E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 |
Time to confirmed cardiovascular (CV) death during the follow-up period of 180 days |
|
E.2.2 | Secondary objectives of the trial |
-Time to all-cause death through Day 180
-Time to worsening of heart failure (WHF) through Day 5 (considering death in the 5-day)
-Length of total hospital stay (LOS) during the index acute heart faliure (AHF) hospitalization
-Time to first occurrence of the composite endpoint of CV death or rehospitalization due to heart failure or renal failure through day 180
-Lenght of Intensive Care Unit (ICU) and/or Coronary care unit (CCU) stay for the index AHF hospitalization
-Change from baseline in congestive signs and symptoms of heart failure through Day 5
-Number of patients reported with total adverse events, serious adverse events and death |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Male or female 18 years of age, with body weight ≤160 kg
-Hospitalized for AHF, i.e. Dyspnea at rest or with minimal exertion, Pulmonary congestion on chest radiograph, BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL
-Systolic BP ≥125 mmHg at the start and at the end of screening
-Able to be randomized within 16 hours from presentation to the hospital, including the emergency department
-Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode. |
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E.4 | Principal exclusion criteria |
-Dyspnea primarily due to non-cardiac causes
-Temperature>38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment
-Clinical evidence of acute coronary syndrome currently or within 30
days prior to enrollment.
-AHF due to significant arrhythmias, which include any of the following: sustained ventricular
tachycardia, bradycardia with sustained ventricular rate <45 beats per minute, or atrial fibrillation/flutter with sustained ventricular response of >130 beats per minute
-Patients with severe renal impairment defined as pre-randomization eGFR < 25mL/min/1.73m2 calculated using the sMDRD equation, and/or those receiving current or planned dialysis or ultrafiltration Other protocol defined inclusion/exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
time to confirmed CV death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
throughout a period of 180 days |
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E.5.2 | Secondary end point(s) |
Efficacy:
• Time to all-cause death
• Time to first occurrence of worsening of heart failure
• Length of total hospital stay for the index AHF hospitalization
• Time to first occurrence of the composite endpoint of CV death or rehospitalization due to heart failure/renal failure
• Length of ICU and/or CCU stay for the index AHF hospitalization
• Change from baseline in congestive signs and symptoms of HF.
• Number of patients reported with total adverse events, serious adverse events and death |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout a period of 180 days except for:
"Time to first occurrence of worsening of heart failure" and "change from baseline in congestive signs and symptoms of HF" where evaluation will be conducted through Day 5. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 314 |
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 |
Australia |
Brazil |
Chile |
Colombia |
Ecuador |
Israel |
Mexico |
Norway |
Peru |
Russian Federation |
Serbia |
South Africa |
Switzerland |
United States |
Croatia |
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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
|
Until at least 513 total confirmed CV deaths occurs or earlier if a significant difference between two treatment arms for the number of CV deaths is achieved by crossing the pre-specified boundary at interim analysis |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |