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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function

Summary
EudraCT number	2016-001685-29
Trial protocol	DE ES CZ NL GB GR IT
Global end of trial date	12 Nov 2019

Results information
Results version number	v1(current)
This version publication date	25 Nov 2020
First version publication date	25 Nov 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

CV013-011

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

12 Nov 2019

Was the trial ended prematurely?

Main objective of the trial

Evaluate the effects of various doses of BMS-986231 compared to placebo on clinically relevant hypotension (defined by systolic blood pressure [SBP] < 90 mmHg or symptoms of hypotension).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jan 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 52

Country: Number of subjects enrolled

Czechia: 53

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Germany: 22

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Greece: 44

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Netherlands: 14

Country: Number of subjects enrolled

Poland: 42

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Argentina: 58

Country: Number of subjects enrolled

Japan: 23

Worldwide total number of subjects

329

EEA total number of subjects

194

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

111

From 65 to 84 years

194

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

100 participants in Part I and 222 in Part II were randomized (322 total), of which 97 and 214, respectively, were treated (311 total). Reasons not treated, Part I: 3 other reasons. Reasons not treated, Part II: 2 no longer met study criteria; 1 adverse event (AE); 5 other reasons. Also, 18 were randomized/treated in Part II Japan-specific cohort.

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Placebo - Part I

Arm description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 - Part I

Arm description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 3-to-6-to-12 µg/kg/min

Placebo - Part II

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Placebo - Part II (Japan cohort)

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Number of subjects in period 1	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Started	48	49	71	71	72	6	6	6
Completed	48	48	70	71	70	6	6	6
Not completed	0	1	1	0	2	0	0	0
Adverse event, serious fatal	-	-	-	-	2	-	-	-
Participant withdrew consent	-	1	-	-	-	-	-	-
Participant refuses assessments	-	-	1	-	-	-	-	-

Period 2 title

32-Day Follow-Up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Placebo - Part I

Arm description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 - Part I

Arm description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 3-to-6-to-12 µg/kg/min

Placebo - Part II

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Placebo - Part II (Japan cohort)

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Number of subjects in period 2	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Started	48	48	70	71	70	6	6	6
Started initial treatment	48	49	71	71	72	6	6	6
Completed	44	47	62	63	64	6	5	6
Not completed	4	2	9	8	8	0	1	0
Adverse event, serious fatal	2	-	5	6	3	-	-	-
Participant refused to visit	-	1	2	-	2	-	-	-
Participant withdrew consent	-	-	-	-	2	-	1	-
withdrew from Day 5, D32 form not done	-	1	-	-	-	-	-	-
Family doctor OK'd participant, per call	-	-	1	-	-	-	-	-
Lost to follow-up	1	-	1	1	-	-	-	-
Poor/non-compliance	1	-	-	1	1	-	-	-
Joined	0	1	1	0	2	0	0	0
Period timeframe started at treatment	-	1	1	-	2	-	-	-

Period 3 title

182-Day Follow-Up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Placebo - Part I

Arm description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 - Part I

Arm description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 3-to-6-to-12 µg/kg/min

Placebo - Part II

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Placebo - Part II (Japan cohort)

Arm description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Placebo

Investigational medicinal product name

Placebo-matching BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

placebo-matching

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 6 µg/kg/min

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Arm description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Arm type

Experimental

Investigational medicinal product name

BMS-986231

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

BMS-986231 240 mg/vial; 12 µg/kg/min

Number of subjects in period 3	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Started	44	47	62	63	64	6	5	6
Started initial treatment	48	49	71	71	72	6	6	6
Completed	44	45	60	58	60	1	2	1
Not completed	4	4	11	13	12	5	4	5
Adverse event, serious fatal	3	3	11	12	9	-	-	1
Participant withdrew consent	-	-	-	-	1	-	1	-
Alive, per civil unit	-	-	-	-	1	-	-	-
Alive, per national insurance system	1	-	-	-	-	-	-	-
withdrew from D5, D32/182 forms not done	-	1	-	-	-	-	-	-
No cont D182 FU, Sponsor admin reason	-	-	-	-	-	5	3	4
Alive, per Family doctor	-	-	-	-	1	-	-	-
Vital status collected via EMR	-	-	-	1	-	-	-	-
Joined	4	2	9	8	8	0	1	0
Period timeframe started at treatment	4	2	9	8	8	-	1	-

Baseline characteristics

Top of page

Reporting group title

Placebo - Part I

Reporting group description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

BMS-986231 - Part I

Reporting group description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

Placebo - Part II

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Reporting group title

BMS-986231 6 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Reporting group title

BMS-986231 12 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Reporting group title

Placebo - Part II (Japan cohort)

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Reporting group values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)	Total
Number of subjects	48	49	71	71	72	6	6	6	329
Age Categorical
Age categorical
Units: Participants
< 65 years	17	24	21	23	19	3	3	1	111
65 -to <=75 years	22	15	36	26	30	0	1	2	132
>75 years	9	10	14	22	23	3	2	3	86
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.0 ± 12.23	64.6 ± 12.23	67.3 ± 11.52	69.2 ± 11.41	70.0 ± 11.52	65.3 ± 17.88	69.5 ± 13.31	76.7 ± 10.48	-
Sex: Female, Male
Units: Participants
Female	8	10	18	20	15	0	1	2	74
Male	40	39	53	51	57	6	5	4	255
Race/Ethnicity, Customized
Race
Units: Subjects
White	35	37	63	62	66	0	0	0	263
Black or African American	11	11	4	7	4	0	0	0	37
Asian	0	0	2	2	2	6	6	6	24
Other	2	1	2	0	0	0	0	0	5
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	9	11	11	0	0	0	32
Not Hispanic or Latino	44	45	18	23	20	0	0	0	150
Unknown or Not Reported	4	3	44	37	41	6	6	6	147

End points

Top of page

Reporting group title

Placebo - Part I

Reporting group description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

BMS-986231 - Part I

Reporting group description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

Placebo - Part II

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Reporting group title

BMS-986231 6 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Reporting group title

BMS-986231 12 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Reporting group title

Placebo - Part II (Japan cohort)

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

Placebo - Part I

Reporting group description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

BMS-986231 - Part I

Reporting group description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

Placebo - Part II

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Reporting group title

BMS-986231 6 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Reporting group title

BMS-986231 12 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Reporting group title

