HF treatments led to better survival and reduced 
hospitalization rate in patients with HFrEF. Current HF guidelines however recognize that this
outcome is still not satisfactory. In the recent European data, 12-month all-cause mortality rate for 
hospitalized and stable ambulatory HF patients were 17% and 7%, respectively and hospitalization 
rates were 44% and 32%, respectively.27 In addition, optimization of the evidence-based 
treatments is often limited by co-morbidities and undesired effects of treatment such as renal 
impairment, hyperkalemia, and low blood pressure, typical for RAAS blocking agents remaining 
the foundational therapy for HFrEF. In addition, no beneficial effects on outcomes were 
demonstrated with similar strategies in patients with HFpEF. Hence, new approaches are required
to improve outcomes both in HFpEF as well as in patients with HFrEF, when optimization of 
therapy is particularly difficult.28
Several studies with recombinant human relaxin have demonstrated short-term multi-organ 
protection in HF patients measured as beneficial effects on biomarkers of cardiac and renal injury 
and improved function. The half-life of serelaxin is short after acute 48 hours infusion and long-
term improvement in CV outcomes has not been seen. Short-term IV injection cannot be expected 
to exhibit lasting effects; therefore, to fully understand the potential long-term benefits of relaxin, 
one needs to develop a formulation that allows for chronic administration.
BMS-986259, is a recombinant form of H2-relaxin that contains a covalently attached fatty acid 
which binds to circulating albumin, extending its half-life. BMS-986259 closely mimicked the 
activity profile of H2-relaxin in a panel of in vitro cell-based assays, as well as in a rodent 
pharmacodynamic in vivo model.29 These activity data, together with the preclinical PK and 
toxicology data, indicate that BMS-986259 can be safely administered subcutaneously. 
Preliminary data from ongoing first in human (FIH) study also support safe subcutaneous use up 
to 14 days. Chronic QD subcutaneous (SC) administration of BMS-986259 has the potential to 
benefit patients with HF. An ongoing Phase 1 study with BMS-986259 will confirm its effects on 
the renal function and support its potential to protect/improve renal function in HF. 
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The population of ADHF patients, early after admission, has the highest rate of 60 to 90 days
mortality and rehospitalizations, with rates as high as 14% and 30%, respectively.30 In the United 
States alone, there are more than 1 million admissions for HF as primary diagnosis per year.31,32
This represents a high unmet need for both patients with HFrEF and HFpEF. In the ADHF 
population, little to no data are available about the benefits of starting chronic treatment in the 
hospital setting, before discharge. 
3.3
Benefit/Risk Assessment
The current study is a Phase 2A, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study of BMS-986259 in medically stabilized participants currently hospitalized for 
ADHF. Participants will continue their therapy as deemed necessary for their condition and receive 
any HF therapy required by HF guidelines. Participants may benefit from an ongoing assessment 
of their health status in the period of time immediately after discharge from the hospital. It is not 
known if 2 weeks of therapy with BMS-986259 can provide any symptomatic improvement and 
50% of participants will receive placebo. Short -term course of BMS-986259 is not expected to 
translate into long-term benefit. 
In the ongoing Phase 1 study in NHV (CV019-002), BMS-986259’s administration was generally 
safe and well-tolerated. The most frequently reported adverse events (AEs) were cannula site 
reaction and cannula site pain related to the study procedures to measure RBF and GFR, but 
unrelated to the study drug. The effect on BP and heart rate (HR) in individual participants appears 
to be minimal. Formal statistical summaries are not available at this time as the treatment is still 
blinded, but no clinically significant or symptomatic hypotension has been reported. The doses 
evaluated thus far have been safe and well-tolerated, with no deaths, serious adverse events 
(SAEs), or AEs leading to discontinuation reported. In the large serelaxin development program,
human recombinant relaxin was generally safe and well tolerated in participants with HF. 
Bristol-Myers Squibb (BMS) nonclinical and preliminary clinical data and the serelaxin clinical 
program suggest that the principal risk associated with the use of BMS-986259 is hypotension. 
Transient reductions in BP are not expected to be associated with long-term sequelae. This study 
is designed specifically to address this risk, and mitigation strategies are implemented, such as 
rigorous BP monitoring, both in-hospital and post-discharge, and a dose-modification algorithm 
in case of symptomatic or asymptomatic hypotension.
3.3.1
COVID-19-related Risks and Risk Mitigation Measures Where Applicable
The following risks and risk mitigating measures apply to any part of the study conducted during 
the coronavirus disease 2019 (COVID-19) pandemic. The study includes several features to 
mitigate this risk:
•
The study sites have implemented standard operating procedures for risk mitigation as 
described in Section 3.3.1.2.
•
The protocol implements severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
testing as shown in Table 2-1 in order to prevent randomization of participants with active 
COVID-19 infection and to ensure participant safety and study integrity.
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3.3.1.1
Investigational Product-related Risk
At this time, BMS is tracking and accumulating data on COVID-19 and its potential effects on 
participants taking BMS-986259 and other investigational products (IPs). The data are analyzed 
on a regular basis. Based on its properties and mechanism of action, BMS-986259 is not believed 
to be implicated in COVID-19 infection and symptomology. The risk of COVID-19 in participants 
taking BMS-986259 is still unknown due to insufficient clinical data.
3.3.1.2
General COVID-19-related Risk Mitigation Measures
General risk mitigation for COVID-19 will be implemented in accordance with the sites’ local 
prevention control procedures
and relevant governmental and Institutional Review 
Board (IRB)-associated requirements. Such measures aim to minimize prevalence and 
transmission of SARS-CoV-2 among site staff and participants and include distancing, 
sanitization, use of personal protective equipment, and testing.
Participants found to test positive for SARS-CoV-2 after enrollment in the study will be treated 
according to site standard practice and in accordance with local and national regulations. In such 
cases, treatment with BMS-986259 will be discontinued as described in Section 8.
The risk mitigation measures are part of the protocol-specific informed consent form (ICF), and 
when and where applicable, will be amended based on emerging guidance. 
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To establish safety & tolerability of 
BMS-986259 when initiated in-hospital 
in participants stabilized after an 
admission for ADHF
•
Incidence of clinically relevant hypotension, defined as:
−
Supine SBP < 85 mmHg (confirmed by repeat 
measurement within 30 minutes), regardless of 
symptoms of hypotension 
OR
−
Supine SBP < 90 mmHg (confirmed by repeat 
measurement within 30 minutes) AND symptoms of 
hypotension
Secondary
•
To evaluate serum PK parameters in 
participants with HF
•
PK parameters of BMS-986259:
−
Cmax, Tmax, and AUC(TAU) on Day 1 and Day 5
−
Ctrough
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Abbreviations: 
 ADHF = acute 
decompensated heart failure; AUC(TAU) = area under the concentration-time curve in one dosing interval;
BMS = Bristol-Myers Squibb; BP = blood pressure; Cmax = maximum observed concentration; Ctrough = trough 
concentration;
 HF = heart failure; 
IV = intravenous; 
 
PK = pharmacokinetic;
 
Tmax = time of maximum observed concentration.
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2A randomized, double-blind, placebo-controlled study of BMS-986259 in 
hemodynamically stabilized patients currently hospitalized for ADHF. The study is designed to 
establish if BMS-986259 is safe and well tolerated in this population with regards to clinically 
significant hypotension.
