E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial fibrillation with preserved left ventricular systolic function and normal levels of the brain natriuretic peptide. |
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E.1.1.1 | Medical condition in easily understood language |
Irregular heart beats in people in normal heart pumping capacity, but reduced heart relaxation. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10069211 |
E.1.2 | Term | Diastolic heart failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 |
People with an irregular heartbeat can find it difficult to exercise and may experience shortness of breath or tiredness because the heart cannot relax properly. This research is trying to find out whether taking a small dose of a drug called Spironolactone can improve the ability to exercise. Spironolactone works as a mild water tablet and is a well-known drug that seems to improve heart function. |
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E.2.2 | Secondary objectives of the trial |
The study also aims to find out if the treatment with spironolactone can improve the capacity of the heart to relax better, improve quality of life and to reduce needs for hospital admissions. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Eligible study patients will be • Age 50 years old or over • Permanent AF as defined by the European Society of Cardiology (ESC) criteria • Normal BNP levels (<100 pg/mL) • Ability to understand and complete questionnaires (with or without use of a translater/translated materials).
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E.4 | Principal exclusion criteria |
• Severe systemic illness with life expectancy of less than 2 years from screening • Left ventricular ejection fraction (LVEF) <50% (echocardiography) • Severe chronic obstructive pulmonary disease (COPD) (e.g., requiring home oxygen or chronic oral steroid therapy) • Severe mitral/aortal valve stenosis/regurgitation • Significant renal dysfunction (serum creatinine 220 µmol/L or above) • Increase in potassium level to > 5mmol/L) • Recent coronary artery bypass graft surgery (within 3 months) • Use of aldosterone antagonist within 14 days before randomisation • Use of or potassium sparing diuretic within 14 days before randomisation • Systolic blood pressure >160 mm Hg • Any participant characteristic that may interfere with adherence to the trial protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Improvement in exercise tolerance at 2 years. This will be assessed by difference between the study groups in peak VO2 on CPET. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of 2 years of treatment with spironolactone or placebo. |
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E.5.2 | Secondary end point(s) |
• Improvement in exercise tolerance measured by 6-minute walking test (a simple and readily available in clinical practice tool for assessment of exercise performance); • Improvement in health-related quality of life assessed using the validated Minnesota Living with Heart Failure (MLWHF) and [EQ-5D] questionnaires self-completed by patients; • Improvement in LV diastolic dysfunction (E/E’ ratio); • Rate of all-cause hospitalisations (which will include HF-related hospitalisations). • Rate of spontaneous cardioversion to the sinus rhythm
Additionally we will record any cases of major adverse clinical events, such as death from any causes, death from cardiac causes, hospitalization for cardiac causes, a change in the NYHA class, stroke or systemic thromboembolism. However, we include all cause hospital admissions (which will include HF-related hospitalisations) as a secondary outcome given that such admissions are common in the study population (about 20% per year in the published literature). This information as well as data on cases of death or strokes would be used as pilot data for future studies focused on these hard clinical outcomes and adequately powered for this purpose (the current study is not powered to reliably assess the hard clinical outcomes, although we have included a pre-specific clinical composite outcome as a secondary endpoint).
Safety outcomes The following safety outcomes will be recorded for analysis: (i) development of hyperkalaemia (>5.0 mmol/L) and creatinine rise, (ii) development of gynecomastia, and (iii) development of side effects requiring withdrawal of the study treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of 2 years of treatment with spironolactone or placebo. |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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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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 | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 30 |