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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Cross-over Phase 2 Study of Continuous 5-Hour Intravenous Infusions of BMS-986231 in Patients with Heart Failure and Impaired Systolic Function

    Summary
    EudraCT number
    		 2016-003586-26
    Trial protocol
    		 GB   NL  
    Global end of trial date
    10 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2020
    First version publication date
    22 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CV013-020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo
    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
    30 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Japan: 2
    Worldwide total number of subjects
    49
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    22
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 49 participants assigned to treatment and 45 treated. Reasons not treated: 2 re-randomized; 1 randomized in error, screen failure; 1 no longer met study criteria. Note: Study designed for all participants to enter all 3 arms (reassignment of arms occurs every period change).

    Period 1
    Period 1 title
    Overall baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 1
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    40
    42
    44
    Completed
    40
    40
    43
    Not completed
    0
    2
    1
         Hypotension
    -
    2
    -
         Acute bradycardia and hypotension
    -
    -
    1
    Period 2
    Period 2 title
    Period 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 2
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    15
    17
    13
    Completed
    15
    16
    12
    Not completed
    0
    1
    1
         stop due to hypotension, cont. period 2
    -
    1
    -
         Acute bradycardia and hypotension
    -
    -
    1
    Period 3
    Period 3 title
    Following Period 1, prior to Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 3
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    15
    16
    12
    Participant return
    15
    17
    12
    Completed
    14
    16
    11
    Not completed
    1
    1
    1
         withdrew consent due to personal reasons
    -
    1
    -
         Lost to follow-up
    -
    -
    1
         withdrew due to acute cholecystitis
    1
    -
    -
    Joined
    0
    1
    0
         stopped Pd. 1 treatment but returned for Pd. 2
    -
    1
    -
    Period 4
    Period 4 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 4
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    13
    13
    15
    Completed
    13
    12
    15
    Not completed
    0
    1
    0
         Hypotension
    -
    1
    -
    Period 5
    Period 5 title
    Following Period 2, prior to Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 5
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    13
    12
    15
    participant re-sequence
    13
    13
    15
    Completed
    13
    12
    15
    Not completed
    0
    1
    0
         Adverse event, non-fatal
    -
    1
    -
    Joined
    0
    1
    0
         participants reassigned treatment for Period 3
    -
    1
    -
    Period 6
    Period 6 title
    Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo-matching treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mL/H for 10 min 10 mL/H for 10 min 20 mL/H for the rest of the 5-hour infusion. Placebo is a solution of 5% dextrose (D5W)

    Arm title
    		 BMS-986231
    Arm description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986231
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 μg/kg/min for 10 min (5 mL/H) 6 μg/kg/min for 10 min (10 mL/H) 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/H)

    Arm title
    		 Nitroglycerin (NTG)
    Arm description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitroglycerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 μg/min for 10 min (5 mL/H) 40 μg/min for 10 min (10 mL/H) 80 μg/min for the rest of the 5-hour infusion (20 mL/H)

    Number of subjects in period 6 [1]
    		Placebo BMS-986231 Nitroglycerin (NTG)
    Started
    12
    12
    15
    Completed
    12
    12
    15
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Note: Study designed for all participants to enter all 3 arms (reassignment of arms occurs every period change)

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall baseline
    Reporting group description
    		 Inclusive of all treatments, all periods

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 49 participants were assigned to treatment and 45 treated. Note: Study designed for all participants to enter all 3 arms (reassignment of arms occurs every period change)
    Reporting group values
    		 Overall baseline Total
    Number of subjects
    		 45 45
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 20 20
        >=65 years
    		 25 25
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.7 ( 12.35 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 8 8
        Male
    		 37 37
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 40 40
        More than one race
    		 0 0
        Unknown or Not Reported
    		 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 2 2
        Unknown or Not Reported
    		 43 43
    Subject analysis sets

    Subject analysis set title
    Overall participants
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Inclusive of all treatments, all periods

    Subject analysis sets values
    		 Overall participants
    Number of subjects
    45
    Age Categorical
    Units: Participants
        <=18 years
    0
        Between 18 and 65 years
    20
        >=65 years
    25
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    63.7 ( 12.35 )
    Sex: Female, Male
    Units: Participants
        Female
    8
        Male
    37
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    3
        Native Hawaiian or Other Pacific Islander
    0
        Black or African American
    1
        White
    40
        More than one race
    0
        Unknown or Not Reported
    1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0
        Not Hispanic or Latino
    2
        Unknown or Not Reported
    43

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matching treatment. Note: Periods are separated by washouts.

    Reporting group title
    BMS-986231
    Reporting group description
    		 BMS-986231: 3 μg/kg/min for 10 min, followed by 6 μg/kg/min for 10 min, followed by 12 μg/kg/min for the rest of the 5-hour infusion. Note: Periods are separated by washouts.

    Reporting group title
    Nitroglycerin (NTG)
    Reporting group description
    		 NTG: 20 μg/min for 10 min, followed by 40 μg/min for 10 min, followed by 80 μg/min for the rest of the 5-hour infusion Note: Periods are separated by washouts.