•
ADHF must be the main reason for hospitalization, and other conditions with similar signs and 
symptoms must be excluded at screening.
•
at least 24 hours after presentation to Emergency Room (ER) and no later than 8 days after
presentation to ER. Time of the presentation is defined as the time of the first dose of IV 
diuretic in the hospital. Randomization must occur within a maximum of 8 days since 
presentation to ER and before hospital discharge.
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•
at least 12 hours since last dose change of IV loop diuretics and at least 24 hours since last 
dose of positive inotropes and ≥12 hours since the last dose of IV vasodilators.
•
Prior to randomization, participants will also be tested for SARS-CoV-2 by reverse 
transcription polymerase chain reaction (RT-PCR) or rapid antigen test. Only participants with 
a negative test result are eligible for randomization.
Participants will be randomized 1:1 to receive BMS-986259 3 mg or placebo. Treatment will be 
administered subcutaneously once daily for 14 days and follow-up will last until Day 30 (± 2 days). 
A minimum hospital stay of 5 days from randomization/first dose of IP is required. If participants 
are discharged home before the end of active study treatment, study visits will be performed daily 
either as an outpatient clinic visit or by a home nurse or healthcare provider (per local 
regulations/requirements) who will be responsible to measure pre-dose BP, draw PK sample(s), 
administer the IP subcutaneously
 
.
Participants will return for up to three ambulatory visits at the site on Day 8, Day 14, Day 30
(follow-up). If the participant cannot return to the site because of COVID-19 local regulations that 
prevent visits in-person, these visits can be done at home by the home nurse in discussion with the 
Principal Investigator (or designee). In addition, at discharge, participants will receive BP 
measuring device and will be instructed to measure BP if symptoms consistent with hypotension 
occur. If systolic BP falls below 85 mmHg (on 2 repeated measurements within 30 minutes) and 
symptoms of hypotension persist, participants will be instructed to report to the study site or 
another healthcare provider if the study site cannot be reached. 
Initially participants with SBP ≥115 mmHg will qualify to be randomized 1:1 to receive 3 mg 
subcutaneous BMS-986259 QD or placebo. After approximately 8 participants with 
SBP ≥115 and < 130 mmHg have completed the treatment period, the Safety Review Committee 
will review the safety data from this sentinel group and ensure it is safe to proceed with the 
Main Group, ie., open the recruitment for participants with SBP less than 115 mmHg (but at least 
100 mmHg). 
The Main Group will include participants with SBP ≥100 mmHg, randomized 1:1 to BMS-986259 
or placebo. The proportion of participants with SBP > 125 mmHg will be capped at 48 participants.
Study drug may be down-titrated to 1 mg or discontinued according to the criteria described in 
dose modification in Section 7.4.
In addition, if systolic BP is < 85 mmHg or symptomatic hypotension occurs, the Principal 
Investigator (or designee; must be a medical doctor [MD]) must be contacted to make a decision 
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as to whether an ambulatory unscheduled study visit or hospitalization is required based on overall 
clinical assessment. For example, asymptomatic study participants who can walk and have normal 
urination may not require hospitalization. BMS Study Director/Medical Monitor (or designee)
must be notified. A blinded clinical contact will be available 24/7 to answer questions and guide 
the home nurse as needed.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Abbreviations: 
 D = day; ER = emergency room; 
 QD = once 
daily; R = randomization; SBP = systolic blood pressure.
a May be down-titrated to 1 mg or discontinued according to the criteria described in Section 7.4.
b Safety review of the sentinel group requires at least 8 participants with systolic blood pressure ≥ 115 mmHg 
and < 130 mmHg.
c If participant is discharged before the end of active study treatment, study visits will be performed daily either as 
an outpatient clinic visit or by a home nurse or healthcare provider.
Physical examinations, vital sign measurements, 12-lead ECGs, and clinical laboratory evaluations 
will be performed at selected times throughout the dosing interval and during follow-up.
Participants will be closely monitored for AEs throughout the study. 
5.1.1
Safety Review Committee
An internal Safety Review Committee will assess BP data after completion of the Sentinel Group. 
The Committee may request access to unblinded treatment codes for individual participants. The 
Committee will consist of senior clinical development individuals not directly involved in the 
study conduct and overseeing, including (but not limited to) senior Worldwide Patient Safety
representative, a statistician, and a senior clinician.  
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5.2
Number of Participants
It is estimated that a total of approximately 72 participants will be randomized with 1:1 ratio 
assigned to either BMS-986259 subcutaneous QD or Placebo to have at least 60 completers by the 
end of the study.
5.3
End of Study Definition
The study treatment’s duration is 14 days with an on-site follow-up visit on Day 30 (± 2 days). 
 
 
The start of 
the trial is defined as the first visit of the first participant screened. End of trial is defined as last 
treatment visit and last follow-up visit of the last participant to complete the study. Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
Relaxin exhibits vasodilatory effect and BMS-986259 is expected to demonstrate similar 
properties including potential for lowering blood pressure. Serelaxin’s development program 
provided extensive data in patients treated for ADHF. Small difference from placebo was observed 
in the absolute SBP lowering, however a substantially larger proportion of patients demonstrated 
clinical AEs related to BP reduction. In the RELAX-AHF study, confirmed events of decreased 
blood pressure were reported in 18% and 29% in the placebo vs the active group, respectively.26
In contrast, in the RELAX-REPEAT study conducted in chronic stable HF patients, there was no 
observed difference in blood pressure between serelaxin and placebo.19 No data are available on 
the risk of clinically significant hypotension with relaxin administered to medically stabilized 
patients admitted for ADHF, especially in the group with SBP < 125 mmHg which was an 
exclusion criterion in the serelaxin program. Hypotension is one of the factors prohibiting 
treatment optimization with standard of care HF medications; thus, a new treatment that would be 
safe and well tolerated in patients with lower range of BP would be clinically valuable. This study 
will allow to establish safety and tolerability of BMS-986259 with regards to the risk of 
hypotension in such population. The population of HF patients early after admission for ADHF 
has the highest rates of mortality and rehospitalization, with the rates as high as 14% and 30% 
within 60 to 90 days, respectively.30 This represents a high unmet need for both patients with 
HFrEF and HFpEF. 
The duration of the study is limited by the availability of the current toxicology data (up to 
2 weeks). The primary goal of the study is safety and tolerability. Fourteen days should be 
sufficient to establish potential for hypotension to inform further development BP margins and 
help to inform the design of Phase 2 / Phase 3 studies. Based on the data from the ongoing Phase 
1 trial, steady state is achieved after approximately 5 days. Study duration will allow to observe 
participants after they achieved steady state and a minimum hospital stay of 5 days after 
randomization will ensure more intense monitoring while the exposures of the study drug are still 
increasing. 
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The secondary 
 efficacy endpoints include PK
 
 which will provide an initial supportive data for the mechanism of action in 
heart failure population. 
Finally, serum PK will be measured to validate data collected from Phase 1 in normal healthy 
volunteers and further inform dosing in Phase 2.
