Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure

Phase 2

Completed

• Conditions: Heart Failure
• Interventions: Drug: HNO Donor; Drug: Placebo

• Registration Number: NCT03016325
• Lead Sponsor: Bristol-Myers Squibb

Brief Summary

A Study to Evaluate Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of HNO Donor in Hospitalized Patients with Heart Failure and Impaired Systolic Function

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-01-09
• Study First Submitted QC: 2017-01-09
• Study First Posted: 2017-01-10
• Study Start: 2017-01-13
• Primary Completion: 2019-06-23
• Study Completion: 2019-11-12
• Results First Submitted: 2020-06-22
• Results First Submitted QC: 2020-08-07
• Results First Posted: 2020-08-19
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-11
• Last Update Posted: 2021-01-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 329

Inclusion Criteria

• Actively being hospitalized for acute decompensated heart failure
• At least 1 administration of IV diuretic for the current episode
• Be randomized within 18 hours of first dose of IV diuretic for current episode for Part 1 Cohort 1, or 48 hours for first dose for Part II Cohort II
• Have shortness of breath at rest or with minimal exertion after administration of 1 dose of IV diuretic
• Have history of heart failure and a left ventricular ejection fraction (LVEF) ≤ 40%

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Exclusion Criteria

• Systolic blood pressure <105mm Hg or >160mm Hg or heart rate <50 or >130 bpm
• Have an active infection requiring IV anti-microbial treatment
• Be hospitalized with acute coronary syndrome, coronary revascularization or acute myocardial infarction during the previous 90 days prior to screening
• Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic attack (TIA) during the previous 90 days prior to screening
• Suspected acute lung disease (e.g pneumonia or asthma) or severe chronic lung disease (e.g. severe chronic obstructive pulmonary disease, or pulmonary fibrosis)

Other protocol defined inclusion/exclusion criteria could apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 2 Cohort 2 HNO Donor- low dose	HNO Donor	-
Part 2 Cohort 2 HNO Donor- high dose	HNO Donor	-
Placebo Part 1 Cohort 1	Placebo	-
Placebo Part 2 Cohort 2	Placebo	-
Part 1 Cohort 1 HNO Donor	HNO Donor	-

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinically Relevant Hypotension up to 6 Hours After the End of Study Drug Infusion	From start of infusion up to 6 hours post end of infusion	Percentage of participants with clinically relevant hypotension, defined by systolic blood pressure (SBP) \< 90 mm Hg (confirmed by a repeated value \< 90 mm Hg) or symptoms of hypotension, up to 6 hours after the end of study drug infusion

