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

Study Overview
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Brief Summary
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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

Official Title
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A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Ranging, Phase 2b Study of the Safety and Efficacy of Continuous 48-Hour Intravenous Infusions of BMS-986231 in Hospitalized Patients With Heart Failure and Impaired Systolic Function

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: HNO Donor
* 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: 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% 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

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1 HNO Donor<br> | Drug: HNO Donor<br>* Infusion<br>* Other names: BMS-986231;|
| Placebo Comparator: Placebo Part 1 Cohort 1<br> | Drug: Placebo<br>* Infusion<br>|
| Experimental: Part 2 Cohort 2 HNO Donor- low dose<br> | Drug: HNO Donor<br>* Infusion<br>* Other names: BMS-986231;|
| Experimental: Part 2 Cohort 2 HNO Donor- high dose<br> | Drug: HNO Donor<br>* Infusion<br>* Other names: BMS-986231;|
| Placebo Comparator: Placebo Part 2 Cohort 2<br> | Drug: Placebo<br>* Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Relevant Hypotension up to 6 Hours After the End of Study Drug 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 | From start of infusion up to 6 hours post end of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NT-proBNP From Baseline to Hour 24, 48, 72, 120 or Discharge (Whichever Comes First), and at Day 32 | Assess the effect of BMS-986231 on NT-proBNP (N-terminal prohormone of brain natriuretic peptide) | 0, 24, 48, 72, 120 hour or discharge; Day 32 | 
| Change in Participant-reported Resting Dyspnea From Baseline Through Hour 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. | Hours 6, 12, 24, 48, and 72 | 
| Percentage of Participants With Symptomatic Hypotension up to 6 Hours After the End of Study Drug Infusion | The percentage of participants experiencing symptoms of hypotension up to 6 hours post-treatment was reported for each arm. | From start of infusion up to 6 hours post end of infusion | 
| Percentage of Participants With SBP < 90 mm Hg (Confirmed by a Repeated Value) | 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. | From start of infusion up to 6 hours post end of infusion | 
| Number of Participants With a Serious Adverse Events (SAE) Assessed up to Day 32 | 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. | 32 days | 
| Number of Participants Who Discontinued Due to Hypotension | 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. | up to 120 hours (for AEs); up to 32 days (for SAEs) | 
| Number of Participants Who Discontinued, Experienced a Down-titration or Dose Interruption Due to Decreased Blood Pressure | 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. | up to 120 hours (for AEs); up to 32 days (for SAEs) | 
| Number of Participants With an Adverse Event (AE) Assessed 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. | up to 120 hours | 
| Number of Participants Who Died (All- Cause and Cardiovascular-related) Through Day 182 | Number of participants who died (all- cause and CV related) through Day 182. Medical Dictionary for Regulatory Activities (MedDRA) version: 22.0 CV=Cardiovascular | through 182 days | 
| Change in Troponin T 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 | from baseline to Hour 24, 48, and 72 | 
| Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Hematology | 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 | to 120 hours | 
| Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Chemistry | 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 | to 120 hours | 
| Number of Participants With Marked Laboratory Abnormality Assessed to 120 Hours - Urinalysis | 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 | to 120 hours | 
| Change in Vital Signs From Baseline to 120 Hours - Blood Pressure | The change in baseline for vital signs was reported for each arm. | to 120 hours | 
| Change in Vital Signs From Baseline to 120 Hours - Heart Rate | The change in baseline for vital signs was reported for each arm. | to 120 hours | 
| Change in Vital Signs From Baseline to 120 Hours - Respiratory Rate | The change in baseline for vital signs was reported for each arm. | to 120 hours | 
| Change in Vital Signs From Baseline to 120 Hours - Temperature | The change in baseline for vital signs was reported for each arm. | to 120 hours | 
| Change in Electrocardiograms (ECGs) From Baseline to 120 Hours - Mean Heart Rate | The change in baseline for ECGs was reported for each arm. | to 120 hours | 
| Change in Electrocardiograms (ECGs) From Baseline to 120 Hours - PR, QT, QTcF Intervals and QRS Duration | The change in baseline for ECGs was reported for each arm. | to 120 hours | 
| Change in Physical Measurements From Baseline to 120 Hours | The change in baseline for physical measurements was reported for each arm. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - x10^9 Cells/L | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - g/L | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - mmol/L | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - U/L | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - mg/dL | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Main Study Cohorts Only - x10^12 c/L | The change in baseline for laboratory assessments was reported for each arm of the Main study cohorts only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Protein (Nmol/L) | The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Creatinine (µmol/L) | The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Cystatin (mg/L) | The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Percentage Fractional Potassium Excretion | The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only. | to 120 hours | 
| Change in Laboratory Assessments From Baseline to 120 Hours, Japan Cohort Only - Percentage Fractional Sodium Excretion | The change in baseline for laboratory assessments was reported for each arm of the Japan cohort only. | to 120 hours |