| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Atrial fibrillation catheter ablation | | Ablación con catéter de la fibrilación auricular | |
| 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. | | Fibrilación auricular es una alteración común del ritmo cardiaco. No suele ser mortal, puede tener consecuencias peligrosas como aumentar hasta cinco veces más riesgo de padecer un infarto cerebral | |
| 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 | |
| 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 | 10071667 | | E.1.2 | Term | Persistent atrial fibrillation | | E.1.2 | System Organ Class | 10007541 - Cardiac disorders | |
| 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 | 10066582 | | E.1.2 | Term | Recurrent atrial fibrillation | | E.1.2 | System Organ Class | 10007541 - Cardiac disorders | |
| 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 | 10003661 | | E.1.2 | Term | Atrial fibrillation paroxysmal | | E.1.2 | System Organ Class | 10007541 - Cardiac disorders | |
| 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. | | Demostrar que la anticoagulación con el inhibidor directo del factor Xa – apixaban no es menos segura que la terapia con VKA en pacientes sometidos a ablación con catéter de la FA no valvular en la prevención de complicaciones peri-operatorias. | |
| 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. | | El subestudio con resonancia magnética nuclear (RMN) cerebral trata de identificar lesiones subclínicas detectadas como “infartos cerebrales silentes” y comparar la incidencia de las mismas entre los grupos control y experimental. | |
| 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: current amended version 20.02.2015) | | Subestudio RMN (la misma fecha del protocolo del estudio principal: Versión modificada 20.02.2015) | |
| 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 greater or equal 75 years,
- hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure greater than 145/90 mm Hg,
- diabetes mellitus,
- symptomatic heart failure (NYHA greater or equal II).
I4. Age above or equal 18 years
I5. Provision of signed informed consent | I1. FA no valvular (documentada con ECG) con indicación clínica para realizar un procedimiento de ablación con catéter
I2. Indicación clínica para someterse al procedimiento de ablación con catéter bajo terapia de anticoagulación continua.
I3. Presencia de al menos uno de los siguientes factores de riesgo de ictus de las escala CHADS2 – ictus o AIT – edad mayor o igual de 75 años – hipertensión, definida como tratamiento crónico para la hipertensión, criterios que indiquen que se va a precisar una terapia antihipertensiva continua o presión sanguínea medida en reposo mayor de 145/90 mmHg – diabetes mellitus – insuficiencia cardiaca sintomática (NYHA mayor o igual de II). I4. Edad mayor o igual de 18 años I5. Entrega del consentimiento informado firmado | |
| 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 2 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.
E14. Documented atrial thrombi less than 3 months prior to randomisation.
Exclusion criteria based on laboratory abnormalities
E15. Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 ml/min. | Criterios generales de exclusión:
E1. Cualquier enfermedad que limite la esperanza de vida a menos de un año.
E2. La participación en otro ensayo clínico actualmente o en los últimos dos meses.
E3. Participación previa en el ensayo AXAFA.
E4. Mujeres embarazadas o mujeres en edad fértil que no usen un adecuado método anticonceptivo. Solo aquellas mujeres que estén usando un método anticonceptivo altamente eficaz (anticonceptivos orales o dispositivo intrauterino) o mujeres con diagnóstico de esterilidad se pueden aleatorizar.
E5. Mujeres en periodo de lactancia.
E6. Drogadicción o alcoholismo clínico.
E7. Infartos cerebrales ocurridos 14 días antes de la aleatorización.
E8. Co-administración de drogas que provoquen una fuerte inhibición dual del cytochrome P450 3A4 (CYP3A4) Y P-glycoprotein (P-gp) o inductores duales del CYP3A4 y P-gp. Criterios de exclusión relacionados con patología estructural cardiaca.
E9. FA valvular (según las definiciones de las directrices del ESC actualizadas y relacionadas con la FA, como por ejemplo, estenosis severa de la válvula mitral, prótesis valvulares mecánicas..). Por otra parte, aquellos pacientes que hayan sido sometidos a una reparación de la válvula mitral no son elegibles para el estudio AXAFA.
