E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Persistant atrial fibrillation requiring conversion of AF |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.0 |
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.1.3 | 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 the study is to evaluate the rate of AF recurrences one month after randomization according to different timings of initiation of dronedarone. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective is to evaluate the rate of AF recurrences two months after randomization.
To assess the safety of the change from amiodarone to dronedarone
To assess dronedarone safety
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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 |
PK sub-study
Date: 25-Mar-2010 Version 1.
Objectives: to explore dronedarone and SR35021 (active metabolite) plasma levels according to different timings of initiation and to explore potential PK interaction between dronedarone and amiodarone.
Pharmacogenetic sub-study, date: 25-Mar-2010, version 1.
Objective: to investigate allelic variants of drug metabolism enzymes or drug transporters as intrinsic factors associated with PK or pharmacodynamic variability of the development compound. |
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E.3 | Principal inclusion criteria |
•Inclusion criteria at screening:
- Male or female adult aged 18 years or more,
- Patient with persistent AF for more than 72 hours (documented by an ECG taken within the last 72 hours) for whom cardioversion, anti-arrhythmic treatment and anticoagulation treatment are indicated in the opinion of the Investigator (Note: patient may already be on anticoagulation treatment),
- Naive of amiodarone treatment in the last three months prior to screening,
- QTcB < 500 ms on 12-lead ECG,
- Patient with at least one cardiovascular risk factor (i.e. age > 70, hypertension, diabetes, prior cerebrovascular disease, left atrial diameter ≥ 50 mm
- Signed written informed consent.
•Inclusion Criteria: to be checked at randomization
- Outpatient and Inpatient. (except patients hospitalized during screening period for SAE).
- Patient in sinus rhythm (Note: if cardioversion is performed on Day 1 prior to randomization, then the patient must be in sinus rhythm for at least one hour before randomization),
- Patient under effective anticoagulation according to ACC/AHA/ESC AF treatment
guidelines [18] verified by INR (target > 2).
INR should be closely monitored after initiating dronedarone in patients taking vitamin K antagonist as per their label
- QTcB < 500 ms and PR < 280 ms on 12-lead ECG,
- Patient having received 28 days ± 2 days of amiodarone.
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E.4 | Principal exclusion criteria |
•Exclusion criteria at screening:
- Contraindication to oral anticoagulation,
- Any documented AF episode motivating inclusion in the study after an acute condition known to cause AF (e.g. alcohol intake, thyrotoxicosis, acute infection, pericarditis, pulmonary embolism, cardiac surgery),
- Patient with permanent AF defined as patients with an AF duration ≥ 6 months (or duration unknown) and attempts to restore sinus rhythm no longer considered by the physician.
- Patient with paroxysmal AF in whom cardioversion is not indicated,
- Bradycardia < 50 beats per minute (bpm) at rest on the 12-lead ECG,
- Clinically overt congestive heart failure:
o with New York Heart Association (NYHA) class III and IV heart failure,
o with LVEF < 35%,
o or NYHA class II with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic,
o as well any patient in unstable hemodynamic conditions.
- Women of childbearing potential without adequate birth control (e.g. oral contraception or intra-uterine device [IUD]) or not menopaused, not sterile or not hysterectomized,
- Pregnant women,
- Breastfeeding women,
- Previous (2 preceding months) or current participation in another clinical trial with an investigational drug or with an investigational device,
- Clinically relevant hematologic, underlying hepatobiliary disease, gastrointestinal, pulmonary, endocrinologic, psychiatric, neurological or dermatological disease,
- Severe hepatic impairment,
- Severe renal impairment (creatinine clearance < 30 mL/min),
- Serum potassium <3.5 millimol/liter (mmol/L) (in patients with hypokalemia, potassium deficiency must be corrected before randomization) or > 5.5 mmol/l,
- Magnesemia < 0.8 mml/l (in patient with hypo-magnesemia, magnesium deficiency must be corrected before randomization),
- Unstable angina pectoris (ischemic symptoms during the last 7 days) or recent myocardial infarction (MI) (< 6 weeks),
- First degree family history of sudden cardiac death below age 50 years in the absence of coronary heart disease,
- Second- or third- degree Atrio-Ventricular block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker),
- Ongoing potentially severe symptoms when in AF such as angina pectoris, transient ischemic attacks, stroke, syncope, as judged by the investigator,
- Wolff-Parkinson-White Syndrome,
- Previous ablation for atrial fibrillation or any planned ablation in the next following 2 months.
•Exclusion criteria to be checked at randomization
- Bradycardia < 50 bpm on the 12-lead ECG before randomization,
- Clinically overt congestive heart failure:
o with New York Heart Association (NYHA) class III and IV heart failure,
o with LVEF < 35%,
o or NYHA class II with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic,
o as well any patients in unstable hemodynamic conditions.
- Serum potassium <3.5 millimol/liter (mmol/L) (in patients with hypokalemia, potassium deficiency must have been corrected before randomization) or > 5.5 mmol/l,
- Magnesemia < 0.8 mml/l (in patient with hypo-magnesemia, magnesium deficiency must have been corrected before randomization)
- Women of childbearing potential without adequate birth control (e.g. oral contraception or intra-uterine device [IUD]) or not menopaused, not sterile or not hysterectomized,
- Severe hepatic impairment.
- Patients with permanent AF defined as patients with an AF duration ≥ 6 months (or duration unknown) and attempts to restore sinus rhythm no longer considered by the physician
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy criterion is the rate of AF recurrences documented by two consecutive scheduled or unscheduled 12-lead ECG or TTEM performed approximately 10 minutes apart |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy criterion is the rate of AF recurrences one month after randomization according to different timings of initiation of dronedarone. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint is the rate of AF recurrences.
Secondary safety endpoints
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy endpoint is AF
recurrences two months after randomization.
bradycardia/tachycardia: from V5 to V10
Laboratory tests:
haematology:at V1 and V10.
creatinine: V1, V7 and V10.
INR: V1, V2, V3, V4, V5, V7, V8, V9 and V10.
thyroid function tests: at V1 and V10
hepatic laboratory assessment:V1, V4, V5, V7, V9 and V10.
ECG parameters: at each visit
Adverse events, adverse events of special interest (AESIs), SAEs: all along the study
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
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 |
Australia |
Austria |
Estonia |
Finland |
France |
Greece |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Portugal |
Spain |
Switzerland |
Taiwan |
Turkey |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |