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

INTERVENTION: Product Name: BMS‐986231‐01 for Injection, 240 mg/vial Product Code: BMS‐986231 Pharmaceutical Form: Powder for concentrate for solution for infusion INN or Proposed INN: HNO CAS Number: 1620330‐72‐4 Current Sponsor code: CV013‐020 Other descriptive name: BMS986231 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 240‐ Pharmaceutical form of the placebo: Concentrate for solution for infusion Route of administration of the placebo: Intravenous use Trade Name: Solinitrina Product Name: nitroglycerin Product Code: nitroglycerin Pharmaceutical Form: Solution for injection INN or Proposed INN: GLYCERYL TRINITRATE CAS Number: C 01 DA Current Sponsor code: C 01 DA Other descriptive name: GLYCERYL TRINITRATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ CONDITION: Heart failure and impaired systolic function ; MedDRA version: 20.0 Level: LLT Classification code 10074631 Term: Systolic heart failure System Organ Class: 100000004849 ; MedDRA version: 20.0 Level: LLT Classification code 10019279 Term: Heart failure System Organ Class: 100000004849 Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective: Evaluate the effects of BMS‐986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo. Primary end point(s): Mean SVI derived from the velocity time integral at the left ventricular outflow tract (LVOT VTI) at the end of the 5‐hours infusion of BMS‐; 986231, versus placebo. Secondary Objective: ‐ Evaluate the effects of BMS‐986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to nitroglycerin (NTG).; ‐ Evaluate the effects of BMS‐986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG Timepoint(s) of evaluation of this end point: At the end of the 5‐hours infusion SECONDARY OUTCOME: Secondary end point(s): ‐ Mean SVI derived from LVOT VTI at the end of the 5‐hours infusion of BMS‐986231, versus NTG. ; ‐ Mean LVEF, computed by Simpson’s method at the end of the 5‐hours infusion of BMS‐986231, versus placebo and NTG. ; ‐ Mean cardiac power index at the end of the 5‐hours infusion of BMS‐986231, versus placebo and NTG. ; ‐ Mean Diastolic indices: E/A, annular e' velocity and E/e' ratio at the end of the 5‐hours infusion of BMS‐986231, versus placebo and NTG. ; ‐ Mean LV global longitudinal strain, computed using STE at the end of the 5‐hours infusion of BMS‐986231, versus placebo and NTG. Timepoint(s) of evaluation of this end point: At the end of the 5‐hours infusion INCLUSION CRITERIA: 1) Signed Written Informed Consent a) Subjects will be required to provide a written informed consent. 2) Type of Participant and Target Disease Characteristics a) Males and Females, ages 18 (or age of majority) or older b) Heart failure with reduced ejection fraction (LVEF on echocardiogram of 40% or less)c) Stable guideline directed therapy for heart failure including oral diuretics, ACEi, ARBs, ARNi, MRAs , and ß blockers as tolerated), with no dose changes of these medications in the past 2 weeks d) Have screening values of NT pro‐BNP = 125 pg/mL (15 pmol/L) or BNP = 35 pg/mL (10 pmol/L). e) In sinus rhythm at the start of the infusion 3) Age and Reproductive Status b) Women must not be breastfeeding c) Wom a) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.