5.5
Justification for Dose
The planned dose for this study (3 mg) has been selected as a pharmacologically active and safe 
dose, likely to be further studied in Phase 2B, thus safety/tolerability data collected in this study 
will inform design of the Phase 2B study. The BMS‑986259 dose selected for this study (3 mg) 
was associated with improvement in RBF after single and multiple doses in normal healthy 
participants (up to 46% increase in RBF).The 3 mg multiple doses in FIH study were also safe and 
well tolerated by the healthy participants. 
In the FIH study (CV019002), single doses as much as 5-fold higher (15 mg) have been safely 
administered to healthy participants. The observed mean exposures at steady state with repeated
3 mg QD dosing (AUC[TAU]) of 9,070 ng h/mL remain under the mean exposure (AUC[INF]) of 
38,200 ng h/mL observed after a single 15 mg dose that was determined to be safe and well 
tolerated in a healthy participants study (Table 5.5-1). 
Based on preliminary results, single dose exposures (Cmax and area under the concentration-time 
curve [AUC]) increased in a dose-proportional manner with increasing dose. With multiple doses 
of 1 mg and 3 mg QD for 14 days, up to 2.5-fold (1 mg) and 2.7-fold (3 mg) accumulation of Cmax 
and AUC(TAU) were observed on Day 14 versus Day 1, with steady-state reached within 
approximately 5 days based on trough concentrations. The geometric mean Cmax and AUC values 
observed with a single 15 mg dose and a 3 mg QD dose are listed in Table 5.5-1. 
Table 5.5-1:
BMS-986259 Exposures in Healthy Participants
Dose
Cmax (ng/mL)
Geometric Mean
AUC (ng·h/mL)
Geometric Mean
15 mg single dose
737
38,200*
3 mg QD, Day 1
184
3,420
3 mg QD, Day 14
469
9,070
* AUC(INF)
Abbreviations: AUC = area under the curve; Cmax = maximum observed concentration; QD = once daily.
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A short‑acting recombinant form of human H2-relaxin, serelaxin, dosed IV, demonstrated 
vasodilatory properties and enhanced both RBF and eGFR in patients with HF.18,19,20 In previous 
studies, serelaxin was safely administered IV for up to 48 hours in healthy participants and over 
4,000 patients with HF and produced increases in RBF and GFR, as well as improvements in 
multiple hemodynamic parameters and biomarkers of cardiac and renal function. 18,19,20,23,24,25,26
Based on the potency ratio between serelaxin and BMS-986259, it is anticipated that the 3 mg dose 
of BMS-986259 is consistent with the doses found to be efficacious, safe and well tolerated in 
heart failure patients in the serelaxin development program.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must be willing to participate in the study and provide a written ICF.
b) Participants must be willing and able to communicate and complete all study-specific 
procedures and visits.
2) Type of Participant and Target Disease Characteristics
a) Patients currently hospitalized for ADHF, regardless of Left Ventricular Ejection Fraction 
(LVEF) ≥24 hours since presentation to ER defined as the time of the first dose of IV
diuretic administered at the hospital, maximum of 8 days since presentation to ER and 
before hospital discharge. 
i)
ADHF is the main reason for admission and there is no other potential cause for 
congestive symptoms leading to index hospitalization (eg, concurrent pneumonia, 
acute chronic obstructive pulmonary disease [COPD] exacerbation).
ii) Dyspnea at rest or with minimal exertion upon presentation to ER, plus signs and 
symptoms of fluid overload that require IV therapy with loop diuretics.
iii) NT-proBNP ≥1400 pg/mL OR BNP ≥350 pg/mL upon presentation to the hospital; 
NT-proBNP ≥2000 pg/mL OR BNP ≥500 pg/mL if Atrial Fibrillation (AFib) present 
at presentation. For participants on Entresto, NT-proBNP should be used.
b) Patients must be hemodynamically stable, as assessed by the investigator, and as defined 
by the following criteria:
i)
≥ 12 hours since the last dose change of IV loop diuretics (ie, participants may still be 
on IV loop diuretics at randomization, as long as dose is stable ≥12 hours).
ii) ≥24 hours since last dose of positive inotropes.
iii) ≥12 hours since the last dose of IV vasodilators.
iv) Absence of symptoms of hypotension (eg, dizziness, lightheadedness, etc).
v) Supine SBP (supine position is preferable, based on participant’s condition and 
comfort) must remain within the following range, on at least 2 routine consecutive 
measurements, over the 12 hours before randomization:
(1) Sentinel Group: SBP ≥115 mmHg.
(2) Main Group: SBP ≥100 mmHg.
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3) Age and Reproductive Status
Investigators shall counsel male participants who are sexually active with women of childbearing 
potential (WOCBP), on the importance of pregnancy prevention, the implications of an unexpected 
pregnancy and the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the participant has undergone a successful 
vasectomy or if the partner is pregnant.
•
Local laws and regulations may require the use of alternative and/or additional contraception 
methods.
a) Female Participants 
i)
Females, ages at least 18 or local age of majority (See Appendix 7 for maximum age 
limit where locally mandated).
ii) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and is not a WOCBP.
iii) Women participants must have documented proof that they are not of childbearing 
potential.
iv) Women must not be breastfeeding.
b) Male Participants 
i)
Males, ages at least 18 or local age of majority (See Appendix 7 for maximum age limit 
where locally mandated).
ii) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in Appendix 4 and as described below.
(1) For males who are sexually active with WOCBP, less than highly effective 
methods of contraception and unacceptable methods of contraception are not 
permitted.
(2) Hormonal contraception is also not permitted. 
iii) Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity 
(eg, vaginal, anal, oral) with WOCBP even if the participant has undergone a successful 
vasectomy or if the partner is pregnant or breastfeeding.
iv) Male participants will be required to always use a latex or other synthetic condom 
during any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the 
participants have undergone a successful vasectomy or if their partner is already 
pregnant or breastfeeding. Males should continue to use a condom during the 
intervention period and for at least 6 days after the last dose of study intervention. 
v) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 6 days 
after the last dose of study intervention in the male participant.
(1) For female partners of males participating in the study, less than highly effective 
methods of contraception and unacceptable methods of contraception are not 
permitted.
(2) Hormonal contraception is also not permitted. 
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vi) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual activity or use a male condom during any sexual activity 
(eg, vaginal, anal, oral) even if the participants have undergone a successful vasectomy, 
during the intervention period and for at least 6 days after the last dose of study 
intervention.
vii)Male participants must refrain from donating sperm during the intervention period and 
for at least 6 days after the last dose of study intervention.
viii)
Breastfeeding partners should be advised to consult their health care providers 
about using appropriate highly effective contraception during the time the participant 
is required to use condoms.
6.2
Exclusion Criteria
1) Target disease exceptions
a) At randomization systolic blood pressure < 100 mmHg or > 145 mmHg.
b) At randomization HR > 120 bpm.
c) Acute cardiovascular condition other than HF decompensation either contributing to 
hospitalization or making participant unstable, such as acute MI/acute coronary syndrome, 
myocarditis, or arrhythmia with the exception of atrial fibrillation if HR within criteria 
limit.
d) Cardiogenic shock (defined as SBP below 90 mmHg, signs of end-organ hypoperfusion 
plus need for intubation, mechanical circulatory support and other life-sustaining 
emergency measures) at presentation to ER or at any time before randomization.
e) History of heart or any other solid organ transplant or currently on the transplant list.
f)
Recipient of ventricular assist devices.
g) Use of any cardiac extracorporeal devices, within 12 weeks of study randomization.