Placebo - Part II (Japan cohort)

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

Placebo - Part I

Reporting group description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

BMS-986231 - Part I

Reporting group description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

Placebo - Part II

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Reporting group title

BMS-986231 6 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Reporting group title

BMS-986231 12 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Reporting group title

Placebo - Part II (Japan cohort)

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Primary: Percentage of participants with clinically relevant hypotension up to 6 hours after the end of study drug infusion

Top of page

End point title

Percentage of participants with clinically relevant hypotension up to 6 hours after the end of study drug infusion

End point description

Percentage of participants with clinically relevant hypotension, defined by systolic blood pressure (SBP) < 90 mm Hg (confirmed by a repeated value < 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug infusion

End point type

Primary

End point timeframe

From start of infusion up to 6 hours post end of infusion

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Percentage of participants
number (confidence interval 95%)
clinically relevant hypotension	8.3 (2.32 to 19.98)	20.4 (10.24 to 34.34)	18.3 (10.13 to 29.27)	21.1 (12.33 to 32.44)	34.7 (23.88 to 46.86)	0 (0.00 to 45.93)	33.3 (4.33 to 77.72)	50.0 (11.81 to 88.19)
symptoms of hypotension	2.1 (0.05 to 11.07)	6.1 (1.28 to 16.87)	1.4 (0.04 to 7.60)	2.8 (0.34 to 9.81)	8.3 (3.12 to 17.26)	0 (0.00 to 45.93)	0 (0.00 to 45.93)	0 (0.00 to 45.93)
confirmed SBP < 90 mmHg	6.3 (1.31 to 17.20)	20.4 (10.24 to 34.34)	18.3 (10.13 to 29.27)	21.1 (12.33 to 32.44)	29.2 (19.05 to 41.07)	0 (0.00 to 45.93)	33.3 (4.33 to 77.72)	50.0 (11.81 to 88.19)

Part I, clinically relevant hypotension - risk

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[1]

Method

Parameter type

Relative risk from placebo

Point estimate

2.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

14.53

Notes
[1] - Part I, clinically relevant hypotension - relative risk

Part I, clinically relevant hypotension - diff.

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[2]

Method

Parameter type

Relative difference from placebo

Point estimate

0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.28

Notes
[2] - Part I, clinically relevant hypotension - relative difference

Part I, symptoms of hypotension - risk

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[3]

Method

Parameter type

Relative risk from placebo

Point estimate

2.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

75.47

Notes
[3] - Part I, symptoms of hypotension - relative risk

Part I, symptoms of hypotension - diff.

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[4]

Method

Parameter type

Relative difference from placebo

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.15

Notes
[4] - Part I, symptoms of hypotension - relative difference

Part I, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[5]

Method

Parameter type

Relative risk from placebo

Point estimate

3.27

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

14.66

Notes
[5] - Part I, confirmed SBP < 90 mmHg - relative risk

Part I, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[6]

Method

Parameter type

Relative difference from placebo

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.29

Notes
[6] - Part I, confirmed SBP < 90 mmHg - relative difference

Part II-low, clinically relevant hypotension, risk

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Parameter type

Relative risk from placebo

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

2.43

Notes
[7] - Part II (low dose), clinically relevant hypotension - relative risk

Part II-low, clinically relevant hypotension, diff

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[8]

Method

Parameter type

Relative difference from placebo

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.16

Notes
[8] - Part II (low dose), clinically relevant hypotension - relative difference

Part II-low, symptoms of hypotension - risk

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[9]

Method

Parameter type

Relative risk from placebo

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

54.35

Notes
[9] - Part II (low dose), symptoms of hypotension - relative risk

Part II-low, symptoms of hypotension - diff.

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[10]

Method

Parameter type

Relative difference from placebo

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.09

Notes
[10] - Part II (low dose), symptoms of hypotension - relative difference

Part II-low, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[11]

Method

Parameter type

Relative risk from placebo

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

2.43

Notes
[11] - Part II (low dose), confirmed SBP < 90 mmHg - relative risk

Part II-low, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[12]

Method

Parameter type

Relative difference from placebo

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.16

Notes
[12] - Part II (low dose), confirmed SBP < 90 mmHg - relative difference

PartII-high, clinically relevant hypotension, risk

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[13]

Method

Parameter type

Relative risk from placebo

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

3.59

Notes
[13] - Part II (high dose), clinically relevant hypotension - relative risk

PartII-high, clinically relevant hypotension, diff

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[14]

Method

Parameter type

Relative difference from placebo

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.31

Notes
[14] - Part II (high dose), clinically relevant hypotension - relative difference

Part II-high, symptoms of hypotension - risk

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[15]

Method

Parameter type

Relative risk from placebo

Point estimate

5.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

149.72

Notes
[15] - Part II (high dose), symptoms of hypotension - relative risk

Part II-high, symptoms of hypotension - diff.

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[16]

Method

Parameter type

Relative difference from placebo

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.16

Notes
[16] - Part II (high dose), symptoms of hypotension - relative difference

Part II-high, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[17]

Method

Parameter type

Relative risk from placebo

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

3.21

Notes
[17] - Part II (high dose), confirmed SBP < 90 mmHg - relative risk

Part II-high, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[18]

Method

Parameter type

Relative difference from placebo

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.25

Notes
[18] - Part II (high dose), confirmed SBP < 90 mmHg - relative difference

Part II J-low, clinically relevant hyp. - diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[19]

Method

Parameter type

Relative difference from placebo

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.78

Notes
[19] - Part II-Japan (low dose), clinically relevant hypotension - relative difference

Part II J-low, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[20]

Method

Parameter type

Relative difference from placebo

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.78

Notes
[20] - Part II-Japan (low dose), confirmed SBP < 90 mmHg - relative difference

Part II J-high, clinically relevant hyp. - diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[21]

Method

Parameter type

Relative difference from placebo

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.88

Notes
[21] - Part II-Japan (high dose), clinically relevant hypotension - relative difference

Part II J-high, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[22]

Method

Parameter type

Relative difference from placebo

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.88

Notes
[22] - Part II-Japan (high dose), confirmed SBP < 90 mmHg - relative difference

Secondary: Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32

Top of page

End point title

Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32

End point description

Assess the effect of BMS-986231 on NT-proBNP (N-terminal prohormone of brain natriuretic peptide)