E10. Cualquier ablación o procedimiento quirúrgico previo de la FA.
E11. Terapia de ablación cardiaca en cualquier indicación clínica (de catéter o quirúrgica) en los 3 meses previos a la aleatorización
E12. Necesidad de terapia clínica triple (combinación de doble antiagregación y anticoagulación con clopidogrel, acido acetylsalicylic y anticoagulante oral).
E13. Cualquier otro tipo de contraindicaciones para el uso de VKA o apixaban.
E14. Trombosis auricular documentada en los tres meses antes de la aleatorización.
E15. Criterios de exclusión basados en anormalidades de laboratorio.
E16. Insuficiencia renal crónica y severa, con una tasa estimada de filtración glomerular < 15ml/min.
| |
| 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. | | Las variables de resultado principales del ensayo AXAFA son: Muerte por cualquier causa, Ictus, (incluye aquellos ictus isquémicos que presenten síntomas clínicos y que se resuelvan completamente dentro de 24 horas posteriores, pero que tienen una lesión correspondiente en las resonancias magnéticas cerebrales, así como aquellos infartos isquémicos con resultado de muerte en menos de 24 horas) Hemorragia subaracnoidea o ictus hemorrágico, y Episodios de hemorragia graves según las definiciones de la ISTH (Sociedad Internacional sobre Trombosis de Hemostasia) como BARC 2 o superior. Esta variable incluye todos aquellos eventos hemorrágicos que requieran intervención clínica ha sido previamente usada para optimizar procedimientos vasculares arteriales como las intervenciones coronarias percutáneas. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Randomisation to end of follow-up, especially at three-months on-site visit | | En la aleatorización, al final del seguimiento y especialmente a los tres meses en visita clínica presencial. | |
| 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 | Las variables de resultado secundarias se definen como:
-Cualquier evento hemorrágico
-Eventos hemorrágicos graves según las definiciones de la ISTH (Sociedad Internacional sobre Trombosis de Hemostasia) y de la TIMI (Trombólisis en Infarto de Miocardio)
-Número de ictus, embolia sistémica y muerte por cualquier causa
-Tiempo desde la aleatorización a la ablación
-Estancia hospitalaria tras la ablación (noches pasadas en el hospital)
-Cálculo de los costes relacionados con la asistencia sanitaria
-Número de hospitalizaciones por causa cardiovascular
-Duración del tratamiento previo a la ablación y tiempo total de anticoagulación oral
-Número de pacientes con ETE indicada clínicamente
-ACT durante la ablación (valores medios, rango, numero de mediciones)
-Tiempo a la recurrencia de la FA
-Ritmo cardiaco al final del seguimiento
-Complicaciones de acceso vascular que lleven a una prolongación de la estancia hospitalaria o a una terapia específica
-Cambios en la encuesta de calidad de vida al tercer mes en comparación con los valores iniciales.
-Cambios en la función cognitiva al tercer mes en comparación con el valor inicial
-Prevalencia de lesiones cerebrales silentes detectadas mediante RMN en las primeras 48 horas tras la ablación (subestudio RMN)
-Ictus clínicamente sintomáticos asociados al procedimiento de ablación que causen alteraciones en las funciones cognitivas (subestudio RMN) o lesiones cerebrales detectadas mediante RMN ya estén asociados a alteraciones en las funciones cognitivas o sean clínicamente silentes | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | Randomisation to end of follow-up, especially at three-months on-site visit | | En la aleatorización, al final del seguimiento, seguimiento y especialmente a los tres meses en visita clínica presencial. | |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description | | Investigator-initiated, prospective, parallel-group, randomised, open, blinded endpoint assessment | |
| 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 | |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | |
| 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 | | Event-driven design: end of trial after number of valid primary endpoints is reached | |
| 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 |
