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    Summary
    EudraCT Number:2016-001685-29
    Sponsor's Protocol Code Number:CV013-011
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-06-20
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGreece - EOF
    A.2EudraCT number2016-001685-29
    A.3Full title of the trial
    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.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international study at different study sites testing the safety and effectiveness of a drug called BMS-986231 in the form of Intravenous Infusions for a duration of 48 hours in hospitalized patients whose heart is unable to pump sufficiently to maintain the blood flow their body needs to function well.
    A.4.1Sponsor's protocol code numberCV013-011
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1181-9195
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol-Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol-Myers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Myers Squibb International Corporation
    B.5.2Functional name of contact pointGCT-SU
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance - Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHNO donor
    D.3.2Product code BMS-986231
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHNO
    D.3.9.1CAS number 1620330-72-4
    D.3.9.2Current sponsor codeCV013-011
    D.3.9.3Other descriptive nameBMS986231
    D.3.9.4EV Substance CodeSUB182812
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart failure and impaired systolic function
    E.1.1.1Medical condition in easily understood language
    Inability of the heart to pump sufficiently to maintain blood flow to meet the body's needs.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074631
    E.1.2Term Systolic heart failure
    E.1.2System Organ Class 100000004849
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10019279
    E.1.2Term Heart failure
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the effects of various doses of BMS-986231 compared to placebo on clinically relevant hypotension (defined by SBP < 90 mm Hg or symptoms of hypotension)
    E.2.2Secondary objectives of the trial
    - Assess the effect of BMS-986231 on NT-proBNP
    - Assess the effect of BMS-986231 on patient-reported resting dyspnea as measured by the 11-point Numerical Rating Scale (NRS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Written Informed Consent

    a) Subjects will be required to provide a written informed consent

    2. Target Population
    b) Subjects being hospitalized for ADHF
    c) Have had at least 1 administration of at least 40 mg furosemide intravenous, or equivalent (e.g 40 mg furosemide equivalent to 20 mg torsemide or to 1 mg bumetanide) for the current ADHF episode
    d) Subject must be randomized and treated within 18 hours of first dose of intravenous diuretic
    e) Have dyspnea at rest or with minimal exertion after administration of at least 1 dose of intravenous diuretics. Subject must not be randomized within 2 hours after an IV bolus dose of intravenous diuretics, or within 2 hours after the initiation or a dose increase of an IV diuretic administered by continuous infusion
    f) Have a history of heart failure and a left ventricular ejection fraction (LVEF) ≤ 40%, as assessed by echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging (MRI) scan
    Note: Ejection fraction documentation up to 18 months prior to screening may be used if there is no clinical expectation of improvement in ejection fraction in that timeframe (eg, the patient has not had biventricular pacing initiated during that period)

    g) Have at least 2 of the following at time of screening:
    i) evidence for pulmonary congestion on chest x-ray
    ii) rales by chest auscultation,
    iii) edema ≥ 2+ on a 0 to 3+ scale (easily identifiable indentation, skin rebounds in 15-30 seconds)
    iv) presence of jugular venous distention
    h) Have an elevated NT-proBNP ≥ 1600 pg/mL (189 pmol/L) or BNP ≥ 400 pg/mL (116 pmol/L) as determined at the local laboratory within 18 hours prior to the start of study drug infusion
    For subjects with atrial fibrillation: NT-proBNP ≥ 2400 pg/ml or BNP ≥ 600 pg/ml
    i) Body weight ≥ 50 kg and < 140 kg at screening
    j) Subject Re-Screening: This study permits the re-screening of a subject that has discontinued the study as a screen failure (has not been randomized).

    3. Age and Reproductive Status
    a) Males and Females, at least age 18 (or age of majority)
    b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 18 hours prior to the start of study treatment
    c) Women must not be breastfeeding
    d) WOCBP must agree to follow instruction for methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle)
    e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for 92 days after discontinuation (duration of study drug plus 90 days (duration of sperm turnover)
    f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section
    E.4Principal exclusion criteria
    1. Target Disease Exceptions
    a) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg at screening
    b) Systolic blood pressure (SBP) < 105 mm Hg or > 160 mm Hg just prior to randomization
    c) Heart rate < 50 beats per minute (bpm) or > 130 bpm at screening
    d) Heart rate < 50 beats per minute (bpm) or > 130 bpm just prior to randomization
    e) Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic or uncorrected severe valvular disease as defined by AHA/ACC/ESC criteria

