E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial fibrillation, stroke, heart failure, myocardial infarction, cognitive dysfunction |
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E.1.1.1 | Medical condition in easily understood language |
Atrial fibrillation is a common type of cardiac rhythm disorder, which represents an important cause for stroke but also for myocardial infarction and heart muscle weakness (heart failure).
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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 | 18.1 |
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 | 18.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10019280 |
E.1.2 | Term | Heart failures |
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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028596 |
E.1.2 | Term | Myocardial infarction |
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 | 18.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10009841 |
E.1.2 | Term | Cognitive and attention disorders and disturbances |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019016 |
E.1.2 | Term | Haemorrhagic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system 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 |
To test whether an early and comprehensive rhythm control therapy can prevent adverse cardiovascular outcomes in patients with atrial fibrillation (AF) compared to usual care. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Recent-onset AF (≤ 1 year prior to enrolment) 2. At least one ECG within recent 12 months that documents AF whereas the AF episode must last longer than 30 s. 3. EITHER one of the following: * age > 75 years or * prior stroke or transient ischemic attack OR two of the following: * age > 65 years, * female sex, * arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg), * diabetes mellitus (treated by drugs or insulin) or impaired glucose tolerance * severe coronary artery disease (previous myocardial infarction, CABG or PCI) * stable heart failure ( NYHA II or LVEF <50%), * left ventricular hypertrophy on echocardiography (more than 15 mm wall thickness), * chronic kidney disease (MDRD stage III or IV), * peripheral artery disease.
4. Provision of signed informed consent. 5. Age ≥ 18 years. |
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E.4 | Principal exclusion criteria |
1. Any disease that limits life expectancy to less than 1 year. 2. Participation in another clinical trial, either within the past two months or ongoing 3. Previous participation in the EAST trial. 4. Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral contraception or intra-uterine device (IUD)] or sterile women can be randomized. 5. Breastfeeding women. 6. Drug abuse. 7. Prior AF ablation or surgical therapy of AF. 8. Previous therapy failure on amiodarone, e.g. patients who suffered from symptomatic recurrent AF that required escalation of therapy while on amiodarone. 9. Patients not suitable for rhythm control of AF. 10. Severe mitral valve stenosis. 11. Prosthetic mitral valve. 12. Clinically relevant hepatic dysfunction requiring specific therapy. 13. Clinically manifest thyroid dysfunction requiring therapy. After successful treatment of thyroid dysfunction, patients may be enrolled when their thyroid function is controlled. 14. Severe renal dysfunction (stage V, requiring or almost requiring dialysis). |
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite of cardiovascular death, stroke, transitoric ischemic attack (TIA), and hospitalization due to worsening of heart failure or due to acute coronary syndrome. The first co-primary outcome parameter is defined as the time to the first occurrence of a composite of cardiovascular death, stroke / transient ischemic attack (TIA), and hospitalization due to worsening of heart failure or due to acute coronary. The second co-primary outcome parameter is nights spent in hospital per year.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A first interim analysis is to be performed when the first 171 events in the 1st co-primary outcome have been observed. If the assumptions are met, this will happen 32 months after the first patient was randomized. The second interim analysis is to be performed when the first 343 events in the 1st co-primary outcome have been observed (approximately 47 months after the first patient was randomized). The third interim analysis is to be performed when the first 514 events have been observed (approximately 59 (11) months after the first (last) patient was randomized). The final analysis is to be performed when 685 events have been observed. If the assumptions are met, this will happen 72 (24) months after the first (last) patient was randomized. |
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E.5.2 | Secondary end point(s) |
1. Cardiovascular death 2. stroke 3. worsening of heart failure assessed by hospitalizations 4. acute coronary syndrome assessed by hospitalizations 5. time to recurrent atrial fibrillation 6. cardiovascular hospitalisations 7. all-cause hospitalisations 8. left ventricular function assessed by transthoracic echocardiography 9. quality of life changes assessed by EQ-5D and SF-12 10. cognitive function assessed by MoCA |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of secondary end points no. 1-7 at the end of the trial (i.e. after 6 years). Evaluation of secondary end points no. 8-10 at month 24 after randomisation. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
usual care as defined by the current ESC guidelines and including delayed rhythm control therapy |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 200 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Czech Republic |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Switzerland |
United Kingdom |
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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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EAST is an event-driven trial. The final analysis will be performed if 685 events in the 1st co-primary outcome have been observed. If the statistical assumptions are met, this will happen 6 years after the first patient has been randomised in the study. Thus a duration of the entire trial of around 6 years is expected. All patients will be followed-up until the end of 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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |