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

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

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

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: HNO Donor

• Study Type: Interventional
• Enrollment (Actual): 329
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Local Institution
  • Cordoba, Argentina, 5000
    • Local Institution
  • Cordoba, Argentina
    • Local Institution
  • Cordoba, Argentina, X5000JHQ
    • Local Institution
  • Cordoba, Argentina, X5000AAX
    • Local Institution
  • Cordoba, Argentina, X5000EPU
    • Local Institution
  • Corrientes, Argentina, 3400
    • Local Institution
  • Santa Fe, Argentina, 3000
    • Local Institution
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1428ART
      • Local Institution
  • Santa FE
    • Rosario, Santa FE, Argentina, Santa Fe, 2000
      • Local Institution
• Canada
  • Quebec, Canada, G1V 4G5
    • Local Institution
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R3
      • Local Institution
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 4S9
      • Local Institution
• Czechia
  • Brno, Czechia, 656 91
    • Local Institution
  • Brno, Czechia, 625 00
    • Local Institution
  • Hradec Kralove, Czechia, 500 05
    • Local Institution
  • Plzen-Bory, Czechia, 305 99
    • Local Institution
  • Prague, Czechia, 12808
    • Local Institution
  • Praha 4, Czechia, 140 21
    • Local Institution
  • Slany, Czechia, 274 01
    • Local Institution
• France
  • Besancon, France, 25000
    • Local Institution
  • Beziers, France, 34500
    • Local Institution
  • Bobigny, France, 93009
    • Local Institution
  • Creteil, France
    • Local Institution
  • Evreux, France, 27015
    • Local Institution
  • La Tronche, France, 38700
    • Local Institution
  • Paris, France, 75013
    • Local Institution
  • Paris Cedex 10, France, 75475
    • Local Institution
• Germany
  • Bad Nauheim, Germany, 61231
    • Local Institution
  • Frankfurt, Germany, 60590
    • Local Institution
  • Gottingen, Germany, 37075
    • Local Institution
  • Greifswald, Germany
    • Local Institution
  • Hamburg, Germany, 20246
    • Local Institution
  • Hannover, Germany, 30625
    • Local Institution
  • Homburg, Germany, 66421
    • Local Institution
  • Ludwigshafen, Germany, 67063
    • Local Institution
  • Mainz, Germany
    • Local Institution
  • Regensburg, Germany, 935053
    • Local Institution
• Greece
  • Athens, Greece, 11527
    • Local Institution
  • Athens, Greece, 12464
    • Local Institution
  • Athens, Greece, 14233
    • Local Institution
  • Athens, Attiki, Greece, 11527
    • Local Institution
  • Ioannina, Greece, 45500
    • Local Institution
  • Kallithea, Greece, 17674
    • Local Institution
  • Larisa, Greece, 41110
    • Local Institution
  • Thessaloniki, Greece, 54636
    • Local Institution
• Italy
  • Brescia, Italy, 25123
    • Local Institution
  • Ferrara, Italy, 44121
    • Local Institution
  • Foggia, Italy, 71121
    • Local Institution
• Japan
  • Osaka, Japan, 558-8558
    • Local Institution
  • Tokyo, Japan, 162-8655
    • Local Institution
  • Tokyo, Japan, 113-8655
    • Local Institution
  • Aichi
    • Nagoya-shi, Aichi, Japan, 4678602
      • Local Institution
    • Seto, Aichi, Japan, 489-0065
      • Local Institution
  • Fukushima
    • Fukushima-shi, Fukushima, Japan, 9601295
      • Local Institution
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan, 0608648
      • Local Institution
  • Hyogo
    • Amagasaki, Hyogo, Japan, 6608550
      • Local Institution
  • Kanagawa
    • Sagamihara-shi, Kanagawa, Japan, 2520375
      • Local Institution
    • Yokohama, Kanagawa, Japan, 232-0024
      • Local Institution
    • Yokohama, Kanagawa, Japan, 227-8501
      • Local Institution
  • Okayama
    • Okayama-shi, Okayama, Japan, 7008558
      • Local Institution
  • Osaka
    • Suita-shi, Osaka, Japan
      • Local Institution
  • Saitama
    • Kawaguchi, Saitama, Japan, 333-0842