End point type

Secondary

End point timeframe

0, 24, 48, 72, 120 hour or discharge; Day 32

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: pmol/L
arithmetic mean (standard deviation)
24 hour	-270.88 ± 400.320	-364.46 ± 456.158	-147.96 ± 452.239	-340.74 ± 430.639	-416.91 ± 503.825	-129.70 ± 255.716	-165.93 ± 185.910	-397.60 ± 330.721
48 hour	-405.06 ± 591.711	-510.51 ± 592.734	-210.87 ± 580.487	-300.87 ± 725.268	-472.32 ± 610.590	-329.24 ± 646.985	-251.73 ± 243.794	-497.35 ± 725.286
72 hour	-396.21 ± 675.761	-373.86 ± 702.530	-249.26 ± 655.999	-118.86 ± 900.798	-293.94 ± 685.681	-433.08 ± 761.573	9.89 ± 523.754	-229.56 ± 809.850
120 hour	-541.36 ± 773.006	-409.53 ± 751.624	-140.60 ± 1358.127	-76.20 ± 993.110	-390.21 ± 717.114	-434.36 ± 659.528	-379.06 ± 244.917	-552.55 ± 824.009
Day 32	-202.07 ± 799.169	-91.61 ± 2254.397	-321.73 ± 600.297	-361.73 ± 782.881	-476.86 ± 716.072	-556.69 ± 1288.342	-343.64 ± 377.590	-706.11 ± 1111.877

No statistical analyses for this end point

Secondary: Change in participant-reported resting dyspnea from baseline through Hour 72

Top of page

End point title

Change in participant-reported resting dyspnea from baseline through Hour 72

End point description

Endpoint was measured by the area under the curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at baseline, and Hours 6, 12, 24, 48, and 72. Participants were asked to report their absolute current severity of dyspnea on an 11-point numerical rating scale (NRS; range 0 to 10). The numerical rating scale (NRS) was used to assess the degree of dyspnea (breathlessness), measured using an 11-point scale provided by the Sponsor. A score of 0 represents “I am not breathless at all” and 10 represents “I am the most breathless I can possibly imagine”.

End point type

Secondary

End point timeframe

Hours 6, 12, 24, 48, and 72

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Scores on a scale
arithmetic mean (standard deviation)
6 hour	-1.5 ± 1.84	-1.5 ± 1.64	-1.1 ± 1.90	-1.7 ± 1.94	-1.7 ± 2.13	-0.3 ± 1.03	0.0 ± 2.90	-1.3 ± 3.44
12 hour	-2.1 ± 2.38	-2.2 ± 1.73	-1.7 ± 2.75	-2.4 ± 2.38	-2.0 ± 2.49	-1.0 ± 1.79	-0.2 ± 3.37	-1.4 ± 4.22
24 hour	-2.0 ± 2.50	-2.1 ± 2.19	-2.1 ± 2.82	-2.9 ± 2.68	-2.2 ± 2.42	-0.8 ± 1.72	-1.5 ± 3.02	-1.2 ± 2.14
48 hour	-2.8 ± 2.15	-2.6 ± 2.51	-2.8 ± 3.00	-3.4 ± 2.44	-2.8 ± 2.45	-1.2 ± 1.47	-0.8 ± 3.43	-2.0 ± 1.67
72 hour	-2.9 ± 2.23	-3.7 ± 2.22	-3.2 ± 3.19	-3.9 ± 2.28	-3.2 ± 2.73	-1.2 ± 2.14	-1.2 ± 3.19	-2.0 ± 2.00

No statistical analyses for this end point

Secondary: Percentage of participants with symptomatic hypotension up to 6 hours after the end of study drug infusion

Top of page

End point title

Percentage of participants with symptomatic hypotension up to 6 hours after the end of study drug infusion

End point description

The percentage of participants experiencing symptoms of hypotension up to 6 hours post-treatment was reported for each arm.

End point type

Secondary

End point timeframe

From start of infusion up to 6 hours post end of infusion

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Percentage of participants
number (confidence interval 95%)	2.1 (0.05 to 11.07)	6.1 (1.28 to 16.87)	1.4 (0.04 to 7.60)	2.8 (0.34 to 9.81)	8.3 (3.12 to 17.26)	0 (0.00 to 45.93)	0 (0.00 to 45.93)	0 (0.00 to 45.93)

Part I, symptoms of hypotension - risk

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[23]

Method

Parameter type

Relative risk from placebo

Point estimate

2.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

75.47

Notes
[23] - Part I, symptoms of hypotension - relative risk

Part I, symptoms of hypotension - diff.

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[24]

Method

Parameter type

Relative difference from placebo

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.15

Notes
[24] - Part I, symptoms of hypotension - relative difference

Part II-low, symptoms of hypotension - risk

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[25]

Method

Parameter type

Relative risk from placebo

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

54.35

Notes
[25] - Part II (low dose), symptoms of hypotension - relative risk

Part II-low, symptoms of hypotension - diff.

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[26]

Method

Parameter type

Relative difference from placebo

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.09

Notes
[26] - Part II (low dose), symptoms of hypotension - relative difference

Part II-high, symptoms of hypotension - risk

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[27]

Method

Parameter type

Relative risk from placebo

Point estimate

5.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

149.72

Notes
[27] - Part II (high dose), symptoms of hypotension - relative risk

Part II-high, symptoms of hypotension - diff.

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[28]

Method

Parameter type

Relative difference from placebo

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.16

Notes
[28] - Part II (high dose), symptoms of hypotension - relative difference

Secondary: Percentage of participants with SBP < 90 mm Hg (confirmed by a repeated value)

Top of page

End point title

Percentage of participants with SBP < 90 mm Hg (confirmed by a repeated value)

End point description

The percentage of participants experiencing SBP < 90 mm Hg (confirmed by a repeated value) up to 6 hours post-treatment was reported for each arm.