    Note: Functional mitral regurgitation, as well as restrictive mitral inflow pattern on echocardiography is not exclusionary

    f) Have a body temperature ≥ 38.5°C (101.3°F) at any time from screening to randomization
    g) Have an active infection requiring IV anti-microbial treatment

    2. Medical History and Concurrent Diseases
    a) Considered clinically unstable for other conditions than acute heart failure, either because of acute coronary syndrome or ongoing arrhythmia (or be receiving concomitant parenteral therapy with any antiarrhythmic drugs), or other unstable non-cardiovascular disease
    b) Severe chronic or acute lung disease that might interfere with the ability to interpret the dyspnea assessments (eg, severe chronic obstructive pulmonary disease, active asthma or acute pneumonia)
    c) Have a history of sudden cardiac death with resuscitation within the past 6 months
    d) Be hospitalized with acute coronary syndrome, coronary revascularization or acute myocardial infarction during the previous 90 days prior to screening
    e) 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
    f) Serious comorbid non cardiovascular disease in which the life expectancy of the subject is < 6 months (eg, acute systemic infection – sepsis, metastatic cancer, or other serious illnesses)
    g) Severe liver disease defined as history of cirrhosis with evidence of portal hypertension such as varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 51 μmol/L)
    h) Prior cardiac or renal transplant

    3. Physical and Laboratory Test Findings
    a) Have persistent abnormal serum electrolytes not resolved before randomization, as defined by any of the following:
    i) A sodium (Na+) concentration < 130 or >145 mEq/L (mmol/L)
    ii) A potassium (K+) concentration < 3.2 or >5.5 mEq/L (mmol/L)
    b) Have severe anemia, as documented by a hemoglobin < 9 g/dL (< 5.59 mmol/L)
    c) Have severe renal insufficiency before randomization (and during the current hospitalization) defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 [based on any standard limit and equation employed by the local lab, eg, Modification of Diet in Renal Disease (MDRD) equation]. For patients with eGFR values less than but close to 30 mL/min/1.73m2 upon testing, retesting is allowed
    4. Prior and Concomitant Medications or Treatments
    a) Subjects administered IV or transdermal nitrate therapy prior to randomization, except if all 3 of the following criteria are met:
    i) Systolic blood pressure at screening or just prior to randomization is > 120 mm Hg
    AND
    ii) The IV nitroglycerin dose is < 100 μg/min (or isosorbide dinitrate < 3 mg/hour),
    AND
    iii) The infusion rate and dose has been unchanged for > 2 hours
    b) History of chronic or intermittent renal support therapy (hemodialysis, ultrafiltration, or peritoneal dialysis)
    c) Subjects treated during the current hospitalization with dopamine, dobutamine, enoximone, nesiritide, nitroprusside, levosimendan, amrinone or milrinone prior to start of study drug infusion, or have an anticipated need to be treated with any of these agents during the study drug infusion
    d) Subjects treated with oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil, vardenafil or avanafil within 24 hours of screening or treated with tadalafil within 4 days of screening
    e) Subjects receiving any mechanical ventilation at the time of screening
    f) Subjects receiving non-invasive ventilation (CPAP/BiPAP) < 2 hours prior to randomization

    5. Allergies and Adverse Drug Reaction
    a) Any history of allergic reaction to BMS-986231, or its components, Captisol® or potassium acetate

    6. Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    c) Participation in an investigational clinical drug study within 30 days or 5 elimination half-lives, (whichever is longer) prior to randomization
    d) Prior participation and treatment in a study using BMS-986231, CXL 1427, or CXL-1020
    e) Alcohol beverage consumption within 6 hours prior to randomization
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the incidence of clinically relevant hypotension, defined by 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 6 hours after the end of study drug infusion.
    E.5.2Secondary end point(s)
    - Change in NT-proBNP from baseline to Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32
    - Change in subject-reported resting dyspnea from baseline through Hour 72, as 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Hour 24, 48, 72, 120 or discharge (whichever comes first), and at Day 32

    - baseline, and Hours 6, 12, 24, 48, and 72
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Dose-Ranging
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Canada
    Czech Republic
    France
    Germany
    Greece
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last subject’s final follow-up visit on Day 182, or the last subject’s scheduled procedure shown in the Time & Events schedule.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 248
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 62
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 204
    F.4.2.2In the whole clinical trial 310
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the in-patient period, BMS will not continue to provide BMS supplied study drug to subjects/investigators unless BMS chooses to extend the study. The investigator should ensure that the subject receives appropriate standard of care to treat the condition under study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-11-12
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