Cardiac Resynchronization Therapy Defibrillator (CRTD) and pacemakers/Implantable 
Cardioverter-Defibrillator (ICDs) are allowed, if implanted at least 4 weeks before 
randomization and no discharge within 4 weeks prior to randomization.
h) Participants with contraindications to vasodilator therapy such as restrictive or obstructive 
cardiomyopathy, severe mitral or aortic stenosis.
2) Medical History and Concurrent Diseases
a) Women cannot be pregnant or breastfeeding.
b) Any major surgery within 12 weeks of study randomization.
c) Suspected acute pulmonary disease such as pneumonia, exacerbation of asthma or COPD 
or severe chronic, pulmonary disease (eg, severe COPD , pulmonary fibrosis, patients with 
hypercapnia or requiring home oxygen or chronic systemic steroids)
d) Hereditary or idiopathic pulmonary hypertension.
e) History of stroke, or transient ischemic attack (TIA) within the 30 days prior to screening 
(according to the participants' records) or during screening.
f)
Acute coronary event within 30 days prior to screening or during screening (myocardial 
infarction, acute coronary syndrome, or unstable angina; according to the participants' 
records).
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g) Terminal non-cardiovascular disease such as cancer with life expectancy < 6 months.
h) Severe liver disease such as cirrhosis with evidence of portal hypertension, or acute viral 
hepatitis.
i)
Participant is on dialysis or history of chronic or intermittent dialysis or ultrafiltration.
j)
Need for mechanical ventilation any time before screening or non-invasive ventilation 
(CPAP, BiPAP) < 2 hrs prior to screening.
3) Prior/Concomitant Therapy:
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7
Concomitant Therapy. The following are prohibited before and during the study: 
a.
Phosphodiesterase type 5 (PDE5) inhibitors used for erectile dysfunction: 
sildenafil, tadalafil, vardenafil, etc (within 48 hours of initial study drug 
administration and throughout the study, up to 5 days after the last dose of study 
drug).
b. Continuous infusion of IV diuretics, inotropes and vasodilators during the study.
b) Guidelines Directed Medical Therapy (GDMT) for HF is allowed, either at screening or 
during the study, as clinically warranted.
c) Exposure to any investigational drug or placebo, including serelaxin; within 30 days of 
initial study drug administration or 4 months prior to the first dose of IP, in case of exposure 
to long-acting biological investigational drug.
4) Laboratory Test Findings
a) Participant has key laboratory testing findings within the following ranges:
i)
Persistent electrolytes abnormalities not corrected before randomization
(1) A sodium concentration < 130 or > 145 mEq/l.
(2) A potassium concentration < 3.1 or > 5.5 mEq/l.
ii) Hemoglobin < 9 g/dL, which is defined as severe anemia.
iii) eGFR < 30 ml/min./1.73 m2.
iv) Not applicable per Revised Protocol 01
v) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or human 
immunodeficiency virus (HIV)-1 and -2 antibodies.
vi) Liver abnormalities including total bilirubin > 1.5 × upper limit of normal (ULN) or 
significant elevation of liver enzymes (aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT] > 3 × ULN).
vii)Positive RT-PCR test or rapid antigen test for SARS-CoV-2 prior to randomization.
5) Allergies and Adverse Drug Reaction
a) History of any significant drug allergy or drug-related SAE (such as anaphylaxis or 
hepatotoxicity).
b) History of ADAs to relaxin (eg, while in a serelaxin development program).
c) History of adverse reactions to aminoglycosides.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
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imprisoned may be included or permitted to continue as a participant. Strict conditions 
apply and BMS approval is required.)
b) Employees of CRO or BMS and their first-line relatives.
c) Legal incapacity or limited legal capacity.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. No waivers will be provided.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
In an effort to find all possible well-qualified participants, participants who 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 
participant must be re-consented and a new participant number will be assigned by the IRT. 
Laboratory parameters and/or assessments that are included in Table 2-1 (Screening Procedural 
Outline) and Table 2-2 (On-treatment and Follow-up Procedural Outline), must be repeated. The 
participant numbers and data will be linked in the clinical database.
All screening laboratory testing 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. The most current result prior to Randomization 
is the value by which study inclusion will be assessed, as it represents the participant’s most 
current, clinical state.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study treatment includes both IP and Non-investigational Product (Non-IP) as shown in Table 7-
1.
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An IP, also known as investigational medicinal product (IMP) 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.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-IPs.
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Table 7-1:
Study treatments for CV019010
Product Description / 
Class and Dosage 
Form
Potency
IP/
Non-IP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-986259 injection 
for SC administration
5 mg/vial (5 mg/mL)
Dose level 3 mg and 1 mg
BMS-986259 will be diluted to administer a 
3 mg or 1 mg dose as a 1 mL SC injection. 
Details of preparation and administration are 
provided in the pharmacy manual
IP
Blinded
Colorless to pale 
yellow liquid in 
vial
Refer to the label on 
the container and/or
the pharmacy manual
Placebo injection for 
SC administration
N/A
IP
Blinded
Colorless to pale 
yellow liquid in 
vial
Refer to the label on 
the container and/or 
the pharmacy manual
Placebo injection to be 
utilized as diluent
N/A
IP
Open Label
Colorless to pale 
yellow liquid in 
vial
Refer to the label on 
the container and/or 
the pharmacy manual
Abbreviations: IP = Investigational Product; N/A = not applicable; Non-IP = Non-investigational Product; SC = subcutaneous.
BMS-986259 is not intended for participant’s self-administration. 
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
BMS-986259
3 mga,
1 mga,b
Daily
Subcutaneous injection
Placebo
N/A
Daily
Subcutaneous injection
a 5 mg/mL solution will be diluted as described in the pharmacy manual to reach the desired dosage strength
b 1 mg for down titration only
In the morning on Days 1 through 14 each participant will receive a subcutaneous dose of 
BMS-986259 or placebo, at approximately the same time.
The time of dose administration of the first dose will be called “0” hour for serum PK reporting.
7.2
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT.
Study treatment will be dispensed at the Day 1 visit.
At the time of screening for both the Sentinel Group and Main Group, participants will be 
randomized to receive either BMS-986259 or placebo in a 1:1 ratio according to a computer-
generated randomization scheme prepared by a Randomization Coordinator within the Drug 
Supply Management Department of BMS Research and Development. 
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001, (eg, 00001, 00002, 00003.... 00010). Sequential numbering may restart at 
00001 for each participating site as the distinct patient identification number (PID) will ultimately 
be comprised of the site number and participant number, (eg, 0002 00001). Those enrolled 
participants meeting inclusion and exclusion criteria will be eligible to be randomized. 
Randomization numbers will be assigned prior to dosing. 
During the screening visit, the investigative site will call into the enrollment option of the 
Interactive Response Technology (IRT) designated by BMS for assignment of a 5-digit participant
number that will be unique across all sites. For example, the first participant screened (ie, enrolled) 
at site number 1, will have a PID of 0001 00001. Once it is determined that the participant meets 
the eligibility criteria following the screening visit, the investigative site will call the IRT to 
randomize the participant. 