    Subject analysis set title
    Overall participants
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Inclusive of all treatments, all periods

    Primary: Mean Stroke Volume Index (SVI) derived from the velocity time integral at the left ventricular outflow tract (LVOT VTI) at the end of the 5-hour infusion of BMS-986231, versus placebo

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    End point title
    		 Mean Stroke Volume Index (SVI) derived from the velocity time integral at the left ventricular outflow tract (LVOT VTI) at the end of the 5-hour infusion of BMS-986231, versus placebo [1]
    End point description
    The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo.
    End point type
    Primary
    End point timeframe
    at the end of the 5-hour infusion
    Notes
    [1] - 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: This endpoint is in regards to placebo and drug arms only
    End point values
    		 Placebo BMS-986231
    Number of subjects analysed
    39
    37
    Units: mL/m^2
    arithmetic mean (standard deviation)
        SVI, placebo and drug
    29.545 ( 7.0243 )
    28.721 ( 9.0174 )
    Statistical analysis title
    		 Mean SVI (placebo and drug)
    Comparison groups
    BMS-986231 v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.0432
         upper limit
    		 -0.257
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9242

    Secondary: Mean SVI derived from LVOT VTI at the end of the 5-hour infusion of BMS-986231, versus NTG

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    End point title
    		 Mean SVI derived from LVOT VTI at the end of the 5-hour infusion of BMS-986231, versus NTG [2]
    End point description
    The objective is to evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to NTG.
    End point type
    Secondary
    End point timeframe
    at the end of the 5-hour infusion
    Notes
    [2] - 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: This endpoint is in regards to NTG and drug arms only
    End point values
    		 BMS-986231 Nitroglycerin (NTG)
    Number of subjects analysed
    37
    41
    Units: mL/m^2
    arithmetic mean (standard deviation)
        SVI, drug and NTG
    28.721 ( 9.0174 )
    27.811 ( 7.9712 )
    Statistical analysis title
    		 Mean SVI (drug and NTG)
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.846
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.193
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8176
         upper limit
    		 2.2042
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9832

    Secondary: Mean LVEF, computed by Simpson’s method at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG

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    End point title
    		 Mean LVEF, computed by Simpson’s method at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG
    End point description
    Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV ejection fraction
    End point type
    Secondary
    End point timeframe
    at the end of the 5-hour infusion
    End point values
    		 Placebo BMS-986231 Nitroglycerin (NTG)
    Number of subjects analysed
    38
    36
    42
    Units: Percentage of blood pumped from the LV
    arithmetic mean (standard deviation)
        LVEF
    31.9 ( 7.15 )
    32.8 ( 8.24 )
    33.5 ( 7.33 )
    Statistical analysis title
    		 Mean LVEF (placebo and drug)
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.177
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 3.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.93
    Statistical analysis title
    		 Mean LVEF (drug and NTG)
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.839
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.08
         upper limit
    		 0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48

    Secondary: Mean cardiac power index at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG

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    End point title
    		 Mean cardiac power index at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG
    End point description
    Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Mean LV power index
    End point type
    Secondary
    End point timeframe
    at the end of the 5-hour infusion
    End point values
    		 Placebo BMS-986231 Nitroglycerin (NTG)
    Number of subjects analysed
    35
    36
    39
    Units: watts per square meter (W/m^2)
    arithmetic mean (standard deviation)
        cardiac power index
    0.4122 ( 0.14404 )
    0.3427 ( 0.10463 )
    0.3568 ( 0.09184 )
    Statistical analysis title
    		 Mean cardiac power index (placebo and drug)
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.0977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16634
         upper limit
    		 -0.02915
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03308
    Statistical analysis title
    		 Mean cardiac power index (drug and NTG)
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.103
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.0371
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08243
         upper limit
    		 0.00814
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02194

    Secondary: Mean Diastolic indices: E/A, annular e’ velocity, and E/e’ ratio at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG

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    End point title
    		 Mean Diastolic indices: E/A, annular e’ velocity, and E/e’ ratio at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG
    End point description
    Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: Diastolic function
    End point type
    Secondary
    End point timeframe
    at the end of the 5-hour infusion
    End point values
    		 Placebo BMS-986231 Nitroglycerin (NTG)
    Number of subjects analysed
    37
    34
    40
    Units: Percentage
    arithmetic mean (standard deviation)
        E/A ratio
    0.80 ( 0.278 )
    0.73 ( 0.270 )
    0.71 ( 0.310 )
        annular e’ velocity ratio
    9.42 ( 4.102 )
    7.00 ( 2.464 )
    7.81 ( 2.652 )
        E/e’ ratio
    7.18 ( 2.467 )
    8.07 ( 2.333 )
    7.18 ( 2.143 )
    Statistical analysis title
    		 Mean E/A ratio (placebo and drug)
    Statistical analysis description
    E/A ratio
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.205
         upper limit
    		 -0.051
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.037
    Statistical analysis title
    		 Mean E/A ratio (drug and NTG)
    Statistical analysis description
    E/A ratio
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.904
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.051
         upper limit
    		 0.057
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026
    Statistical analysis title
    		 Diastolic Indices E/e ratio (placebo and drug)
    Statistical analysis description
    Diastolic Indices E/e ratio
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.763
         upper limit
    		 -0.549
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.527
    Statistical analysis title
    		 Diastolic Indices E/e ratio (drug and NTG)
    Statistical analysis description
    Diastolic Indices E/e ratio
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.503
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.085
         upper limit
    		 0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.392
    Statistical analysis title
    		 Mean E/e' ratio (placebo and drug)
    Statistical analysis description
    E/e' ratio
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.994
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.827
         upper limit
    		 0.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.398
    Statistical analysis title
    		 Mean E/e' ratio (drug and NTG)
    Statistical analysis description
    E/e' ratio
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.049
         upper limit
    		 1.013
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.258

