Clinical Trials Register

Summary
EudraCT Number:	2014-002442-45
Sponsor's Protocol Code Number:	AXAFA_AFNET5
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-15
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2014-002442-45

A.3

Full title of the trial

Anticoagulation using the direct factor Xa inhibitor apixaban during Atrial Fibrillation catheter Ablation: Comparison to vitamin K antagonist therapy.

Anticoagulación mantenida con apixaban (inhibidor directo del factor Xa) durante la Ablación con catéter de la Fibrilación Auricular: Comparación con la terapia mantenida con antagonistas de la vitamina K (AXAFA)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

During atrial fibrillation catheter ablation procedure treatment with anticoagulant drugs is necessary in order to prevent blood clotting and thereby decrease the risk of procedure related strokes. In this study two different types of anticoagulant drugs are being compared during and after the atrial fibrillation catheter ablation procedure: the novel direct factor Xa inhibitor apixaban and any of the standard vitamin K antagonists.

Durante ablación de fibrilación auricular, es necesario realizar el procedimiento bajo tratamiento con anticoagulantes para prevenir coagulación y poder reducir riesgo de que puedan producirse infartos cerebrales relacionados con el mismo. Este estudio compara dos tipos de drogas anticoagulantes antes y después del procedimiento de ablación con catéter de fibrilación auricular. Las drogas son: El inhibidor directo del factor Xa – apixaban y cualquiera fármacos antagonistas estándares vitamina K.

A.3.2

Name or abbreviated title of the trial where available

AXAFA

A.4.1

Sponsor's protocol code number

AXAFA_AFNET5

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN87711003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02227550

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The Kompetenznetz Vorhofflimmern e.V. [German Atrial Fibrillation Competence Network association (AFNET e.V.)]
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bristol-Myers Squibb
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kompetenznetz Vorhofflimmern e.V. [Atrial Fibrillation Competence Network (AFNET) e.V.]
B.5.2	Functional name of contact point	AFNET e.V.
B.5.3	Address:
B.5.3.1	Street Address	Mendelstraße 11
B.5.3.2	Town/ city	Münster
B.5.3.3	Post code	48149
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492519801340
B.5.5	Fax number	+492519801349
B.5.6	E-mail	info@kompetenznetz-vorhofflimmern.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Eliquis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb/Pfizer EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Apixaban
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	APIXABAN
D.3.9.3	Other descriptive name	Apixaban
D.3.9.4	EV Substance Code	SUB25425
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Acenocoumarol
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACENOCOUMAROL
D.3.9.1	CAS number	152-72-7
D.3.9.3	Other descriptive name	acenocoumarol
D.3.9.4	EV Substance Code	SUB05211MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Warfarin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	warfarin
D.3.9.3	Other descriptive name	WARFARIN SODIUM
D.3.9.4	EV Substance Code	SUB05128MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Eliquis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb/Pfizer EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Apixaban
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	APIXABAN
D.3.9.3	Other descriptive name	Apixaban
D.3.9.4	EV Substance Code	SUB25425
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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

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

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Vitamin K antagonist

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

500

F.4.2.2

In the whole clinical trial

650

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the end of the study course of each individual patient (planned or premature study discontinuation), the investigator is free to decide on which further anticoagulant medication to put the patient.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-09-12

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Orphan Designation Number:
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