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7.3
Blinding
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
IP is critical to the participant's management, the blind for that participant may be broken by the 
investigator. The participant’s safety takes priority over any other considerations in determining if 
a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving active 
product. It is highly desirable that the decision to unblind treatment assignment be discussed with 
the BMS Study Director / Medical Monitor (or designee), but the investigator always has ultimate 
authority for the decision to unblind. The actual TASK of unblinding can be delegated by the 
investigator to a designee assigned the task on the Delegation of Authority. The Principal 
Investigator or appointed designee should only call in for emergency unblinding AFTER the 
decision to unblind the participant has been documented. 
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 BMS Study Director / Medical Monitor (or designee) 
and ensure every attempt is made to preserve the blind. 
Any request to unblind a participant for non-emergency purposes should be discussed with the 
BMS Study Director / Medical Monitor (or designee).
Except as noted below, members of BMS Research and Development personnel involved in the 
study conduct and evaluation, as well as all vendors responsible for the conduct of the trial 
(protocol team) will remain blinded.
A bioanalytical scientist in the Bioanalytical Sciences department of BMS Research & 
Development (or a designee in the external central bioanalytical laboratory) will be unblinded to 
(may obtain) the randomized treatment assignments in order to minimize unnecessary 
bioanalytical analysis of samples as PK will not be analyzed placebo samples.
An internal Safety Review Committee, independent from the study team, will assess BP data after 
completion of approximately 8 participants randomized with SBP ≥ 115 mmHg and < 130 mmHg 
in the Sentinel Group. The internal Safety Review Committee will also assess safety results, 
including hypotension, from the planned interim analysis (IA; Section 10.3.5).
For the assessment of BP data in the Sentinel Group and for the planned IA, an unblinded 
statistician and programmer(s), separate from the study team, will be performing the required 
safety analyses for the internal Safety Review Committee. The internal Safety Review Committee 
may require access to unblinded treatment codes for individual participants. Additional designated 
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staff of BMS Company will be provided with aggregate data from the IA for future study planning 
as described in the statistical analysis plan.
7.4
Dosage Modification
Any decision to decrease the dose level of study drug or discontinue study drug should be based 
on the investigator’s assessment of the participants’ clinical stability and in the overall context of 
the participant’s condition. A dose reduction to 1 mg is allowed if certain criteria are met, as 
described in the section below. Study drug may be also permanently discontinued early as 
described in the following section.
7.4.1
Dose Down-titration
•
On Days 1 through 6, if the participant experiences SBP < 85 mmHg without symptoms related 
to hypotension, the measurement must be repeated in 30 minutes. If the SBP remains 
< 85 mmHg the next day’s study drug administration should be skipped and dosing should 
resume at 1 mg, the following day, if SBP is ≥85 mmHg (ie, after a 1-day drug “holiday”, the 
treatment will resume at a reduced dose).
•
On Days 1 through 6, if the participant experiences SBP < 90 mmHg and symptoms of 
hypotension (such as dizziness, light headedness etc), the measurement must be repeated in 
30 minutes. If the SBP remains < 90 mmHg the next day’s study drug administration should 
be skipped and dosing should resume at 1 mg, the following day, if SBP is ≥85 mmHg and 
symptoms of hypotension resolved (ie, after a 1-day drug “holiday”, the treatment will resume 
at a reduced dose).
•
On Days 1 through 6, if the participant experiences SBP fall ≥40 mmHg with symptoms of 
hypotension that in the opinion of investigator preclude further safe dosing of the participant 
at the initial dose level, the next day’s study drug administration should be skipped and dosing 
should resume at 1mg the following day, if SBP is ≥85 mmHg and symptoms of hypotension 
resolved (ie, after a1-day drug “holiday”, the treatment will resume at a reduced dose).
•
After dose reduction, the dose cannot be increased again.
7.4.2
Permanent discontinuation of the study drug
•
If the participant experiences SBP < 85 mmHg regardless of symptoms of hypotension, or 
symptomatic hypotension with SBP < 90 mmHg (measurements must be repeated in 30 
minutes), despite dose reduction, then the study drug must be discontinued.
•
On Days 7 through 14, if the participant experiences SBP < 85 mmHg regardless of symptoms 
of hypotension, the measurement must be repeated in 30 minutes. If the SBP remains 
< 85 mmHg, the study drug should be discontinued.
•
On Days 7 through 14, if the participant experiences SBP < 90 mmHg and symptoms of 
hypotension (such as dizziness, lightheadedness, etc), the measurement must be repeated in 
30 minutes. If the SBP remains < 90 mmHg, the study drug should be discontinued.
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•
Regardless of the day of the treatment, if the participant experiences SBP fall ≥40 mmHg with 
symptoms of hypotension, that in the opinion of investigator preclude further safe dosing of 
the participant, then the study drug should be discontinued.
•
If the participant requires intravenous vasodilators, continuous IV diuretics or IV inotropes, 
the study drug should be discontinued
7.5
Preparation/Handling/Storage/Accountability
The IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study participants. The IP must be dispensed 
only from official study sites by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
For study drugs not provided by BMS and obtained commercially by the site, storage should in 
accordance with the product label.
Detailed instructions for preparing, and handling of BMS-986259 and placebo and information on 
dosing solution stability are provided in the Study Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability / Bioequivalence / 
Biocomparability
Not applicable.
7.6
Treatment Compliance
Not applicable.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications for this study are described below. Medications taken 
within 8 days in hospital prior to study drug administration must be recorded on the electronic case 
report form (eCRF).
BMS-986259 can be administered on top of Guideline Directed Medical Therapy (GDMT) for HF, 
as appropriate.
The following are prohibited before and during the study:
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1) Exposure to any investigational drug or placebo, including serelaxin; within 30 days of initial 
study drug administration or 4 months prior to the first dose of IP, in case of exposure to long-
acting biological investigational drug.
2) PDE5 inhibitors used for erectile dysfunction: sildenafil, tadalafil, vardenafil, etc (within 
48 hours of initial study drug administration and throughout the study, up to 5 days after the 
last dose of study drug).
3) Continuous infusion of IV diuretics, inotropes and vasodilators during the study.
7.8
Treatment After the End of the Study
At the end of the study treatment period, BMS will not continue to provide BMS supplied study 
treatment to participants/investigators unless BMS chooses to extend the study. The investigator 
should ensure that the participant receives appropriate standard of care to treat the condition under 
study.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue IP (and non-IP at the discretion of the investigator) for any of the 
following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant
•
Positive RT-PCR or rapid antigen test for SARS-CoV-2
•
Participants’ clinical condition requires the use of continuous infusion of IV diuretics, 
inotropes and vasodilators
•
Inability to comply with the protocol
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
•
BP related criteria are described in dose modification (Section 7.4)
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
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All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
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•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities (Section 2).
•
Blood pressure device will be provided to participants at discharge to measure BP if symptoms 
consistent with hypotension occur. If systolic BP falls below 85 mmHg (in 2 repeated 
measurements within 30 minutes) and symptoms of hypotension persist, participants will be 
instructed to report to the study site or another healthcare provider. 
