E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure and impaired systolic function |
|
E.1.1.1 | Medical condition in easily understood language |
Inability of the heart to pump sufficiently to maintain blood flow to meet the body's needs. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074631 |
E.1.2 | Term | Systolic heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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), and no more than 85 years.
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.4 | Principal 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), or elevated AST or elevated ALT <3 times ULN
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 <10 g/dL (<6.21 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 30mL/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
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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 6 hours after the end of study drug infusion. |
|
E.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |