The effect of eplerenone versus placebo on cardiovascular mortality and heart failure hospitalization in subjects with NYHA Class II Chronic Systolic Heart Failure - N/A

• Register: EUCTR
• Last refreshed on: 11 March 2013
• Main ID: EUCTR2005-003351-12-SE
• Date of registration: 03/10/2005
• Prospective Registration: Yes
• Primary sponsor: Pfizer AB
• 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 - N/A
• 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 - N/A
• Date of first enrolment: 06/02/2006
• Target sample size: 2715
• 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: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no 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:
Inclusion Criteria: Double-Blind Phase
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Written informed consent obtained prior to the initiation of any study procedures;
2. Male or female subjects, =55 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, magnetic resonance imaging or nuclear imaging, based on local clinical practice. The most recent measurement within 6 months prior to randomization must be used.
OR
Left ventricular ejection fraction (LVEF) =35% in addition to QRS duration =130 msec. It is mandatory that subjects with LVEF 31-35% must also have QRS duration =130 msec to be eligible for this trial.
c. Functional Capacity: Currently NYHA II (in the investigator’s opinion);
d. Treatments (for ACE inhibitors, ARBs and ß-blockers, optimal target or maximal tolerated dose [See Appendix 1 of the protocol Optimal Target Doses of Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARBs) and ß- Blockers] unless contraindicated).
• Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs);
• ß-blocker;
• Diuretic, if clinically indicated to reduce fluid retention;
4. Serum potassium (K+) level =5.0mmol/L within 24 hours prior to randomization.
5. Estimated glomerular filtration rate (eGFR) =30 ml/min/1.73m2 within 24 hours prior to randomization (See Appendix 2 of the protocol Calculation of Estimated Glomerular Filtration Rate (eGFR)).
6. Randomization must occur no later than 6 months from the date of admission to hospital for a cardiovascular reason (see definition of cardiovascular hospitalization below). If the subject is clinically stable, he or she may be randomized during admission for a cardiovascular reason.
OR
In the absence of a recent admission to hospital for a cardiovascular reason, documentation of a plasma concentration of B type natriuretic peptide (BNP) of at least 250 pg/ml or amino terminal proB type natriuretic peptide (NT proBNP) of at least 500 pg/ml for males and 750 pg/ml for females, within 15 days of randomization.

Cardiovascular (CV) hospitalization is defined as hospitalization for:
Heart Failure (first or subsequent)
Acute myocardial infarction
Angina pectoris (unstable)
Cardiac arrhythmia (atrial fibrillation, atrial flutter, supraventricular arrhythmias, or ventricular arrhythmias)
Stroke/cerebral vascular accident (CVA)
Other CV reasons (eg, hypotension, peripheral vascular disease)
Hospitalization for an elective cardiovascular procedure does not qualify for entry into this trial unless the subject was hospitalized for implantation of an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT).

7. If the subject is a female, the following should apply.
a. Have a negative serum pregnancy within 72 hours prior to the first dose of study drug, except if she previously had a total hysterectomy or is >65 years old;
b. Agree to use an adequate form of contraception (Abstinence will not be considered an acceptable form of contraception) if she is of child bearing potential.
8. Subjects previously treated with an aldosterone antagonist for >7 consecutive days will be allowed if they fulfill the following criteria:
a. No history of clinic
Exclusion criteria:
Exclusion Criteria: Double-Blind Phase
Subjects presenting with any of the following will not be included in the trial:
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 with stroke within 30 days prior to randomization.
4. Patients who have had cardiac surgery within 30 days prior to randomization.
5. Patients who have had percutaneous coronary intervention (PCI) within 30 days prior to randomization.
6. Patients previously exposed to treatment with an aldosterone antagonist for >7 consecutive days, in whom the aldosterone antagonist has not been discontinued permanently for at least 3 months prior to randomization, or patients who have a history of clinically significant hyperkalemia or renal impairment during a previous exposure to an aldosterone antagonist.
7. Patients who require treatment with eplerenone, spironolactone or potassium canrenoate and either have prior NYHA class IV heart failure associated with a LVEF =0.35 (as in the RALES trial) [2] or heart failure or diabetes and a LVEF <0.40 after acute MI (as in EPHESUS trial).
8. Patients with uncontrolled hypertension, defined as having a systolic blood pressure >180 mmHg and/or a diastolic blood pressure >110 mmHg.
9. Patients with symptomatic hypotension or having a systolic blood pressure <85 mmHg.
10. Patients, who in the opinion of the investigator, require treatment with potassium sparing diuretics.
11. History of hypersensitivity to eplerenone or spironolactone.
12. Evidence of cardiogenic shock.
13. Patients in whom the primary cause of heart failure is surgically amenable valve disease, pericardial disease or an obstructive or restrictive cardiomyopathy.
14. Intra aortic balloon pump or other mechanical assist device.
15. Patients awaiting cardiac transplantation.
16. Serum potassium >5.0 mmol/L within 24 hours prior to randomization.
17. Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 within 24 hours prior to randomization (See Appendix 2 of the protocol, Calculation of eGFR).
18. 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.
19. Concomitant use of cytochrome p450 3A4 (CYP3A4) inducers, such as but not limited to:
a St. John’s Wort;
b Rifampin;
c Carbamazepine;
d Phenytoin;
e Phenobarbitol.
20. Hemoglobin <10g/dL.
21. Patients with preexisting significant hepatic disease (for example, known positive serology for viral hepatitis) or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 times the upper limits of normal.
22. Patients status post gastric bypass surgery, partial gastrectomy or other surgery of the gastrointestinal tract that may interfere with the absorption of eplerenone.
23. Patients with preexisting serious conditions (eg, cancer, Acquired Immunodeficiency Syndrome (AIDS). Patients with a previous history of cancer will be eligible if in the opinion of the investigator life expectancy is anticipated to be greater than 5 years.
24. Patients unable to give written informed consent.
25. Patients with a progressively fatal disease (except congestive heart failure) and/or life expectancy less than 3

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
Product Code: N/A
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Eplerenone
CAS Number: 107724-20-9
Other descriptive name: Pregn-4-ene-7,21-dicarboxylic Acid, 9,11-epoxy-17-hydroxy3oxo, glactone, methyl ester, (7a,11a,17a)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

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 or HF hospitalization (a composite primary endpoint).

The objective of the open label phase is to ensure that all subjects who participated in the double-blind phase of the trial can be offered treatment with eplerenone.

Primary end point(s): The primary efficacy endpoint is the first occurrence of cardiovascular (CV) mortality or heart failure (HF) hospitalization.

Cardiovascular (CV) mortality is defined as death due to:
Heart Failure
Myocardial infarction
Cardiac arrhythmia
Stroke/cerebral vascular accident (CVA)
Other CV cause (eg, aneurysm or pulmonary embolism)

Hospitalization for HF
Hospitalization for HF is defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in patient care, or similar facility including admission to a day care facility) with a discharge diagnosis that includes a CV reason for hospitalization.

Secondary Objective: Not Applicable

Secondary ID(s)

A6141079

N/A

2005-003351-12-CZ