9.1
Efficacy Assessments
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9.1.2
Investigator Assessment of Signs and Symptoms
New York Heart Association (NYHA) class will be evaluated by the investigator on Day 1, at 
discharge, and on Day 14 and Day 30. (See Appendix 6)
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Appendix 1 in the Investigator’s Brochure (IB) represent the Reference Safety Information to 
determine expectedness of SAEs for expedited reporting.
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures and within 30 days of discontinuation of dosing and 
if there are participants who develop ADAs, for those participants, SAEs must be collected up to 
3 months. 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (eg, a follow-up skin biopsy).
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
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•
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. Care should be taken not to introduce bias when collecting AE and/or 
SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context of known
AEs, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the 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.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the IB and will notify the IRB/Independent Ethics Committee (IEC), if appropriate according 
to local requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected Serious 
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Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory authorities 
and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least for
6 days after study product administration, the investigator must immediately notify the BMS 
Medical Monitor/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 Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
If any sexual activity (eg, vaginal, anal, oral) has occurred between a male participant and a 
pregnant partner(s) without the use of a condom during and at least for, 6 days after study product 
administration, the information should be reported to the Sponsor or designee, even if the male 
participant has undergone a successful vasectomy.
In order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner(s) must sign an ICF for disclosure of this information. Information on 
the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or reduced.
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
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It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 × ULN
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECGs, 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.
9.3
Overdose
For this study, any dose of BMS-986259 greater than the designated dose described in Section 7
will be considered an overdose. All occurrences of intentional overdose must be reported as an 
SAE (see Section 9.2).
In the event of an overdose, the investigator should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities until BMS-986259 
can no longer be detected systemically 
3) Obtain a serum sample for PK analysis if requested by the Medical Monitor (determined on a 
case-by-case basis)
4) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
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9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities (Section 2).
The individual performing the physical examinations must be licensed by state law (or applicable 
local law) to perform a physical examination.
Documentation of who performed the examination is to be recorded in source notes. A targeted
physical examination may note any changes in the participant’s condition (body systems) since 
the last assessment and does not preclude examination of any of the other body systems as 
clinically indicated (ie, skin). Every effort should be made to ensure the same evaluator will 
complete the examination for each participant at all visits throughout the study.
9.4.2
Vital signs
Refer to Schedule of Activities (Section 2).
9.4.3
Electrocardiograms
Planned time points for ECGs are listed in the Schedule of Activities (Section 2). Single standard 
12-lead ECGs will be recorded after the participant has been resting for at least 5 minutes in the 
supine position.
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 participant must be supine and should refrain from movement during the ECG 
recording.
Ensure that the participant 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.
9.4.5
Clinical Safety Laboratory Assessments
Participants 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.
9.4.5.1
Local Laboratory Assessments for Screening
A local laboratory will perform the following analyses and will provide reference ranges for these 
tests. Local Laboratory results obtained for the current episode of heart failure as part of standard 
of care, within 24 hours of randomization, may be used. The results of local labs will be used for 
eligibility determination.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
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Blood Urea Nitrogen (BUN) or Serum Urea
Uric acid
Glucose
Magnesium
Creatine kinase
eGFR
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, HIV-1 and -2 antibody (screening 
only)
Other Analyses
SARS-CoV-2 test (RT-PCR or rapid antigen test)
NT-proBNP or BNP
Follicle stimulating hormone (FSH) only required to confirm menopause in women < age 55
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; 
BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; FSH = follicle stimulating hormone;
HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; NT-proBNP = N-terminal pro-brain 
natriuretic peptide; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2.
9.4.5.2
Central Laboratory Assessments (On Treatment)
The following laboratory tests will be performed and submitted to the Central Laboratory for 
analysis as per the Study Assessment and Procedures in Section 2. The following samples should 
be collected predose: Hematology, Chemistry, and Urinalysis.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
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Creatinine
Blood Urea Nitrogen (BUN) or Serum Urea
Uric acid
Fasting glucose
Phosphorus
Magnesium
Creatine kinase
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive 
on the dipstick
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration;
 
LDH = lactate dehydrogenase.
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. 
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.
9.4.6
Imaging Safety Assessment
Not applicable.
9.5
Pharmacokinetics
Pharmacokinetics of BMS-986259 will be derived from serum concentration versus time. The PK 
parameters to be assessed include:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
AUC(0-T)
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
AUC(TAU)
Area under the concentration-time curve in one dosing interval
Ctrough
Trough observed plasma concentration
Individual participant PK parameter values will be derived by non-compartmental methods by a 
validated PK analysis program. Actual times will be used for the analyses. When multiple 
procedures are required at a time point, prioritize that the PK samples are collected as close to the 
scheduled time point as possible.
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Table 9.5-1:
Pharmacokinetic 
 Sampling Schedule for All Participants (CV019010)
Study Day of Sample Collection
Event
Timea
(Relative 
to BMS-
986259 or 
Placebo
Dose)
Hour: 
Min
BMS-986259/ 
Placebo 
PK Serum 
Sample
Day 1
predoseb
00:00
X
3:00
X
6:00
X
8:00
X
10:00
X
14:00
X
Day 2
predoseb
00:00
X
Day 3
predoseb
00:00
X
Day 5
predoseb
00:00
X
3:00
X
6:00
X
8:00
X
10:00
X
14:00
X
Day 6
predoseb
00:00
X
Day 8
predoseb
00:00
X
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Table 9.5-1:
Pharmacokinetic 
 Sampling Schedule for All Participants (CV019010)
Study Day of Sample Collection
Event
Timea
(Relative 
to BMS-
986259 or 
Placebo
Dose)
Hour: 
Min
BMS-986259/ 
Placebo 
PK Serum 
Sample
Day 14 End of Study Visitc
predoseb
00:00
X
Day 30 Follow-up
Follow-up
Abbreviations: 
Min = minutes;
 PK = pharmacokinetic.
a All the PK samples should be collected as close to the scheduled time point as clinically feasible.
b All predose samples should be taken (preferably with 30 minutes) prior to the start of subcutaneous injection. If it is known that a dose is going to be delayed, 
then the predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected but the dose is delayed, an additional 
predose sample should not be collected.
c If the study is ended early and the End of Study Visit takes place on Day 13 instead of Day 14, indicated Day 14 samples should be collected on Day 13.
 
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The serum will be analyzed for BMS-986259 by a validated or a qualified enzyme-linked 
immunosorbent assay (ELISA) method assay. PK samples collected from a participant who 
received placebo will not be analyzed.
 
Detailed instructions for the PK blood collection, labeling, processing, storage, and shipping will 
be provided to the investigative site and home healthcare provider in the laboratory manual.
9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The primary objective of the study is to evaluate safety and tolerability of BMS-986259. It is 
estimated there may be ~10% to 20% early treatment withdrawal. Approximately 72 participants
will be randomized with 1:1 ratio to BMS-986259 subcutaneous QD and Placebo to have at least 
60 completers by the end of the study. An estimation approach will be used for comparison 
between BMS-986259 and placebo for hypotension rate. Point estimates and associated 95% 
confidence intervals for event rate and relative risk ratio will be constructed to provide plausible 
range of values for the true comparison of interest.
