An Investigational Study of Continuous 8-Hour Intravenous Administrations of BMS-986231 in Participants With Heart Failure and Reduced Heart Function Given a Standard Dose of Loop Diuretic

Phase 2

Completed

Conditions: Myocardial Failure
Congestive Heart Failure
Heart Decompensation
Cardiac Failure

Interventions: Drug: BMS-986231
Drug: Furosemide
Drug: Placebo

Registration Number: NCT03730961

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: The purpose of this study is to investigate continuous 8-hour introductions of BMS-986231 in participants with heart failure and weakened heart function given a standard dose of diuretic.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Left ventricular ejection fraction <45%, as assessed by echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging (MRI) scan within 18 months
On stable chronic guideline-directed therapy for HF including chronic loop diuretics, ACEi, ARBs, MRAs, ARNI or / and β-blockers as tolerated, with no changes of these medications in the past 2 weeks
At least an oral dose of 40 mg of furosemide/day or equivalent (20 mg torsemide, 1 mg bumetamide)

Exclusion Criteria

SBP < 115 mm Hg or > 180 mm Hg at screening or pre-randomization
Heart rate < 50 beats per minute (bpm) or > 120 bpm at screening or pre-randomization
Primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic or uncorrected severe valvular disease

Other protocol defined inclusion/exclusion criteria could apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo+Diuretic to BMS-986231+Diuretic	BMS-986231	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
Placebo+Diuretic to BMS-986231+Diuretic	Placebo	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
BMS-986231+Diuretic to Placebo+Diuretic	BMS-986231	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
BMS-986231+Diuretic to Placebo+Diuretic	Furosemide	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
BMS-986231+Diuretic to Placebo+Diuretic	Placebo	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
Placebo+Diuretic to BMS-986231+Diuretic	Furosemide	Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods

Primary Outcome Measures

Name	Time	Method
4-hour Urinary Output Following Intravenous Administration of 40 mg Furosemide to HFrEF Participants Receiving BMS-986231 Infusion Compared to Placebo	4 hours	The total volume of urinary output 4 hours after 40 mg furosemide bolus given to participants with HFrEF while on BMS-986231 compared to placebo: absolute difference in total volume and % change from placebo. Sequence 1: Placebo in period 1, drug in period 2 Sequence 2: Drug in period 1, placebo in period 2

Secondary Outcome Measures

Name	Time	Method
Ratio Urinary Sodium (Na) to Urinary Furosemide at 8 Hours Post-start Infusion	0-4 hours after furosemide	Summary of urinary concentrations 0-4 hours after furosemide Ratio = Cumulative Sodium Excretion / Cumulative Furosemide in Urine
Number of Participants With an Adverse Event (AE)	up to 8 days	Clinically relevant hypotension is defined as systolic blood pressure (SBP) \< 90 mmHg or symptomatic hypotension during infusion
Change From Baseline in Vital Signs - Blood Pressure	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for vital signs was reported for each arm.
FeK in Participants With HFrEF While on BMS-986231 Compared to Placebo	Day 1, predose; 0-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours	Secondary efficacy analyses was performed using the randomized population. The FeNa, FeK, furosemide urinary and plasma concentration and the ratio of urinary sodium to urinary furosemide was calculated at each time point over 4-hour urine/plasma collection after a bolus injection of 40 mg furosemide while receiving BMS-986231 or placebo. Fractional Excretion K = ((Urine Potassium \* Plasma Creatinine) / (Plasma Potassium \* Urine Creatinine)) \* 100
Furosemide Plasma Concentrations	Day 1: 4, 5, 6, 8, 10 hours	Summary of plasma concentrations by interval.
Number of Participants With Clinically Relevant Hypotension	up to 8 hours	Clinically relevant hypotension is defined as systolic blood pressure (SBP) \< 90 mmHg or symptomatic hypotension during infusion
Number of Participants With an Abnormal Clinical Laboratory Value	from first dose to 30 days post-last dose (ca. 5-8 weeks)	Number of participants who experienced an in-study abnormal clinical laboratory event under the category of Hematology, Chemistry or Urinalysis.
FeNa in Participants With HFrEF While on BMS-986231 Compared to Placebo	Day 1, predose; 0-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours	Secondary efficacy analyses was performed using the randomized population. The FeNa, FeK, furosemide urinary and plasma concentration and the ratio of urinary sodium to urinary furosemide was calculated at each time point over 4-hour urine/plasma collection after a bolus injection of 40 mg furosemide while receiving BMS-986231 or placebo. Fractional Excretion Na = ((Urine Sodium \* Plasma Creatinine) / (Plasma Sodium \* Urine Creatinine)) \* 100
Furosemide Urinary Concentrations	Day 1, predose, 0-2 hours, 2-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-10 hours	Summary of urine recovery by interval, measured by amount excreted.
Change From Baseline in Electrocardiograms (ECGs) - Mean Heart Rate	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for ECGs was reported for each arm.
Change From Baseline in Vital Signs - Heart Rate	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for vital signs was reported for each arm.
Change From Baseline in Vital Signs - Oxygen Saturation	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for vital signs was reported for each arm.
Change From Baseline in Electrocardiograms (ECGs) - PR, QRS Duration, QT, QTcF Intervals	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for ECGs was reported for each arm.
Telemetry	Day 1, 8 hours post-dose	Telemetry data not collected.
Change From Baseline in Physical Examination - Body Weight	Day 1, 8 hours post-dose (end of infusion)	The change in baseline for physical examinations was reported for each arm.