| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic systolic heart failure |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008908 |
|
| 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 of this trial is to evaluate the efficacy and safety of eplerenone plus standard heart failure (HF) therapy versus placebo plus standard HF therapy on the cumulative incidence of cardiovascular (CV) mortality and HF hospitalization (a composite primary endpoint). |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained prior to the initiation of any study procedures
2. Male or female subjects, ≥60 years of age at the time informed consent is obtained
3. Chronic systolic heart failure (HF) of either ischemic or non-ischemic etiology:
a) Duration: at least 4 weeks
b) Left ventricular ejection fraction (LVEF): ≤30% by echocardiography, contrast
ventriculography or nuclear imaging
c) Functional Capacity: Usually NYHA II (in the investigator’s opinion)
d) Treatments (for ACE inhibitors, ARBs and b-blockers, optimal target or maximal
tolerated dose [see Appendix 1 of the protocol] unless contraindicated):
i) Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor
blockers (ARBs)
ii) b-blocker
iii) Diuretic, if clinically indicated to reduce fluid retention
4. Serum potassium (K+) level ≤5.0mmol/L
5. Estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2 (see Appendix 2 of the protocol)
6. Randomization must occur no later than 90 days from the date of admission for index cardiovascular (CV) hospitalization. (If clinically stable, the subject may be randomized during this index cardiovascular (CV) hospitalization.) |
|
| E.4 | Principal exclusion criteria |
1. Patients with severe chronic systolic heart failure, defined as patients who demonstrate symptoms usually at rest despite optimal medical therapy
2. Patients with a myocardial infarction complicated by left ventricular systolic dysfunction and clinical heart failure within 30 days prior to randomization
3. Patients, who in the opinion of the investigator, require treatment with eplerenone or spironolactone
4. Patients, who in the opinion of the investigator, require treatment with potassium-sparing diuretics or potassium supplements
5. History of hypersensitivity to eplerenone or spironolactone
6. Evidence of cardiogenic shock
7. Intra-aortic balloon pump or other mechanical assist device
8. Patients awaiting cardiac transplantation
9. Serum potassium > 5.0 mmol/L within 24 hours prior to randomization
10. Estimated glomerular filtration rate (eGFR) ≤30 ml/min/1.73m2 within 24 hours prior to randomization (see Appendix 2 of the protocol)
11. Concomitant use of potent cytochrome p450 3A4 (CYP3A4) inhibitors, such as but not limited to:
a. Ketoconazole
b. Itraconazole
c. Nefazodone
d. Troleandomycin
e. Clarithromycin
f. Ritonavir
g. Nelfinavir
12. Patients with significant hepatic disease, defined as follows:
EITHER
h. Aspartate aminotransferase (AST) >3 times the upper limit of normal
AND/OR
i. Alanine aminotransferase (ALT) >3 times the upper limits of normal
AND/OR
j. Known positive serology for viral hepatitis
13. Patients status-post gastric bypass surgery, partial gastrectomy or other surgery of the gastrointestinal tract that may interfere with the absorption of eplerenone |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the composite of cardiovascular (CV) mortality and heart failure (HF) hospitalization.
Cardiovascular (CV) mortality is defined as death due to:
Heart Failure
Myocardial infarction
Cardiac arrhythmia
Stroke/cerebral vascular accident (CVA) or transient ischemic attack (TIA)
Other CV cause (e.g., aneurysm or pulmonary embolism)
Hospitalization for HF is defined as follows:
1. Admission to an emergency room, observation unit and/or inpatient facility for at least 24 hours
AND
2. HF or suspicion of HF must be a reason for admission, (i.e. an admitting diagnosis)
AND
3. At least one symptom must be present:
• Increased dyspnea (at rest and/or with exertion)
• Increased orthopnea
• Paroxysmal nocturnal dyspnea
• Weight gain
• Increased fatigue
• Decreased exercise tolerance
AND
4. At least one clinical or radiologic sign must be present:
• S3 gallop
• Post-tussive rales
• Jugular venous distension
• Hepatojugular reflux
• Increased peripheral edema
• Pulmonary venous congestion or pleural effusion documented by chest radiography (if performed as part of routine clinical practice)
AND
5. At least one treatment must be instituted:
• Increased dose (≥ 50%) of oral diuretic
• New oral diuretic
• Intravenous diuretic
• Intravenous vasodilator
• Intravenous inotrope
AND
6. The patient must be discharged on an oral diuretic to minimize fluid retention |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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