Secondary Outcome Measures

Name	Time	Method
Change in Troponin T From Baseline to Hour 24, 48, and 72	from baseline to Hour 24, 48, and 72	Baseline = Last non-missing result with a collection date-time less than or on the date-time of the start of infusion of study drug
Number of Participants Who Discontinued, Experienced a Down-titration or Dose Interruption Due to Decreased Blood Pressure	up to 120 hours (for AEs); up to 32 days (for SAEs)	Number of participants who discontinued study treatment, experienced a down-titration (dose reduction) or dose interruption due to decreased blood pressure/hypotension are reported below.; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0; Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment and serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment.; If the participant experienced systolic blood pressure (SBP) \< 95 mm Hg, without symptoms related to hypotension, the measurement was repeated within 15 minutes. If the SBP remained \< 95 mm Hg, the dose reduction occurred.
Number of Participants With an Adverse Event (AE) Assessed up to 120 Hours	up to 120 hours	Number of participants who experienced an in-study AE.; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0; Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment.
Number of Participants Who Discontinued Due to Hypotension	up to 120 hours (for AEs); up to 32 days (for SAEs)	Number of participants who discontinued study treatment due to hypotension.; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0; Included nonserious adverse events with onset time from the start of study treatment, up to and including 120 hours after the start of study treatment and serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment.; Hypotension defined as systolic blood pressure (SBP) \< 90 mmHg.
Number of Participants Who Died (All- Cause and Cardiovascular-related) Through Day 182	through 182 days	Number of participants who died (all- cause and CV related) through Day 182.; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0; CV=Cardiovascular
Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Hematology	to 120 hours	Number of participants who experienced an in-study Hematology marked laboratory abnormality (reported in \> 5% of total participants).; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0
Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Chemistry	to 120 hours	Number of participants who experienced an in-study Chemistry marked laboratory abnormality (reported in \> 5% of total participants).; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - mg/dL	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - x10^12 c/L	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Urinalysis	to 120 hours	Number of participants who experienced an in-study Urinalysis marked laboratory abnormality (reported in \> 5% of total participants).; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0
Change in Vital Signs From Baseline to 120 Hours - Heart Rate	to 120 hours	The change in baseline for vital signs was reported for each arm.
Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Creatinine (µmol/L)	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.
Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Percentage Fractional Sodium Excretion	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - x10^9 Cells/L	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Change in Vital Signs From Baseline to 120 Hours - Blood Pressure	to 120 hours	The change in baseline for vital signs was reported for each arm.
Change in NT-proBNP From Baseline to Hour 24, 48, 72, 120 or Discharge (Whichever Comes First), and at Day 32	0, 24, 48, 72, 120 hour or discharge; Day 32	Assess the effect of BMS-986231 on NT-proBNP (N-terminal prohormone of brain natriuretic peptide)
Percentage of Participants With Symptomatic Hypotension up to 6 Hours After the End of Study Drug Infusion	From start of infusion up to 6 hours post end of infusion	The percentage of participants experiencing symptoms of hypotension up to 6 hours post-treatment was reported for each arm.
Percentage of Participants With SBP < 90 mm Hg (Confirmed by a Repeated Value)	From start of infusion up to 6 hours post end of infusion	The percentage of participants experiencing SBP \< 90 mm Hg (confirmed by a repeated value) up to 6 hours post-treatment was reported for each arm.
Number of Participants With a Serious Adverse Events (SAE) Assessed up to Day 32	32 days	Number of participants who experienced an in-study SAE.; Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 Included serious adverse events with onset time from the start of study treatment, up to and including 32 days after the start of study treatment.
Change in Electrocardiograms (ECGs) From Baseline to 120 Hours - PR, QT, QTcF Intervals and QRS Duration	to 120 hours	The change in baseline for ECGs was reported for each arm.
Change in Physical Measurements From Baseline to 120 Hours	to 120 hours	The change in baseline for physical measurements was reported for each arm.
Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Protein (Nmol/L)	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.
Change in Participant-reported Resting Dyspnea From Baseline Through Hour 72	Hours 6, 12, 24, 48, and 72	Endpoint was measured by the area under the curve (AUC) of the 11-point Numerical Rating Scale (NRS) obtained at baseline, and Hours 6, 12, 24, 48, and 72.; Participants were asked to report their absolute current severity of dyspnea on an 11-point numerical rating scale (NRS; range 0 to 10).; The numerical rating scale (NRS) was used to assess the degree of dyspnea (breathlessness), measured using an 11-point scale provided by the Sponsor.; A score of 0 represents "I am not breathless at all" and 10 represents "I am the most breathless I can possibly imagine".
Change in Vital Signs From Baseline to 120 Hours - Temperature	to 120 hours	The change in baseline for vital signs was reported for each arm.
Change in Electrocardiograms (ECGs) From Baseline to 120 Hours - Mean Heart Rate	to 120 hours	The change in baseline for ECGs was reported for each arm.
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - g/L	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - U/L	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Cystatin (mg/L)	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.
Change in Vital Signs From Baseline to 120 Hours - Respiratory Rate	to 120 hours	The change in baseline for vital signs was reported for each arm.
Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - mmol/L	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only.
Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Percentage Fractional Potassium Excretion	to 120 hours	The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only.

Trial Locations

Locations (25)

DMC Detroit Receiving Hospital; 🇺🇸 Detroit, Michigan, United States

Henry Ford Health System; 🇺🇸 Detroit, Michigan, United States

University of Cincinnati; 🇺🇸 Cincinnati, Ohio, United States

Wexner Medical Center at The Ohio State University; 🇺🇸 Columbus, Ohio, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

University of Arizona Sarver Heart Center; 🇺🇸 Tucson, Arizona, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Indiana University Health Methodist Hospital; 🇺🇸 Indianapolis, Indiana, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

Harper University Hospital; 🇺🇸 Detroit, Michigan, United States

Sinai Grace Hospital; 🇺🇸 Detroit, Michigan, United States

Saint Louis University; 🇺🇸 Saint Louis, Missouri, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

University of Virginia Health System; 🇺🇸 Charlottesville, Virginia, United States

Medical University of South Carolina - PPDS; 🇺🇸 Charleston, South Carolina, United States

Ben Taub General Hospital; 🇺🇸 Houston, Texas, United States

University of Utah Medical Center; 🇺🇸 Salt Lake City, Utah, United States

Local Institution; 🇬🇧 London, United Kingdom

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States