End point type

Secondary

End point timeframe

From start of infusion up to 6 hours post end of infusion

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Percentage of participants
number (confidence interval 95%)	6.3 (1.31 to 17.20)	20.4 (10.24 to 34.34)	18.3 (10.13 to 29.27)	21.1 (12.33 to 32.44)	29.2 (19.05 to 41.07)	0 (0.00 to 45.93)	33.3 (4.33 to 77.72)	50.0 (11.81 to 88.19)

Part I, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[29]

Method

Parameter type

Relative risk from placebo

Point estimate

3.27

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

14.66

Notes
[29] - Part I, confirmed SBP < 90 mmHg - relative risk

Part I, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part I v BMS-986231 - Part I

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[30]

Method

Parameter type

Relative difference from placebo

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.29

Notes
[30] - Part I, confirmed SBP < 90 mmHg - relative difference

Part II-low, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[31]

Method

Parameter type

Relative risk from placebo

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

2.43

Notes
[31] - Part II (low dose), confirmed SBP < 90 mmHg - relative risk

Part II-low, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II v BMS-986231 6 µg/kg/min - Part II

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

^[32]

Method

Parameter type

Relative difference from placebo

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.16

Notes
[32] - Part II (low dose), confirmed SBP < 90 mmHg - relative difference

Part II-high, confirmed SBP < 90 mmHg - risk

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[33]

Method

Parameter type

Relative risk from placebo

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

3.21

Notes
[33] - Part II (high dose), confirmed SBP < 90 mmHg - relative risk

Part II-high, confirmed SBP < 90 mmHg - diff.

Comparison groups

Placebo - Part II v BMS-986231 12 µg/kg/min - Part II

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

^[34]

Method

Parameter type

Relative difference from placebo

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.25

Notes
[34] - Part II (high dose), confirmed SBP < 90 mmHg - relative difference

Part II J-low, confirmed SBP < 90 mmHg, diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[35]

Method

Parameter type

Relative difference from placebo

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.78

Notes
[35] - Part II-Japan (low dose), confirmed SBP < 90 mmHg - relative difference

Part II J-high, confirmed SBP < 90 mmHg, diff.

Comparison groups

Placebo - Part II (Japan cohort) v BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[36]

Method

Parameter type

Relative difference from placebo

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.88

Notes
[36] - Part II-Japan (high dose), confirmed SBP < 90 mmHg - relative difference

Secondary: Number of participants with a Serious Adverse Events (SAE) assessed up to Day 32

Top of page

End point title

Number of participants with a Serious Adverse Events (SAE) assessed up to Day 32

End point description

Number of participants who experienced an in-study SAE. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 Included serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment.

End point type

Secondary

End point timeframe

32 days

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants	11	14	23	15	15	1	0	1

No statistical analyses for this end point

Secondary: Number of participants who discontinued due to hypotension

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End point title

Number of participants who discontinued due to hypotension

End point description

Number of participants who discontinued study treatment due to hypotension. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment and serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment. Hypotension defined as systolic blood pressure (SBP) < 90 mmHg.

End point type

Secondary

End point timeframe

up to 120 hours (for AEs); up to 32 days (for SAEs)

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants	4	8	7	13	16	0	1	3

No statistical analyses for this end point

Secondary: Number of participants who discontinued, experienced a down-titration or dose interruption due to decreased blood pressure

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End point title

Number of participants who discontinued, experienced a down-titration or dose interruption due to decreased blood pressure

End point description

Number of participants who discontinued study treatment, experienced a down-titration (dose reduction) or dose interruption due to decreased blood pressure/hypotension are reported below. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment and serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment. If the participant experienced systolic blood pressure (SBP) < 95 mm Hg, without symptoms related to hypotension, the measurement was repeated within 15 minutes. If the SBP remained < 95 mm Hg, the dose reduction occurred.

End point type

Secondary

End point timeframe

up to 120 hours (for AEs); up to 32 days (for SAEs)

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants
discontinuation	4	8	7	13	15	0	1	3
down-titration	3	9	9	10	25	0	1	3
interruption	3	4	4	12	13	0	0	0

No statistical analyses for this end point

Secondary: Number of participants with an Adverse Event (AE) assessed up to 120 hours

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End point title

Number of participants with an Adverse Event (AE) assessed up to 120 hours

End point description

Number of participants who experienced an in-study AE. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment.

End point type

Secondary

End point timeframe

up to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants	31	39	48	48	55	2	6	6

No statistical analyses for this end point

Secondary: Number of participants who died (all- cause and Cardiovascular-related) through Day 182

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End point title

Number of participants who died (all- cause and Cardiovascular-related) through Day 182

End point description

Number of participants who died (all- cause and CV related) through Day 182. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 CV=Cardiovascular

End point type

Secondary

End point timeframe

through 182 days

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants
number (confidence interval 95%)
All-cause	3 (1.31 to 17.20)	3 (1.28 to 16.87)	11 (8.00 to 26.03)	12 (9.05 to 27.66)	9 (5.88 to 22.41)	0 (0.00 to 45.93)	0 (0.00 to 45.93)	1 (0.42 to 64.12)
CV-related	3 (1.31 to 17.20)	2 (0.50 to 13.98)	9 (5.96 to 22.70)	10 (6.97 to 24.38)	4 (1.53 to 13.62)	0 (0.00 to 45.93)	0 (0.00 to 45.93)	0 (0.00 to 45.93)

No statistical analyses for this end point

Secondary: Change in Troponin T from baseline to Hour 24, 48, and 72

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End point title

Change in Troponin T from baseline to Hour 24, 48, and 72

End point description

Baseline = Last non-missing result with a collection date-time less than or on the date-time of the start of infusion of study drug

End point type

Secondary

End point timeframe

from baseline to Hour 24, 48, and 72

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: ng/L
arithmetic mean (standard deviation)
24 hour	4.11 ± 27.303	-1.31 ± 12.278	-1.80 ± 11.266	-3.45 ± 20.030	-8.09 ± 37.864	-4.67 ± 3.983	1.33 ± 5.750	-7.67 ± 16.669
48 hour	-0.93 ± 22.714	14.56 ± 81.979	-2.88 ± 16.424	8.08 ± 71.672	-11.15 ± 45.495	-10.67 ± 10.633	49.50 ± 118.417	-8.40 ± 25.501
72 hour	6.07 ± 30.033	6.76 ± 66.673	-1.44 ± 16.472	5.00 ± 65.766	-13.05 ± 68.276	-10.50 ± 12.145	248.00 ± 433.581	-15.00 ± 25.169

No statistical analyses for this end point

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Hematology

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End point title

Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Hematology

End point description

Number of participants who experienced an in-study Hematology marked laboratory abnormality (reported in > 5% of total participants). Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants
high leukocyte counts	5	2	5	4	3	0	0	0
low hemoglobin values	4	5	5	6	4	1	1	0
low platelet values	4	2	2	7	1	0	0	0
low neutrophils values	0	1	1	1	0	0	0	0
low leukocyte counts	0	1	2	0	0	0	0	0
low hematocrit values	1	1	1	3	0	0	0	0
low erythrocytes values	1	1	1	3	0	0	0	0

