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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Cross-over Phase 2 Study of Continuous 8-Hour Intravenous Infusions of BMS-986231 in Patients With Heart Failure and Impaired Systolic Function Given a Standard Dose of Loop Diuretic

Conditions
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Cardiac Failure, Myocardial Failure, Congestive Heart Failure, Heart Decompensation

Intervention / Treatment
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* Drug: BMS-986231
* Drug: Furosemide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo+Diuretic to BMS-986231+Diuretic<br>Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods | Drug: BMS-986231<br>* Intravenous administration<br>Drug: Furosemide<br>* Intravenous administration<br>Drug: Placebo<br>* Intravenous administration<br>|
| Experimental: BMS-986231+Diuretic to Placebo+Diuretic<br>Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods | Drug: BMS-986231<br>* Intravenous administration<br>Drug: Furosemide<br>* Intravenous administration<br>Drug: Placebo<br>* Intravenous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-hour Urinary Output Following Intravenous Administration of 40 mg Furosemide to HFrEF Participants Receiving BMS-986231 Infusion Compared to Placebo | 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 | 4 hours | 

Secondary Outcome Measures

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