      • Local Institution
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 1138431
      • Local Institution
    • Bunkyo-ku, Tokyo, Japan, 1138603
      • Local Institution
    • Itabashi-ku, Tokyo, Japan, 1738610
      • Local Institution
• Netherlands
  • Amersfoort, Netherlands, 3818 ES
    • Local Institution
  • Deventer, Netherlands, 7416 SE
    • Local Institution
  • Hardenberg, Netherlands, 7772 SE
    • Local Institution
  • Leeuwarden, Netherlands, 8934 AD
    • Local Institution
• Poland
  • Bialystok, Poland, 15-276
    • Local Institution
  • Katowice, Poland, 40-635
    • Local Institution
  • Krakow, Poland, 31-202
    • Local Institution
  • Lodz, Poland, 91-347
    • Local Institution
  • Lodz, Poland, 92-213
    • Local Institution
  • Warszawa, Poland, 04-628
    • Local Institution
  • Wroclaw, Poland, 50-981
    • Local Institution
  • Wroclaw, Poland, 54-049
    • Local Institution
  • Zamosc, Poland, 22-400
    • Local Institution
• Spain
  • Alicante, Spain, 03010
    • Local Institution
  • Barcelona, Spain, 08025
    • Local Institution
  • Barcelona, Spain, 8035
    • Local Institution
  • L'Hospitalet de Llobregat, Spain, 08907
    • Local Institution
  • Madrid, Spain, 28041
    • Local Institution
  • Madrid, Spain, 28007
    • Local Institution
  • Sant Joan Despi, Spain, 08970
    • Local Institution
  • Santiago De Compostela, Spain, 15706
    • Local Institution
• United Kingdom
  • Belfast, United Kingdom, BT16 1RH
    • Local Institution
  • Blackpool, United Kingdom, FY3 8NR
    • Local Institution
  • Glasgow, United Kingdom, G4 0SF
    • Local Institution
  • Glasgow, United Kingdom, G51 4TF
    • Local Institution
  • London, United Kingdom, SW17 0QT
    • Local Institution
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Sarver Heart Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Methodist Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Harper University Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai Grace Hospital
    • Detroit, Michigan, United States, 48201
      • DMC Detroit Receiving Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • Wexner Medical Center at the Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina - PPDS
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Ben Taub General Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Cohort 1 HNO Donor	Drug: HNO Donor; Infusion; Other Names: BMS-986231
Placebo Comparator: Placebo Part 1 Cohort 1	Drug: Placebo; Infusion
Experimental: Part 2 Cohort 2 HNO Donor- low dose	Drug: HNO Donor; Infusion; Other Names: BMS-986231
Experimental: Part 2 Cohort 2 HNO Donor- high dose	Drug: HNO Donor; Infusion; Other Names: BMS-986231
Placebo Comparator: Placebo Part 2 Cohort 2	Drug: Placebo; Infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Felker GM, McMurray JJV, Cleland JG, O'Connor CM, Teerlink JR, Voors AA, Belohlavek J, Bohm M, Borentain M, Bueno H, Cole RT, DeSouza MM, Ezekowitz JA, Filippatos G, Lang NN, Kessler PD, Martinez FA, Mebazaa A, Metra M, Mosterd A, Pang PS, Ponikowski P, Sato N, Seiffert D, Ye J. Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study. JACC Heart Fail. 2021 Feb;9(2):146-157. doi: 10.1016/j.jchf.2020.10.012. Epub 2020 Nov 25.
• Cowart D, Venuti RP, Lynch K, Guptill JT, Noveck RJ, Foo SY. A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS-986231 in Healthy Volunteers. J Clin Pharmacol. 2019 May;59(5):717-730. doi: 10.1002/jcph.1364. Epub 2019 Jan 31.

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 13, 2017
• Primary Completion (Actual): June 23, 2019
• Study Completion (Actual): November 12, 2019

Study Registration Dates

• First Submitted: January 9, 2017
• First Submitted That Met QC Criteria: January 9, 2017
• First Posted (Estimate): January 10, 2017

Study Record Updates

• Last Update Posted (Actual): January 6, 2021
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CV013-011; 2016-001685-29 (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