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The incidence of clinically relevant hypotension in the placebo group is estimated to be between 
~ 5% to 15%. With N=60 and 1:1 treatment assignment ratio, the study will be able to detect a 
significant increase of clinical hypotension event compared to placebo ranging from 2.7 fold
increase (eg, placebo rate =15%) to 5 fold increase (eg, placebo rate =5%). 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Randomized
All participants who have been randomized by IRT system
Randomized population will be used for Disposition, Demographic and 
baseline characteristic Analyses
Safety
All randomized participants who take at least 1 dose of double blind- study 
treatment. Participants will be included in the treatment group they were 
randomized to. 
eg, “Data in this data set will be analyzed based on randomized treatment, 
except in the following cases:
•
If a participant received the same incorrect treatment throughout the 
study, then the participant will be analyzed based on the treatment 
received.
•
If a participant received study drug from more than one treatment group, 
and none of the administrations were consistent with the assigned 
randomized treatment group, then  the participant will be analyzed based 
on the first treatment received.
Safety Population will be used for all efficacy, safety 
 
analyses
PK Population
All participants who have received at least one dose of treatment and have at 
least one valid PK measurement. If feasible, PK population will be used for 
all PK analyses
Abbreviations: IRT = Interactive Response Technology; PK = pharmacokinetic.
10.3
Statistical Analyses
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender and race.
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10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Not Applicable
Secondary
Not Applicable
10.3.2
Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Primary
¾ Clinically
relevant 
hypotension
¾ AEs
¾ Vital Signs
¾ Laboratory Test 
Results
¾ ECGs
¾ Physical 
Examination
The incidence of clinically relevant hypotension 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 relaxin and placebo.
All recorded AEs 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.
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Abbreviations: 
 AE = adverse event; CI = confidence interval; ECG = electrocardiogram  
.
10.3.3
PK Analyses
Endpoint
Statistical Analysis Methods
Serum PK parameters in participants with 
HF
PK parameters will be listed, plotted and 
summarized descriptively
Abbreviations: HF = heart failure; PK = pharmacokinetic.
10.3.5
Interim Analyses
An IA to evaluate clinically relevant hypotension for the purpose of future study planning will be 
conducted when 1) approximately 30 participants complete the Day 14 End of Study Visit, and 
2) approximately 15 of these have baseline SBP less than or equal to 125 mmHg. Details of the 
analysis conducted at the IA will be described in the statistical analysis plan.
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REFERENCES
1
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of 
heart failure: a report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62(16):e147-239.
2
Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of 
hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J 
Am Coll Cardiol 2014;63(12):1123-33.
3
Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: 
A Report From the American Heart Association. Circulation 2018;137(12):e67-e492.
4
Klatsky AL, Gronningen S, Udaltsova N, et al. Heart failure etiology is usually pluricausal 
whether or not there is associated coronary disease. Perm J 2007;11(1):13-8.
5
Streng KW, Nauta JF, Hillege HL, et al. Non-cardiac comorbidities in heart failure with 
reduced, mid-range and preserved ejection fraction. Int J Cardiol 2018;271:132-9.
6
Tromp J, Westenbrink BD, Ouwerkerk W, et al. Identifying pathophysiological mechanisms 
in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 
2018;72(10):1081-90. 
7
Metra M, Teerlink JR. Heart failure. Lancet 2017;390(10106):1981-95. 
8
McAlister FA, Ezekowitz J, Tarantini L, et al. Renal dysfunction in patients with heart failure 
with preserved versus reduced ejection fraction: impact of the new Chronic Kidney Disease-
Epidemiology Collaboration Group formula. Circ Heart Fail 2012;5:309-14. 
9
Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: 
systematic review and meta-analysis. J Am Coll Cardiol 2006;47(10):1987-96. 
10 Ueda T, Kawakami R, Sugawara Y, et al. Worsening of renal function during 1 year after 
hospital discharge is a strong and independent predictor of all-cause mortality in acute 
decompensated heart failure. J Am Heart Assoc 2014;3(6):e001174. 
11 Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol 
Regul Integr Comp Physiol 2011;301(2):R267-75. 
12 Poppas A, Shroff SG, Korcarz CE, et al. Serial assessment of the cardiovascular system in 
normal pregnancy Role of arterial compliance and pulsatile arterial load. Circulation 
1997;95(10):2407-15.
13 Clapp JF, Capeless E. Cardiovascular function before, during, and after the first and subsequent 
pregnancies. Am J Cardiol 1997;80(11):1469-73.
14 Dunlop W. Serial changes in renal haemodynamics during normal human pregnancy. Br J 
Obstet Gynaecol 1981;88(1):1-9. 
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15 Bathgate RA, Ivell R, Sanborn BM, et al. International Union of Pharmacology LVII: 
recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol 
Rev 2006;58(1):7-31.
16 Vodstrcil LA, Tare M, Novak J, et al. Relaxin mediates uterine artery compliance during 
pregnancy and increases uterine blood flow. FASEB J 2012;26:4035-44.
17 Feng S, Ferlin A, Truong A, et al. INSL3/RXFP2 signaling in testicular descent. Ann NY Acad
Sci 2009;1160:197-204.
18 Voors AA, Dahlke M, Meyer S, et al. Renal hemodynamic effects of serelaxin in patients with 
chronic heart failure: a randomized, placebo-controlled study. Circ Heart Fail 2014;7:994-
1002.
19 Teerlink JR, Saini R, Gullestad L, et al. RELAX-REPEAT: A multicenter, prospective, 
randomized, double-blind study evaluating the safety and tolerability of repeat doses of 
Serelaxin in patients with chronic heart failure. J Card Fail 2016;22:S14-5
20 Ponikowski P, Mitrovic V, Ruda M, et al. A randomized, double-blind, placebo-controlled, 
multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart 
failure. Eur Heart J 2014;35:431-41. 
21 Bennett RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res 
2009;154(1):1-6.
22 Wu XP, Wang HJ, Wang YL, et al. Serelaxin inhibits differentiation and fibrotic behaviors of 
cardiac fibroblasts by suppressing ALK-5/Smad2/3 signaling pathway. Exp Cell Res 
2018;362(1):17-27.
23 Metra M, Teerlink JR, Cotter G et al. Effects of serelaxin in patients with acute heart failure. 
N Engl J Med 2019;381:716-26.
24 Smith MC, Danielson LA, Conrad KP et al. Influence of recombinant human relaxin on renal 
hemodynamics in healthy volunteers. J Am Soc Nephrol 2006;17:3192-7.
25 Dahlke M, Ng D, Yamaguchi M et al. Safety and tolerability of serelaxin, a recombinant human 
relaxin-2 in development for the treatment of acute heart failure, in healthy Japanese volunteers 
and a comparison of pharmacokinetics and pharmacodynamics in healthy Japanese and 
Caucasian populations. J Clin Pharmacol 2015;55(4):415-22.
26 Teerlink JR, Cotter G, Davison BA et al. Serelaxin, recombinant human relaxin-2, for 
treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 
2013;381:29-39.
27 Ponikowski P, Voors AA, Anker SD et al. 2016 ESC guidelines for the diagnosis and treatment 
of acute and chronic heart failure. Eur Heart J 2016;37:2129-2200.
