The effect of eplerenone versus placebo on cardiovascular mortality and heart failure hospitalization in subjects with NYHA Class II Chronic Systolic Heart Failure Efecto de eplerenona versus placebo sobre la mortalidad cardiovascular y la hospitalización por insuficiencia cardiaca en sujetos con insuficiencia cardiaca sistólica crónica, clasificación NYHA II

• Register: EUCTR
• Last refreshed on: 29 May 2012
• Main ID: EUCTR2005-003351-12-ES
• Date of registration: 13/10/2005
• Prospective Registration: Yes
• Primary sponsor: PFIZER
• Public title: The effect of eplerenone versus placebo on cardiovascular mortality and heart failure hospitalization in subjects with NYHA Class II Chronic Systolic Heart Failure Efecto de eplerenona versus placebo sobre la mortalidad cardiovascular y la hospitalización por insuficiencia cardiaca en sujetos con insuficiencia cardiaca sistólica crónica, clasificación NYHA II
• Scientific title: The effect of eplerenone versus placebo on cardiovascular mortality and heart failure hospitalization in subjects with NYHA Class II Chronic Systolic Heart Failure Efecto de eplerenona versus placebo sobre la mortalidad cardiovascular y la hospitalización por insuficiencia cardiaca en sujetos con insuficiencia cardiaca sistólica crónica, clasificación NYHA II
• Date of first enrolment: 23/11/2005
• Target sample size: 2584
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003351-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: Parallel-group trial If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: yes Other specify the comparator: Standard Therapy

Countries of recruitment

Belgium, Czech Republic, Greece, Hungary, Ireland, Italy, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

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.)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Chronic systolic heart failure
MedDRA version: 8.0 Level: LLT Classification code 10008908

Intervention(s)

Trade Name: INSPRA
Product Name: Inspra
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Eplerenone
CAS Number: 107724-20-9
Other descriptive name: Methyl hydrogen (7<,11<,17<)-9,11-epoxy-17-hydroxy-3-oxopregn-4-ene-7,21-dicarboxylate©-lactone
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 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).

Secondary Objective:

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

Secondary ID(s)

2005-003351-12-CZ

A6141079