    Secondary: Mean LV global longitudinal strain, computed using STE at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG

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    End point title
    		 Mean LV global longitudinal strain, computed using STE at the end of the 5-hour infusion of BMS-986231, versus placebo and NTG
    End point description
    Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG: LV global longitudinal strain
    End point type
    Secondary
    End point timeframe
    at the end of the 5-hour infusion
    End point values
    		 Placebo BMS-986231 Nitroglycerin (NTG)
    Number of subjects analysed
    38
    36
    43
    Units: Percentage of blood pumped from the LV
    arithmetic mean (standard deviation)
        LV global longitudinal strain
    -11.98 ( 2.860 )
    -11.94 ( 3.458 )
    -11.36 ( 3.067 )
    Statistical analysis title
    		 LV global longitudinal strain (placebo and drug)
    Comparison groups
    Placebo v BMS-986231
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.705
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 0.976
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    		 LV global longitudinal strain (drug and NTG)
    Comparison groups
    BMS-986231 v Nitroglycerin (NTG)
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105
    Method
    		 Kenward-Roger degree of freedom
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.504
         upper limit
    		 0.151
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.404

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) were collected from the date of informed consent up to 30 days post-infusion of the last period. Non-serious AEs were collected from the start of the study drug infusion. until 24 hours post-infusion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were intravenously administered with a single infusion of placebo (5% dextrose) at a rate of 5 milliliters per hour (mL/hr) for 10 min; 10 mL/hr for 10 min and 20 mL/hr for the rest of the 5-hour. Subjects received treatment on Day 1 during Period 1, 2 and 3 followed by wash-out from Day 2 up to Day 28 during Period 1 and 2.

    Reporting group title
    Nitroglycerin
    Reporting group description
    		 Nitroglycerin: Subjects were intravenously administered with a single infusion of Nitroglycerin at a dose of 20 μg/min for 10 min (5 mL/hr); 40 μg/min for 10 min (10 mL/hr) and 80 μg/min for the rest of the 5-hour infusion (20 mL/hr). Subjects received treatment on Day 1 during Period 1, 2 and 3 followed by wash-out from Day 2 up to Day 28 during Period 1 and 2.

    Reporting group title
    BMS-986231
    Reporting group description
    		 Subjects were intravenously administered with a single infusion of BMS-986231 at a dose of 3 microgram per kilogram per minute (μg/kg/min) for 10 min (5 mL/hr); 6 μg/kg/min for 10 min (10 mL/hr) and 12 μg/kg/min for the rest of the 5-hour infusion (20 mL/hr). Subjects received treatment on Day 1 during Period 1, 2 and 3 followed by wash-out from Day 2 up to Day 28 during Period 1 and 2.

    Serious adverse events
    		 Placebo Nitroglycerin BMS-986231
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 44 (0.00%)
    0 / 42 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nitroglycerin BMS-986231
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 40 (5.00%)
    10 / 44 (22.73%)
    12 / 42 (28.57%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 44 (6.82%)
    5 / 42 (11.90%)
         occurrences all number
    0
    3
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 40 (5.00%)
    7 / 44 (15.91%)
    10 / 42 (23.81%)
         occurrences all number
    2
    7
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2017
    Inserted additional text into Section 8.1: ‘Discontinuation from Study Treatment’ to allow the patient to be part of the IP continuation discussion when confirmed pregnant.
    01 Sep 2017
    Clarification of allowable contraceptives for WOCBP, addition of chronic nitrates use criteria, clarification of IP preparation, handling and storage
    17 Jul 2018
    To modify the inclusion/exclusion criteria to allow the true representation of stable heart failure participants into the study, shorten the washout period, allow use of contrast echocardiography to improve endocardial definition, as needed, and clarification on the procedures for participants prior to day 1.
    05 Sep 2018
    Incorporating Administrative Letters 03 and 04 content that was not included in Revised Protocol 03: - To clarify the origin of Nitroglycerin supplied by BMS. - Correct minor typographical errors identified throughout the protocol.
    24 Jan 2019
    Clarified the wording the Appendix 3 to harmonize AE definitions in BMS clinical studies. Clarified the enrollment numbers under study drug.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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