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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

Primary Purpose

Cardiac Failure, Myocardial Failure, Congestive Heart Failure

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
BMS-986231
Furosemide
Placebo
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiac Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Glasgow Clinical Research Facility
  • Richmond Pharmacology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Placebo+Diuretic to BMS-986231+Diuretic

BMS-986231+Diuretic to Placebo+Diuretic

Arm Description

Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods

Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
Furosemide Urinary Concentrations
Summary of urine recovery by interval, measured by amount excreted.
Furosemide Plasma Concentrations
Summary of plasma concentrations by interval.
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
Number of Participants With Clinically Relevant Hypotension
Clinically relevant hypotension is defined as systolic blood pressure (SBP) < 90 mmHg or symptomatic hypotension during infusion
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
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.
Change From Baseline in Vital Signs - Blood Pressure
The change in baseline for vital signs was reported for each arm.
Change From Baseline in Vital Signs - Heart Rate
The change in baseline for vital signs was reported for each arm.
Change From Baseline in Vital Signs - Oxygen Saturation
The change in baseline for vital signs was reported for each arm.
Change From Baseline in Electrocardiograms (ECGs) - Mean Heart Rate
The change in baseline for ECGs was reported for each arm.
Change From Baseline in Electrocardiograms (ECGs) - PR, QRS Duration, QT, QTcF Intervals
The change in baseline for ECGs was reported for each arm.
Telemetry
Telemetry data not collected.
Change From Baseline in Physical Examination - Body Weight
The change in baseline for physical examinations was reported for each arm.

Full Information

First Posted
November 1, 2018
Last Updated
February 24, 2021
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT03730961
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
January 17, 2019 (Actual)
Primary Completion Date
December 11, 2019 (Actual)
Study Completion Date
January 9, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

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

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiac Failure, Myocardial Failure, Congestive Heart Failure, Heart Decompensation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo+Diuretic to BMS-986231+Diuretic
Arm Type
Experimental
Arm Description
Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
Arm Title
BMS-986231+Diuretic to Placebo+Diuretic
Arm Type
Experimental
Arm Description
Administered in a cross over design with 8-hour continuous infusions and 7-28 day wash-out periods
Intervention Type
Drug
Intervention Name(s)
BMS-986231
Intervention Description
Intravenous administration
Intervention Type
Drug
Intervention Name(s)
Furosemide
Intervention Description
Intravenous administration
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Intravenous administration
Primary Outcome Measure Information:
Title
4-hour Urinary Output Following Intravenous Administration of 40 mg Furosemide to HFrEF Participants Receiving BMS-986231 Infusion Compared to Placebo
Description
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
Time Frame
4 hours
Secondary Outcome Measure Information:
Title
FeNa in Participants With HFrEF While on BMS-986231 Compared to Placebo
Description
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
Time Frame
Day 1, predose; 0-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours
Title
FeK in Participants With HFrEF While on BMS-986231 Compared to Placebo
Description
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
Time Frame
Day 1, predose; 0-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours
Title
Furosemide Urinary Concentrations
Description
Summary of urine recovery by interval, measured by amount excreted.
Time Frame
Day 1, predose, 0-2 hours, 2-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-10 hours
Title
Furosemide Plasma Concentrations
Description
Summary of plasma concentrations by interval.
Time Frame
Day 1: 4, 5, 6, 8, 10 hours
Title
Ratio Urinary Sodium (Na) to Urinary Furosemide at 8 Hours Post-start Infusion
Description
Summary of urinary concentrations 0-4 hours after furosemide Ratio = Cumulative Sodium Excretion / Cumulative Furosemide in Urine
Time Frame
0-4 hours after furosemide
Title
Number of Participants With Clinically Relevant Hypotension
Description
Clinically relevant hypotension is defined as systolic blood pressure (SBP) < 90 mmHg or symptomatic hypotension during infusion
Time Frame
up to 8 hours
Title
Number of Participants With an Adverse Event (AE)
Description
Clinically relevant hypotension is defined as systolic blood pressure (SBP) < 90 mmHg or symptomatic hypotension during infusion
Time Frame
up to 8 days
Title
Number of Participants With an Abnormal Clinical Laboratory Value
Description
Number of participants who experienced an in-study abnormal clinical laboratory event under the category of Hematology, Chemistry or Urinalysis.
Time Frame
from first dose to 30 days post-last dose (ca. 5-8 weeks)
Title
Change From Baseline in Vital Signs - Blood Pressure
Description
The change in baseline for vital signs was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)
Title
Change From Baseline in Vital Signs - Heart Rate
Description
The change in baseline for vital signs was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)
Title
Change From Baseline in Vital Signs - Oxygen Saturation
Description
The change in baseline for vital signs was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)
Title
Change From Baseline in Electrocardiograms (ECGs) - Mean Heart Rate
Description
The change in baseline for ECGs was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)
Title
Change From Baseline in Electrocardiograms (ECGs) - PR, QRS Duration, QT, QTcF Intervals
Description
The change in baseline for ECGs was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)
Title
Telemetry
Description
Telemetry data not collected.
Time Frame
Day 1, 8 hours post-dose
Title
Change From Baseline in Physical Examination - Body Weight
Description
The change in baseline for physical examinations was reported for each arm.
Time Frame
Day 1, 8 hours post-dose (end of infusion)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Glasgow Clinical Research Facility
City
Glasgow
ZIP/Postal Code
G51 4TF
Country
United Kingdom
Facility Name
Richmond Pharmacology
City
London
ZIP/Postal Code
SW17 0RE
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
31168885
Citation
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.
Results Reference
derived
Links:
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
BMS Clinical Trial Information
URL
https://www.bmsstudyconnect.com/s/US/English/USenHome
Description
BMS Clinical Trial Patient Recruiting
URL
https://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
Description
FDA Safety Alerts and Recalls

Learn more about this trial

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

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