No statistical analyses for this end point

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Chemistry

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End point title

Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Chemistry

End point description

Number of participants who experienced an in-study Chemistry marked laboratory abnormality (reported in > 5% of total participants). Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants
high blood urea nitrogen values	23	16	23	23	18	0	1	2
high urate values	10	15	10	20	8	0	1	1
high potassium values	2	5	6	7	2	0	1	0
high alanine aminotransferase (ALT) values	6	1	5	2	2	0	0	0
high alkaline phosphatase values	5	0	2	0	1	0	0	0
low protein values	3	9	3	8	4	0	1	0
high asparate aminotransferase values	4	0	4	2	1	0	0	0
high bilirubin values	2	2	0	0	0	0	1	0
high bicarbonate values	1	2	0	0	0	0	0	0
low chloride counts	1	2	1	4	1	0	0	0
high creatine kinase values	0	1	0	0	0	0	0	0
high protein values	1	0	2	0	2	0	0	0
high sodium values	0	1	2	0	0	0	0	0
low bicarbonate values	0	0	2	1	1	0	0	0
low sodium values	0	0	0	2	0	0	0	0
low albumin values	0	0	0	1	2	0	0	0
low calcium values	0	0	2	1	2	0	0	0

No statistical analyses for this end point

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Urinalysis

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End point title

Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Urinalysis

End point description

Number of participants who experienced an in-study Urinalysis marked laboratory abnormality (reported in > 5% of total participants). Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Participants
high protein values	10	11	16	13	17	2	2	2
high erythrocyte values	1	1	1	3	2	0	0	0
high leukocytes values	0	1	0	2	1	0	0	0

No statistical analyses for this end point

Secondary: Change in Vital Signs from baseline to 120 hours - blood pressure

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End point title

Change in Vital Signs from baseline to 120 hours - blood pressure

End point description

The change in baseline for vital signs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	29	26	50	48	44	6	6	6
Units: mmHg
arithmetic mean (standard deviation)
systolic blood pressure, mmHg	-6.8 ± 16.60	0.0 ± 17.75	-4.3 ± 15.23	-7.9 ± 15.60	-8.8 ± 14.01	-10.3 ± 15.60	-17.5 ± 9.14	-6.2 ± 16.44
diastolic blood pressure, mmHg	-4.0 ± 12.67	-1.9 ± 13.53	-4.4 ± 12.99	-3.4 ± 14.37	-1.6 ± 10.83	1.7 ± 16.24	-15.7 ± 19.08	-9.3 ± 14.45

No statistical analyses for this end point

Secondary: Change in Vital Signs from baseline to 120 hours - heart rate

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End point title

Change in Vital Signs from baseline to 120 hours - heart rate

End point description

The change in baseline for vital signs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: beats/min
arithmetic mean (standard deviation)	-1.8 ± 15.53	-9.1 ± 17.13	-8.3 ± 15.55	-4.6 ± 15.40	-6.3 ± 15.60	-6.7 ± 21.88	-3.0 ± 13.31	3.8 ± 11.55

No statistical analyses for this end point

Secondary: Change in Vital Signs from baseline to 120 hours - respiratory rate

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End point title

Change in Vital Signs from baseline to 120 hours - respiratory rate

End point description

The change in baseline for vital signs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: breaths/min
arithmetic mean (standard deviation)	-2.6 ± 3.93	-3.0 ± 4.82	-2.9 ± 3.80	-2.6 ± 4.33	-1.8 ± 3.96	-2.3 ± 2.88	0.0 ± 9.98	-1.4 ± 3.58

No statistical analyses for this end point

Secondary: Change in Vital Signs from baseline to 120 hours - temperature

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End point title

Change in Vital Signs from baseline to 120 hours - temperature

End point description

The change in baseline for vital signs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: Celsius (C)
arithmetic mean (standard deviation)	-0.04 ± 0.643	0.09 ± 0.649	0.04 ± 0.427	0.00 ± 0.342	-0.05 ± 0.481	-0.47 ± 0.650	-0.27 ± 0.535	0.44 ± 0.541

No statistical analyses for this end point

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - mean heart rate

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End point title

Change in Electrocardiograms (ECGs) from baseline to 120 hours - mean heart rate

End point description

The change in baseline for ECGs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	5	6	6
Units: beats/min
arithmetic mean (standard deviation)	-5.3 ± 9.36	-6.8 ± 21.31	-7.1 ± 17.46	-5.1 ± 18.64	-6.1 ± 17.33	2.0 ± 10.72	-13.0 ± 12.62	-5.2 ± 14.85

No statistical analyses for this end point

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - PR, QT, QTcF Intervals and QRS Duration

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End point title

Change in Electrocardiograms (ECGs) from baseline to 120 hours - PR, QT, QTcF Intervals and QRS Duration

End point description

The change in baseline for ECGs was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: msec
arithmetic mean (standard deviation)
PR Interval, Aggregate, msec	-17.4 ± 66.31	-2.3 ± 32.11	-0.1 ± 23.49	10.9 ± 22.02	2.0 ± 25.41	-1.5 ± 16.50	10.4 ± 26.32	6.0 ± 30.10
QRS Duration, Aggregate, msec	5.1 ± 22.19	-0.1 ± 12.46	1.6 ± 20.29	-1.6 ± 13.22	2.7 ± 16.77	-3.0 ± 4.80	-2.5 ± 7.20	3.0 ± 4.38
QT Interval, Aggregate, msec	-10.6 ± 49.20	7.2 ± 48.25	8.7 ± 53.17	5.8 ± 42.19	-0.3 ± 45.39	-30.0 ± 28.17	5.7 ± 24.41	16.5 ± 50.22
QTcF Interval, Aggregate, msec	-27.5 ± 41.79	-13.9 ± 41.56	-4.0 ± 51.04	-4.0 ± 33.59	-10.3 ± 37.63	-24.8 ± 20.00	-8.8 ± 22.35	3.2 ± 22.93

