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

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

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.

Study Overview

• Status: Completed
• Conditions: Congestive Heart Failure; Heart Decompensation; Cardiac Failure; Myocardial Failure
• Intervention / Treatment: Drug: Placebo; Drug: BMS-986231; Drug: Furosemide

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Glasgow Clinical Research Facility
  • London, United Kingdom, SW17 0RE
    • Richmond Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Felker GM, Borentain M, Cleland JG, DeSouza MM, Kessler PD, O'Connor CM, Seiffert D, Teerlink JR, Voors AA, McMurray JJV. Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Eur J Heart Fail. 2019 Aug;21(8):1022-1031. doi: 10.1002/ejhf.1504. Epub 2019 Jun 6.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 17, 2019
• Primary Completion (ACTUAL): December 11, 2019
• Study Completion (ACTUAL): January 9, 2020

Study Registration Dates

• First Submitted: November 1, 2018
• First Submitted That Met QC Criteria: November 2, 2018
• First Posted (ACTUAL): November 5, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Furosemide
• Other Study ID Numbers: CV013-034; 2018-000970-31 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes