E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
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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 study is to determine in subjects with diastolic heart failure whether spironolactone is superior to placebo in improving maximal exercise capacity and diastolic function. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to determine in subjects with diastolic heart failure whether spironolactone is superior to placebo in improving several other measures of exercise capacity and diastolic function, as well as quality of life, neuroendocrine activation, morbidity and mortality. The study will also investigate clinical safety aspects. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Aldo-FIBRO (Effect of aldosterone receptor blockade on diastolic function and fibrosis) Aldo-FIBRO will assess the effects of spironolactone on invasive parameters of diastolic function and on myocardial fibrosis. A detailed investigational plan, including patient informed consent forms, will be provided by the coordinating investigator. The study will be performed at the centres Berlin Campus Benjamin-Franklin and Göttingen.
2. Aldo-SYST (Effects of aldosterone receptor blockade on systolic function in patients with diastolic heart failure) Aldo-SYST will test the effects of spironolactone on subtle alterations of systolic function in patients with diastolic heart failure. Subtle alterations in systolic heart failure will be assessed by modern echocardiographic parameters (e.g., strain, strain rate). The study will be performed at centres willing to participate and able to perform these analyses. Data will be obtained during echocardiographic procedures scheduled in Aldo-DHF.
3. Aldo-INFLAM (Effects of aldosterone receptor blockade on inflammatory markers in patients with diastolic heart failure) Aldo-INFLAM will assess markers of inflammation (TNF, IL-6, sTNFR-1) and their influence on primary endpoints of the study. Those markers are highly predictive of adverse outcomes in patients with systolic heart failure, but have so far not been assessed in diastolic dysfunction. This study is open for all centres willing to participate. Data will be obtained from blood samples scheduled in Aldo-DHF; no additional sampling will be necessary.
4. Aldo-ECG (Effects of aldosterone receptor blockade on myocardial repolarisation, conduction and heart rate variability in patients with diastolic heart failure) Aldo-ECG will test the effects of spironolactone on markers for altered myocardial repolarisation, conduction and heart rate variability. Altered myocardial repolarisation and conduction have prognostic value by increasing the incidence of sudden cardiac death. Reduced heart rate variability is associated with increased morbidity and mortality in patients with chronic heart failure. The study will be performed at centres willing to participate. Data will be obtained with 12-lead Holter ECG which will be provided from Charité Berlin. Analyses will be done blinded at Charité.
5. Aldo-CYP (Effects of aldosterone receptor blockade on aldosterone synthesis and influence of CYP11B2-polymorphism in patients with diastolic heart failure) Aldo-CYP will investigate the effects of spironolactone on plasma levels of aldosterone and factors of aldosterone synthesis, e.g. expression of aldosterone synthase (CYP11B2). Also the relevance of CYP11B2- polymorphism in patients with symptomatic diastolic heart failure will be assessed. Furthermore the impact of aldosterone baseline levels on treatment effects will be investigated. The study will be performed at centres willing to participate. Analyses will be done blinded at the reference lab in Göttingen.
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E.3 | Principal inclusion criteria |
· Current heart failure symptoms consistent with NYHA II or beyond · Left ventricular ejection fraction (LVEF) ≥ 50% at rest · Sinus rhythm or atrial fibrillation · if sinus rhythm Echocardiographic parameters of diastolic dysfunction (Grade ≥ I, see Appendix) · Peak VO2 ≤ 25 ml/kg/min · Males and females of age ≥ 50 years · Written informed consent of the patient
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E.4 | Principal exclusion criteria |
Patients will be excluded for ANY ONE of the following reasons: · definite or probable pulmonary disease (VC<80% or FEV1<80% of reference values on spirometry) · severe obesity (BMI ≥ 36 kg/m2) · psychological disorders with suspected interaction to study outcome · Prior documented intolerance to an aldosterone receptor antagonist · Prior documented systolic heart failure (LVEF ≤ 40%) · Changes in concomitant medication within the last two weeks prior screening visit · Significant coronary artery disease (current angina pectoris or ischemia on stress tests; untreated coronary stenosis >50%; Myocardial infarction or CABAG within the last 3 months) · Known contraindications for spironolactone · Significant laboratory abnormalities (potassium ≥ 5.1 mmol/L; hemoglobin ≤ 11g/dL, hematocrit ≤ 33%) · Significant renal dysfunction (creatinine > 1.8 mg/dL or eGFR < 30 mL/min/1,73m²) · Concomitant therapy with a potassium-sparing diuretic (e.g., triamterene, amiloride), potassium substitution, or high-dose acetylsalicylic acid (>500 mg/d) or permanent intake of non-steroidal antiphlogistic agents · Insulin-dependent diabetes mellitus with a history of ketoacidosis · Significant hypotension (blood pressure < 90 mmHg systolic and/or 50 mmHg diastolic) · Pregnant or nursing women · Women with child bearing potency without effective contraception (i.e. implants, injectables, combined oral contraceptives, some IUDs or vasectomised partner) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change in maximum exercise capacity (peak VO2 on spiroergometry) at 12 months compared to baseline 2. Change in E/E´ (relation peak early transmitral ventricular filling velocity/ early diastolic tissue Doppler velocity) as indicator of LVEDP at 12 months |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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Patients will be followed on study medication for 12 months. Additionally, patients recruited in the first 6 months will be followed up to 18 months.
In case of the following situations, a premature termination of the trial has to be considered: - Serious adverse drug reactions / not justifiable toxicity - Substantial changes in risk-benefit considerations - New insights from other trials - Insufficient efficacy - Insufficient recruitment rate - Unsustainable trial organisation
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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 | 3 |
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 | 3 |