No statistical analyses for this end point

Secondary: Change in physical measurements from baseline to 120 hours

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End point title

Change in physical measurements from baseline to 120 hours

End point description

The change in baseline for physical measurements was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	48	49	71	71	72	6	6	6
Units: kg
arithmetic mean (standard deviation)	0.00 ± 0383	0.10 ± 0.285	-2.87 ± 4.447	-2.96 ± 4.231	-1.83 ± 5.295	-3.58 ± 2.182	-3.97 ± 2.160	-6.08 ± 4.009

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^9 cells/L

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End point title

Change in laboratory assessments from baseline to 120 hours - x10^9 cells/L ^[37]

End point description

The change in baseline for laboratory assessments was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	30	23	41	36	39
Units: x10^9 cells/L
arithmetic mean (standard deviation)
leukocyte, x10^9 c/L	0.12 ± 3.078	-1.38 ± 1.892	-0.20 ± 4.370	0.20 ± 2.549	-0.09 ± 1.980
platelet, x10^9 c/L	5.63 ± 31.679	-5.77 ± 34.666	1.84 ± 40.808	3.26 ± 37.888	1.26 ± 31.135

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - g/L

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End point title

Change in laboratory assessments from baseline to 120 hours - g/L ^[38]

End point description

The change in baseline for laboratory assessments was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	30	23	46	42	43
Units: g/L
arithmetic mean (standard deviation)
hemoglobin, g/L	-0.67 ± 11.851	-0.70 ± 8.573	1.20 ± 11.487	0.94 ± 11.684	1.38 ± 9.161
protein, g/L	1.10 ± 6.172	2.77 ± 5.839	0.57 ± 8.178	0.38 ± 6.048	-0.05 ± 5.367

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - mmol/L

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End point title

Change in laboratory assessments from baseline to 120 hours - mmol/L ^[39]

End point description

The change in baseline for laboratory assessments was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	48	49	71	71	72
Units: mmol/L
arithmetic mean (standard deviation)
blood urea nitrogen, mmol/L	4.01 ± 5.474	0.32 ± 3.164	1.96 ± 3.920	2.15 ± 5.016	1.24 ± 3.655
urate, mmol/L	0.06 ± 0.154	0.01 ± 0.108	-0.01 ± 0.126	0.04 ± 0.147	-0.03 ± 0.111
potassium, mmol/L	0.19 ± 0.697	0.28 ± 0.513	0.21 ± 0.692	0.13 ± 0.558	0.15 ± 0.651

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - U/L

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End point title

Change in laboratory assessments from baseline to 120 hours - U/L ^[40]

End point description

The change in baseline for laboratory assessments was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	48	49	71	71	72
Units: U/L
arithmetic mean (standard deviation)
alanine aminotransferase (ALT), U/L	148.13 ± 837.833	-2.73 ± 11.089	-3.22 ± 102.038	30.36 ± 189.310	-13.07 ± 76.357
alkaline phosphatase, U/L	-1.00 ± 28.018	1.65 ± 11.052	-1.31 ± 25.186	5.43 ± 26.007	-0.49 ± 21.474
asparate aminotransferase, U/L	214.77 ± 1204.410	-2.77 ± 10.277	-11.15 ± 127.903	10.81 ± 65.009	-10.00 ± 52.075

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - mg/dL

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End point title

Change in laboratory assessments from baseline to 120 hours - mg/dL ^[41]

End point description

The change in baseline for laboratory assessments was reported for each arm. Note: 9999 = NA, not available, 120 hour data not collected

End point type

Secondary

End point timeframe

to 120 hours

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	48	49	71	71	72
Units: mg/dL
arithmetic mean (standard deviation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^12 c/L

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End point title

Change in laboratory assessments from baseline to 120 hours - x10^12 c/L ^[42]

End point description

The change in baseline for laboratory assessments was reported for each arm.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Lab assessments for Japan-cohort reported separately from this endpoint

End point values	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II
Number of subjects analysed	48	49	71	71	72
Units: x10^12 c/L
arithmetic mean (standard deviation)	-0.02 ± 0.394	0.02 ± 0.305	0.04 ± 0.409	0.04 ± 0.481	0.09 ± 0.337

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Protein (nmol/L)

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End point title

Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Protein (nmol/L) ^[43]

End point description

The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting of lab assessments for this endpoint is in regards to Japan-cohort only

End point values	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	6	6	5
Units: nmol/L
arithmetic mean (standard deviation)	79.38 ± 192.568	74.13 ± 110.919	131.64 ± 407.611

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Creatinine (µmol/L)

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End point title

Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Creatinine (µmol/L) ^[44]

End point description

The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting of lab assessments for this endpoint is in regards to Japan-cohort only

End point values	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	6	6	5
Units: µmol/L
arithmetic mean (standard deviation)	4.33 ± 17.728	-1.50 ± 6.775	12.40 ± 23.891

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Cystatin (mg/L)

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End point title

Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Cystatin (mg/L) ^[45]

End point description

The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting of lab assessments for this endpoint is in regards to Japan-cohort only

End point values	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	6	6	5
Units: mg/L
arithmetic mean (standard deviation)	0.18 ± 0.268	0.17 ± 0.150	0.25 ± 0.077

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Potassium Excretion

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End point title

Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Potassium Excretion ^[46]

End point description

The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting of lab assessments for this endpoint is in regards to Japan-cohort only

End point values	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	6	5	5
Units: Fractional Potassium Excretion percent
arithmetic mean (standard deviation)	4.88 ± 8.009	-1.22 ± 4.926	-12.34 ± 13.316

No statistical analyses for this end point

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Sodium Excretion

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End point title

Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Sodium Excretion ^[47]

End point description

The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

End point type

Secondary

End point timeframe

to 120 hours

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Reporting of lab assessments for this endpoint is in regards to Japan-cohort only

End point values	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Number of subjects analysed	6	6	5
Units: Fractional Sodium Excretion percent
arithmetic mean (standard deviation)	0.02 ± 2.076	-2.62 ± 4.538	-5.50 ± 7.984

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Non-serious AEs from treatment, up to and including 120 hours after treatment and serious AEs from treatment, up to and including 32 days after treatment. Mortality data reported through 182 days post-treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Placebo - Part I

Reporting group description

Escalating dose of placebo (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

BMS-986231 - Part I

Reporting group description

Escalating dose of BMS-986231 (3 µg/kg/min for 4 hours, then 6 µg/kg/min for another 4 hours, then 12 µg/kg/min for the remaining 40 hours)

