E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial fibrillation catheter ablation |
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E.1.1.1 | Medical condition in easily understood language |
Atrial fibrillation is a common cardiac rhythm disturbance. Although not directly life-threatening, it may have dangerous consequences: e.g., an up to fivefold increased risk of suffering a stroke. |
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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 | 17.1 |
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071667 |
E.1.2 | Term | Persistent 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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003661 |
E.1.2 | Term | Atrial fibrillation paroxysmal |
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066582 |
E.1.2 | Term | Recurrent 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 |
To demonstrate that anticoagulation with the direct factor Xa inhibitor apixaban is not less safe than VKA therapy in patients undergoing catheter ablation of non-valvular AF in the prevention of peri-procedural complications. |
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E.2.2 | Secondary objectives of the trial |
The substudy involving MRI scans after the ablation procedure aims to identify invisible damage such as 'silent'strokes in the test versus the comparator group. |
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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 |
MRI Sub-study (same version date as main study protocol: 28.07.2014) |
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E.3 | Principal inclusion criteria |
I1. Non-valvular AF (ECG-documented) with a clinical indication for catheter ablation I2. Clinical indication to undergo catheter ablation on continuous anticoagulant therapy I3. Presence of at least one of the CHADS2 stroke risk factors - Stroke or TIA - age ≥ 75 years, - hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mm Hg, - diabetes mellitus, - symptomatic heart failure (NYHA ≥ II). I4. Age ≥ 18 years I5. Provision of signed informed consent |
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E.4 | Principal exclusion criteria |
General exclusion criteria E1. Any disease that limits life expectancy to less than 1 year E2. Participation in another clinical trial, either within the past two months or still ongoing E3. Previous participation in AXAFA E4. 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) or sterile women can be randomised. E5. Breastfeeding women E6. Drug abuse or clinically manifest alcohol abuse E7. Any stroke within 14 days before randomisation E8. Coadministration with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P glycoprotein (P-gp) or strong dual inducers of CYP3A4 and P-gp Exclusion criteria related to a cardiac condition E9. Valvular AF (as defined by the focussed update of the ESC guidelines on AF, i.e. severe mitral valve stenosis, mechanical heart valve). Furthermore, patients who underwent mitral valve repair are not eligible for AXAFA. E10. Any previous ablation or surgical therapy for AF E11. Cardiac ablation therapy for any indication (catheter-based or surgical) within 3 months prior to randomisation E12. Clinical need for “triple therapy” (combination therapy of clopidogrel, acetylsalicylic acid, and oral anticoagulation) E13. Other contraindications for use of VKA or apixaban Exclusion criteria based on laboratory abnormalities E14. Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 ml/min |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome parameter of AXAFA is a composite of - all-cause death, - stroke, and - major bleeding events. Stroke comprises ischemic strokes as defined by the FDA (including ischemic infarction with (transient) clinical symptoms that resolve completely within 24 hours, but have a matching lesion on brain imaging as well as ischemic infarction interrupted by death within 24 hours), subarachnoid hemorrhage and hemorrhagic stroke. Major bleeding events will be defined according to the Bleeding Academic Research Consortium (BARC) definition as BARC 2 or higher, i.e. all bleeding events that require an action by a health care professional. This outcome parameter comprises all relevant bleeding events in a clinical setting and has been used to optimise arterial vascular procedures such as percutaneous coronary interventions. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Randomisation to end of follow-up, especially at 3-months on-site visit |
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E.5.2 | Secondary end point(s) |
The secondary outcome parameters are defined as - any bleeding event - major bleeding events according to the ISTH and TIMI definitions, - number of strokes, other systemic embolic events, and all-cause deaths, - time from randomisation to ablation - nights spent in hospital after ablation - health-care related cost calculation estimated by quantification of interventions, nights spent in hospital, and the costs of outpatient treatment, - number of hospitalizations (at least one over-night stay) for cardiovascular reasons , - treatment duration prior to ablation and total time on oral anticoagulation, - number of patients with clinically indicated TEE - ACT during ablation (assessed as mean, range, and number of ACT measurements within the target range) - time to recurrent AF (determined clinically, and according to ECG and Holter ECG recording at the end of follow-up), - rhythm status at the end of follow-up (assessed by Holter ECG), - vascular access complications leading to prolongation of in-hospital stay or specific therapy, - quality-of-life changes at month 3 compared to baseline (assessed by EQ-5D, SF-12 questionnaires, and by the Karnofsky scale), - change of cognitive function at month 3 compared to baseline (assessed by Montreal Cognitive Assessment Scale; MoCA), - MRI sub-study, only: Prevalence of clinically “silent” MRI-detected brain lesions within 48 hours after the ablation procedure, - MRI sub-study, only: Impact of ablation-associated clinically overt strokes or MRI-detected but clinically “silent” acute brain lesions on cognitive function after ablation
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Randomisation to end of follow-up, especially at 3-months on-site visit |
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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 | 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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Investigator-initiated, prospective, parallel-group, randomised, open, blinded endpoint assessment |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Denmark |
Germany |
Italy |
Netherlands |
Spain |
United Kingdom |
United States |
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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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Event-driven design: end of trial after number of valid primary endpoints is reached |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |