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    EudraCT Number:2005-003351-12
    Sponsor's Protocol Code Number:A6141079
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-09-12
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2005-003351-12
    A.3Full title of the trial
    The effect of eplerenone versus placebo on cardiovascular mortality and heart failure hospitalization in subjects with NYHA Class II Chronic Systolic Heart Failure
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberA6141079
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberN/A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Ltd
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Inspra
    D. of the Marketing Authorisation holderPfizer bv
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameInspra
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEplerenone
    D.3.9.1CAS number 107724-20-9
    D.3.9.3Other descriptive namePregn-4-ene-7,21-dicarboxylic Acid, 9,11-epoxy-17-hydroxy3oxo, glactone, methyl ester, (7α,11α,17α)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic systolic heart failure
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.0
    E.1.2Level LLT
    E.1.2Classification code 10008908
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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 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.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    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 β-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 β- Blockers] unless contraindicated).
    • Angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs);
    • β-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.
    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 clinically significant hyperkalemia or renal impairment during earlier use of an aldosterone antagonist;
    b. The aldosterone antagonist must have been discontinued for at least 3 months prior to randomization.
    A washout period of 48 hours is deemed adequate for subjects treated with an aldosterone antagonist for less than or equal to7 days. Subjects who have a bona fide need for an aldosterone antagonist must not be discontinued from treatment just to make them eligible for entry into this trial.
    9. Subjects in whom the primary cause of heart failure is inoperable valve disease.

    Inclusion Criteria: Open Label Phase
    All subjects who have been randomized into the double blind phase of the trial, and have not withdrawn consent, will be eligible to participate in the open label phase. This includes subjects who may have previously discontinued study drug treatment.
    E.4Principal 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 years.
    26. Patients receiving immunosuppressive or antineoplastic therapy.
    27. Patients with a history of alcohol and/or any other drug abuse that in the opinion of the investigator will make the patient unreliable.
    28. Patients who previously participated in this trial.
    29. Patients who are likely to require treatment during the trial period with drugs not permitted by this protocol.
    30. Women who are either pregnant, lactating or of childbearing potential and not using an acceptable method of contraception.
    31. Donation of blood or blood products for transfusion at any time during the trial or until 30 days after completion of treatment.
    32. Participation in any other trial involving investigational or marketed products (including devices) concomitantly or within 30 days prior to entry in the trial.
    33. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial.

    Exclusion Criteria: Open Label Phase
    Subjects with both an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 as the last recorded value during the double-blind phase and who are confirmed to be on placebo are ineligible to participate in the open label phase.
    E.5 End points
    E.5.1Primary 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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    Standard Therapy
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA172
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    As per protocol.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1548
    F.4.2.2In the whole clinical trial 2715
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will only be given drug during their participation in the trial
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2005-10-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-10-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-01-24
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