Reporting group title

Placebo - Part II

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours

Reporting group title

BMS-986231 6 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours

Reporting group title

BMS-986231 12 µg/kg/min - Part II

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours

Reporting group title

Placebo - Part II (Japan cohort)

Reporting group description

Matching placebo dose of 6 µg/kg/min or 12 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 6 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 6 µg/kg/min for 48 hours for Japanese participants

Reporting group title

BMS-986231 12 µg/kg/min - Part II (Japan cohort)

Reporting group description

BMS-986231 dose of 12 µg/kg/min for 48 hours for Japanese participants

Serious adverse events	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 48 (22.92%)	14 / 49 (28.57%)	23 / 71 (32.39%)	15 / 71 (21.13%)	15 / 72 (20.83%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
number of deaths (all causes)	3	3	11	12	9	0	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BLADDER CANCER
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
ANGIOPATHY
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILIAC ARTERY OCCLUSION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY OCCLUSION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
Additional description: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERCAPNIA
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SLEEP APNOEA SYNDROME
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE PULMONARY OEDEMA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DELIRIUM
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORGANIC BRAIN SYNDROME
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
ELECTROCARDIOGRAM QRS COMPLEX PROLONGED
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
WRIST FRACTURE
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
CARDIAC FAILURE
subjects affected / exposed	2 / 48 (4.17%)	6 / 49 (12.24%)	8 / 71 (11.27%)	2 / 71 (2.82%)	7 / 72 (9.72%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 9	0 / 2	0 / 7	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	2 / 48 (4.17%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	1 / 48 (2.08%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOGENIC SHOCK
subjects affected / exposed	1 / 48 (2.08%)	1 / 49 (2.04%)	3 / 71 (4.23%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIORENAL SYNDROME
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK COMPLETE
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE ACUTE
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	2 / 71 (2.82%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CORONARY ARTERY STENOSIS
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANGINA PECTORIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VENTRICULAR FIBRILLATION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CHRONIC
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CORONARY ARTERY DISEASE
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	2 / 71 (2.82%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SINUS BRADYCARDIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VENTRICULAR ARRHYTHMIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
HEPATIC CONGESTION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	3 / 48 (6.25%)	1 / 49 (2.04%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BLADDER MASS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
END STAGE RENAL DISEASE
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ACINETOBACTER BACTERAEMIA
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	2 / 71 (2.82%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENDOCARDITIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPERNATRAEMIA
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FLUID OVERLOAD
subjects affected / exposed	1 / 48 (2.08%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo - Part I	BMS-986231 - Part I	Placebo - Part II	BMS-986231 6 µg/kg/min - Part II	BMS-986231 12 µg/kg/min - Part II	Placebo - Part II (Japan cohort)	BMS-986231 6 µg/kg/min - Part II (Japan cohort)	BMS-986231 12 µg/kg/min - Part II (Japan cohort)
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 48 (37.50%)	40 / 49 (81.63%)	47 / 71 (66.20%)	43 / 71 (60.56%)	54 / 72 (75.00%)	2 / 6 (33.33%)	6 / 6 (100.00%)	6 / 6 (100.00%)
Vascular disorders
HYPOTENSION
subjects affected / exposed	5 / 48 (10.42%)	14 / 49 (28.57%)	15 / 71 (21.13%)	20 / 71 (28.17%)	31 / 72 (43.06%)	0 / 6 (0.00%)	3 / 6 (50.00%)	4 / 6 (66.67%)
occurrences all number	7	21	27	25	47	0	3	5
Psychiatric disorders
INSOMNIA
subjects affected / exposed	2 / 48 (4.17%)	2 / 49 (4.08%)	6 / 71 (8.45%)	2 / 71 (2.82%)	1 / 72 (1.39%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	2	2	6	2	1	1	1	1
Investigations
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	4 / 71 (5.63%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	4	0	0	0	0
Cardiac disorders
CARDIAC FAILURE
subjects affected / exposed	2 / 48 (4.17%)	6 / 49 (12.24%)	8 / 71 (11.27%)	2 / 71 (2.82%)	7 / 72 (9.72%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	6	8	2	7	0	0	0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	3 / 48 (6.25%)	1 / 49 (2.04%)	2 / 71 (2.82%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	1	2	1	0	0	0	0
ATRIAL FIBRILLATION
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	1 / 71 (1.41%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0	0	0	1	0
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Nervous system disorders
HEADACHE
subjects affected / exposed	1 / 48 (2.08%)	6 / 49 (12.24%)	5 / 71 (7.04%)	4 / 71 (5.63%)	2 / 72 (2.78%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	7	6	4	2	0	0	1
DIZZINESS
subjects affected / exposed	0 / 48 (0.00%)	3 / 49 (6.12%)	0 / 71 (0.00%)	0 / 71 (0.00%)	2 / 72 (2.78%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0	3	0	0	0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	2 / 72 (2.78%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	2	0	0	1
Eye disorders
VITREOUS DETACHMENT
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Gastrointestinal disorders
CONSTIPATION
subjects affected / exposed	2 / 48 (4.17%)	0 / 49 (0.00%)	1 / 71 (1.41%)	1 / 71 (1.41%)	0 / 72 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	2	0	1	1	0	0	1	1
DIARRHOEA
subjects affected / exposed	0 / 48 (0.00%)	1 / 49 (2.04%)	1 / 71 (1.41%)	1 / 71 (1.41%)	1 / 72 (1.39%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	1	1	0	1	0
Hepatobiliary disorders
CHOLECYSTITIS
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
RASH PRURITIC
subjects affected / exposed	0 / 48 (0.00%)	0 / 49 (0.00%)	0 / 71 (0.00%)	0 / 71 (0.00%)	0 / 72 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	3 / 48 (6.25%)	1 / 49 (2.04%)	1 / 71 (1.41%)	1 / 71 (1.41%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	1	1	1	1	0	0	0
RENAL IMPAIRMENT
subjects affected / exposed	3 / 48 (6.25%)	0 / 49 (0.00%)	3 / 71 (4.23%)	2 / 71 (2.82%)	1 / 72 (1.39%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	3	2	1	0	0	0
Musculoskeletal and connective tissue disorders
MUSCLE SPASMS
subjects affected / exposed	2 / 48 (4.17%)	0 / 49 (0.00%)	0 / 71 (0.00%)	2 / 71 (2.82%)	1 / 72 (1.39%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	0	2	1	0	1	0
Infections and infestations
URINARY TRACT INFECTION
subjects affected / exposed	1 / 48 (2.08%)	2 / 49 (4.08%)	0 / 71 (0.00%)	3 / 71 (4.23%)	3 / 72 (4.17%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	2	0	3	3	0	1	1
Metabolism and nutrition disorders
HYPERURICAEMIA
subjects affected / exposed	1 / 48 (2.08%)	4 / 49 (8.16%)	3 / 71 (4.23%)	1 / 71 (1.41%)	2 / 72 (2.78%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	4	3	1	2	0	0	0
HYPOKALAEMIA
subjects affected / exposed	1 / 48 (2.08%)	3 / 49 (6.12%)	7 / 71 (9.86%)	8 / 71 (11.27%)	8 / 72 (11.11%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	3	8	8	8	0	0	1
HYPOGLYCAEMIA
subjects affected / exposed	1 / 48 (2.08%)	1 / 49 (2.04%)	0 / 71 (0.00%)	1 / 71 (1.41%)	2 / 72 (2.78%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	2	0	1	2	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