28 Maggioni AP, Anker SD, Dahlström U et al. Are hospitalized or ambulatory patients with heart 
failure treated in accordance with European Society of Cardiology guidelines? Evidence from 
12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 
2013;15(10):1173-84.
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29 BMS-986259 Investigator’s brochure. Nov. 2019.
30 Gheorghiade M, Abraham WT, Albert NM et al. Systolic blood pressure at admission, clinical 
characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 
2006;296:2217-26.
31 Mozaffarian D, Benjamin EJ, Go AS et al. Heart disease and stroke statistics-2016 update; a 
report from the American Heart Association. Circ 2016;133(4):e38-360.
32 Blecker S, Paul M, Taksler G et al. Heart failure-associated hospitalizations in the United 
States. J Am Coll Cardiol 2013;61:1259-67.
 
 
 
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
 
ADHF
acute decompensated heart failure
ACE
angiotensin-converting enzymes
AE
adverse event
AFib
Atrial Fibrillation 
ALK5
activin-like kinase 5
ALT
alanine aminotransferase
AR
additional research
ARNI
angiotensin receptor-neprilysin inhibitor
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
BMI
body mass index
BMS
Bristol-Myers Squibb
BNP
brain natriuretic peptide
BP
Blood pressure
BUN
Blood Urea Nitrogen
CBC
complete blood count
CI
confidence interval
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
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Term
Definition
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
Case Report Form, paper or electronic
CRO
Contract Research Organization
CRTD
Cardiac Resynchronization Therapy Defibrillator
CSR
clinical study report
CTA
clinical trial agreement
Ctrough
trough concentration
D
day
DILI
drug induced liver injury
ECG
electrocardiogram
EDC
electronic data capture
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EHR
electronic health record
ELISA
enzyme-linked immunosorbent assay
EMR
electronic medical record
ER
emergency room
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle stimulating hormone
FU
Follow-up
GCP
Good Clinical Practice
GDMT
Guidelines Directed Medical Therapy
GFR
glomerular filtration rate
H2-relaxin
human relaxin
HCG
Human chorionic gonadotropin
HF
heart failure
HIV
human immunodeficiency virus
HFmrEF
heart failure with a mid-range ejection fraction
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Term
Definition
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HR
heart rate
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure
ICD
Implantable Cardioverter-Defibrillator
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
INSL3
insulin-like peptide 3
IMP
investigational medicinal product
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction
MD
medical doctor
Mo
month
MOA
mechanism of action
MRA
mineralocorticoid receptor antagonist
MRI
mineralocorticoid receptor inhibitor
N/A
not applicable
NHV
normal healthy volunteers
NOAEL
no observed adverse effect level
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PAP
pulmonary arterial pressure
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Term
Definition
PCWP
pulmonary capillary wedge pressure
PDE5
phosphodiesterase type 5
PE
physical examination
PID
Patient identification number
PK
pharmacokinetics
QD
once daily
RAAS
renin-angiotensin-aldosterone-system
R&D
research and development
RBF
renal blood flow
RT-PCR
reverse transcription polymerase chain reaction
RXFP1
relaxin/insulin-like family peptide receptor 1
RXFP2
relaxin/insulin-like family peptide receptor 2
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SBP
systolic blood pressure
SC
subcutaneous
SMAD2
mothers against decapentaplegic homolog 2
SOA
schedule of activities
SOC
standard of care
SOP
standard operating procedures
SUSAR
Suspected, Unexpected Serious Adverse Reaction
SVR
systemic vascular resistance
T-HALF
half-life
TIA
transient ischemic attack
Tmax
time of maximum observed concentration
ULN
upper limit of normal
WOCBP
women of childbearing potential
WRF
worsening renal function
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following:  (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. 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/participants and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants 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/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants 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 by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
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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 participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator,
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
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devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its 
vendors):
Records or logs must comply with applicable regulations and 
guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each participant, 
including unique participant 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/biocomparability, if 
applicable 
•
dates and initials of person responsible for Investigational 
Product dispensing/accountability, as per the Delegation of 
Authority Form.
Sourced by site, and not 
supplied by BMS or its 
vendors (examples include 
IP sourced from the sites 
stock or commercial supply, 
or a specialty pharmacy)
The investigator or designee accepts responsibility for 
documenting traceability and study treatment integrity in 
accordance with requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
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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.
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. 
The confidentiality of records that could identify subjects/participants 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 The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site 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. 
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In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by 
BMS (including its vendors
Any unused study treatments supplied by BMS can only be 
destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study treatments 
containers must be immediately destroyed as required for 
safety, or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return will be 
arranged by the responsible Study Monitor.
Study treatments sourced by site, 
not supplied by BMS (or its 
vendors) (examples include study 
treatments sourced from the sites 
stock or commercial supply, or a 
specialty pharmacy)
It is the investigator’s or designee’s responsibility to 
dispose of all containers according to the institutional 
guidelines and procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
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institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant 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)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
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Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study 
treatment and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/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 participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Intensity
The intensity of AEs is determined by a physician and will use the following levels:
•
Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and not 
interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
•
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
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If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
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.
End of Relevant Systemic Exposure
•
End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
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human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy
•
Progestogen-only hormonal contraception associated with inhibition of ovulation (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol)b 
−
oral 
−
injectable 
•
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol) b,c
•
Bilateral tubal occlusion
•
Vasectomized partner 
Male participants will be required to always use a latex or other synthetic condom during any sexual 
activity (eg, vaginal, anal, oral) with WOCBP; even if the participants have undergone a successful 
vasectomy or if their partner is already pregnant or breastfeeding.
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•
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
•
Continuous abstinence must begin at least 30 days prior to initiation of study therapy
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
•
Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine hormone releasing systems are acceptable methods of contraception in the absence of definitive drug 
interaction studies when hormone exposures from intrauterine devices do not alter contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
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Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 6
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION
Heart failure is usually classified according to the severity of the patient’s symptoms. The table
below describes the most commonly used classification system, the New York Heart Association 
(NYHA) functional classification. It places patients in 1 of 4 categories based on how much they 
are limited during physical activity.
Class
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, or dyspnea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest. If any physical activity is undertaken, discomfort 
increases.
Class
Objective Assessment
A
No objective evidence of cardiovascular disease. No symptoms and no 
limitation in ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild symptoms and 
slight limitation during ordinary activity. Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. Marked 
limitation in activity due to symptoms, even during less-than-ordinary 
activity. Comfortable only at rest.
D
Objective evidence of severe cardiovascular disease. Severe limitations. 
Experiences symptoms even while at rest.
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APPENDIX 7
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES
Original Language
Country-specific Language or Differences
Section 6.1 Inclusion criteria: Inclusion criterion 
3) a) i): Females, ages at least 18 or local age of 
majority
Czech Republic specific language: Adding a max age of 
75 years
Section 6.1 Inclusion criteria. Inclusion criterion 3) a) i): 
Females, ages at least 18 or local age of majority and 
maximum 75
Section 6.1 Inclusion criteria: Inclusion criterion 
3) b) i): Males, ages at least 18 or local age of 
majority
Czech Republic specific language: Adding a max age of 
75 years
Section 6.1 Inclusion criteria. Inclusion criterion 3) b) i): 
Males, ages at least 18 or local age of majority and 
maximum 75
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