11 Oct 2016

Addition of two unblinded interim analysis, addition of Sensory Motor Survey, clarification and updates to Eligibility criteria, and additional edits throughout the document to improve readability.

09 Apr 2018

Expansion of screening period, addition of Holter Monitoring in a subset of patients, addition of Actigraphy monitoring in a subset of patients, and clarifications throughout the document.

13 Mar 2019

Clarify the milestone, timing of enrollment and inclusion/exclusion criteria of the Japanese population. While the enrollment in the main study protocol will continue until 210 patients have been randomized globally in Part II (Cohort 2), enrollment in Japan may continue further only in Japan until approximately 18 total Japanese participants are randomized.

30 May 2019

Additional blood pressure and heart rate measurements at 15 minutes, 45 minutes and 1.5 hours. Clarification that blood pressure measurements within  5 min in the first hour, then  15 min of the specified timepoints in Table 5.1-2.

24 Sep 2019

Advise that Japan participants who were enrolled after the end of global Part II enrollment will be followed for safety and rehospitalization endpoints through Day 32 only. The global study provides adequate safety follow up data and additional Day 182 data from the

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants with clinically relevant hypotension up to 6 hours after the end of study drug infusion

Primary: Percentage of participants with clinically relevant hypotension up to 6 hours after the end of study drug infusion

Secondary: Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32

Secondary: Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32

Secondary: Change in participant-reported resting dyspnea from baseline through Hour 72

Secondary: Change in participant-reported resting dyspnea from baseline through Hour 72

Secondary: Percentage of participants with symptomatic hypotension up to 6 hours after the end of study drug infusion

Secondary: Percentage of participants with symptomatic hypotension up to 6 hours after the end of study drug infusion

Secondary: Percentage of participants with SBP < 90 mm Hg (confirmed by a repeated value)

Secondary: Percentage of participants with SBP < 90 mm Hg (confirmed by a repeated value)

Secondary: Number of participants with a Serious Adverse Events (SAE) assessed up to Day 32

Secondary: Number of participants with a Serious Adverse Events (SAE) assessed up to Day 32

Secondary: Number of participants who discontinued due to hypotension

Secondary: Number of participants who discontinued due to hypotension

Secondary: Number of participants who discontinued, experienced a down-titration or dose interruption due to decreased blood pressure

Secondary: Number of participants who discontinued, experienced a down-titration or dose interruption due to decreased blood pressure

Secondary: Number of participants with an Adverse Event (AE) assessed up to 120 hours

Secondary: Number of participants with an Adverse Event (AE) assessed up to 120 hours

Secondary: Number of participants who died (all- cause and Cardiovascular-related) through Day 182

Secondary: Number of participants who died (all- cause and Cardiovascular-related) through Day 182

Secondary: Change in Troponin T from baseline to Hour 24, 48, and 72

Secondary: Change in Troponin T from baseline to Hour 24, 48, and 72

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Hematology

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Hematology

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Chemistry

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Chemistry

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Urinalysis

Secondary: Number of participants with Marked Laboratory Abnormality assessed to 120 hours - Urinalysis

Secondary: Change in Vital Signs from baseline to 120 hours - blood pressure

Secondary: Change in Vital Signs from baseline to 120 hours - blood pressure

Secondary: Change in Vital Signs from baseline to 120 hours - heart rate

Secondary: Change in Vital Signs from baseline to 120 hours - heart rate

Secondary: Change in Vital Signs from baseline to 120 hours - respiratory rate

Secondary: Change in Vital Signs from baseline to 120 hours - respiratory rate

Secondary: Change in Vital Signs from baseline to 120 hours - temperature

Secondary: Change in Vital Signs from baseline to 120 hours - temperature

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - mean heart rate

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - mean heart rate

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - PR, QT, QTcF Intervals and QRS Duration

Secondary: Change in Electrocardiograms (ECGs) from baseline to 120 hours - PR, QT, QTcF Intervals and QRS Duration

Secondary: Change in physical measurements from baseline to 120 hours

Secondary: Change in physical measurements from baseline to 120 hours

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^9 cells/L

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^9 cells/L

Secondary: Change in laboratory assessments from baseline to 120 hours - g/L

Secondary: Change in laboratory assessments from baseline to 120 hours - g/L

Secondary: Change in laboratory assessments from baseline to 120 hours - mmol/L

Secondary: Change in laboratory assessments from baseline to 120 hours - mmol/L

Secondary: Change in laboratory assessments from baseline to 120 hours - U/L

Secondary: Change in laboratory assessments from baseline to 120 hours - U/L

Secondary: Change in laboratory assessments from baseline to 120 hours - mg/dL

Secondary: Change in laboratory assessments from baseline to 120 hours - mg/dL

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^12 c/L

Secondary: Change in laboratory assessments from baseline to 120 hours - x10^12 c/L

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Protein (nmol/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Protein (nmol/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Creatinine (µmol/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Creatinine (µmol/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Cystatin (mg/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - Cystatin (mg/L)

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Potassium Excretion

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Potassium Excretion

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Sodium Excretion

Secondary: Change in laboratory assessments from baseline to 120 hours, Japan cohort only - percentage Fractional Sodium Excretion

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in Hospitalized Patients with Heart Failure and Impaired Systolic Function