| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Subjects undergoing catheter ablation of non-valvular
atrial fibrillation |
| Pacientes que se someten a ablación con catéter de la fibrilación auricular no valvular |
|
| E.1.1.1 | Medical condition in easily understood language |
Subjects undergoing catheter ablation of non-valvular
atrial fibrillation |
| Pacientes que se someten a ablación con catéter de la fibrilación auricular no valvular |
|
| 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 | 19.1 |
| 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 |
|
| 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 |
Primary efficacy objective:
To compare descriptively the incidence of the composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined) and Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH] definition) in the edoxaban group against the vitamin K antagonist (VKA) group in subjects undergoing catheter ablation of atrial fibrillation (AF) in the period from the end of the catheter ablation procedure to Day 90/end-of-treatment (EOT).
Primary safety objective:
To compare descriptively the incidence of Major Bleeding (ISTH definition) in the edoxaban group against the VKA group in the period from date of first intake of study medication to Day 90/EOT. |
Objetivo principal de eficacia:
Comparar de forma descriptiva la incidencia de la combinación de muerte por cualquier causa, ictus (isquémico, hemorrágico o indeterminado) y hemorragia mayor (definición de la International Society on Thrombosis and Hemostasis [Sociedad Internacional de Trombosis y Hemostasia; ISTH, por su siglas en inglés]) en el grupo de edoxabán frente al grupo de antagonistas de la vitamina K (AVK) en pacientes que se someten a ablación con catéter de la fibrilación auricular (FA) en el periodo comprendido entre el final del procedimiento de ablación con catéter y el día 90/fin de tratamiento (FdT).
Objetivo principal de seguridad:
Comparar de forma descriptiva la incidencia de hemorragia mayor (definición de la ISTH) en el grupo de edoxabán frente al grupo de AVK en el periodo comprendido entre la fecha de la primera toma del medicamento del estudio y el día 90/FdT. |
|
| E.2.2 | Secondary objectives of the trial |
-Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined, according to alternative definition (see Protocol Section 7.4.2) and Major Bleeding [ISTH]
-Composite of stroke , SEE, CV mortality
-Composite of stroke, SEE, and all-cause mortality
-Composite of stroke and TIA
-Stroke
-SEE
-TIA
-Fatal stroke
-Non-fatal stroke
-Disabling stroke
-Non-disabling stroke
-Major Bleeding, Bleeding Academic Research Consortium [BARC] (2 or higher))
-Major and Clinically Relevant Non-Major (CRNM) Bleeding
-CRNM Bleeding
-Minor Bleeding
-Any Bleeding
-Intracranial hemorrhage (ICH)
-Life-threatening bleeding
-Fatal Major Bleeding
-Non-fatal Major Bleeding
-Fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
-Non-fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
-AEs, SAEs, laboratory parameters, electrocardiogram and vital signs
-Relevant Health Economics Outcome Research
-Cardiac and anticoagulation markers |
Combinación de muerte por cualquier causa, ictus (isquémico, hemorrágico o indeterminado, según una definición alternativa (ver protocolo 7.4.2) y hemorragia mayor (ISTH)
Combinación de ictus, AES, mortalidad cardiovascular CV
Combinacion de ictus, AES, y mortalidad por cualquier causa
Combinación de ictus y AIT
Ictus
AES
AIT
Ictus mortal
Ictus no mortal
Ictus discapacitante
Ictus no discapacitante
Hemorragia mayor,consorcio investigación hemorragia BARC, 2 o más
Hemorragia no mayor clínicamente relevante ISTH
ISTH Hemorragia
Hemorragia menor
Cualquier hemorragia
Hemorragia intracraneal (HIC)
Hemorragia potencialmente mortal
Hemorragia mayor mortal
Hemorragia mayor mortal (definida según TIMI y BARC [2 o más]
Hemorragia mayor no mortal (definida según TIMI y BARC [2 o más]
AA, AAG, parámetros laboratorio,electrocardiograma,constantes vitales
Parámetros relevantes de investigación resultados económicos de salud
Marcadores cardiacos y anticoagulación |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female at least 18 years of age with documented history of paroxysmal (lasting ≤7 days), persistent (lasting >7 days but ≤12 months) or long-standing [long-lasting] persistent (>12 months) non-valvular AF. Duration of AF can be confirmed by any electrical tracing or a recording in the subject’s medical records (e.g., medical chart, hospital discharge summary).
2. Subject is eligible and is scheduled for either radiofrequency (RF) or cryoballoon catheter ablation (both first and repeated procedure included).
3. Signed ICF. |
1. Hombres y mujeres de al menos 18 años con antecedentes documentados de FA no valvular paroxística (que dura ≤7 días), persistente (que dura >7 días pero ≤12 meses) o persistente prolongada [de larga duración] (>12 meses). La duración de la FA se puede confirmar por medio de cualquier trazado eléctrico o un registro en la historia clínica del paciente (p. ej., anamnesis, informe de alta hospitalario).
2. Pacientes aptos y que tienen programada una ablación con catéter de radiofrecuencia (RF) o crioablación con balón (se incluyen el primer procedimiento y los procedimientos repetidos).
3. Consentimiento informado (CI) firmado. |
|
| E.4 | Principal exclusion criteria |
1.AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery, ionic disturbances, thyrotoxicosis, pneumonia, severe anemia etc.).
2.Subject post stroke, or with a systemic thromboembolic event within the past 6 months prior to randomization.
3.Subject has a thrombus in the left atrial appendage (LAA), left atrium (LA), left ventricle (LV), or aorta, or an intracardial mass.
4.Subject had a myocardial infarction (MI) within the 2 months prior to randomization or coronary artery bypass graft (CABG) surgery within 3 months prior to the randomization.
5.Subject has signs of bleeding, history of clinically-relevant bleeding according to ISTH, or conditions associated with high risk of bleeding such as past history of intracranial
(spontaneous or traumatic), or spontaneous intraocular, spinal, retroperitoneal, or intra-articular bleeding; overt gastrointestinal (GI) bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy; active infective endocarditis; uncontrolled hypertension (blood pressure [BP] above 170/100 mmHg); or hemorrhagic disorder including known or suspected hereditary or acquired bleeding or coagulation disorder in the last 12 months prior to randomization.
6. Subjects with mechanical heart valves, subjects with moderate to severe mitral stenosis and subjects who have new implantation (within 3 months prior to randomization) of a bioprosthetic heart valve, with or without AF.
7. Subjects with a history of LAA occlusion/exclusion (either by surgery or by a procedure).
8. Subjects with any contraindication for edoxaban, VKA, low molecular weight heparin (LMWH), heparin therapy.
9. Subjects receiving dual antiplatelet therapy (DAPT, i.e., aspirin and P2Y12 antagonist) or planned to receive DAPT during the study
10. Subjects who require chronic use of medicines affecting hemostasis such as higher doses of aspirin (acetylsalicylic acid [ASA]) (ASA up to 100 mg per day allowed) or chronic oral or parenteral intake of non-aspirin non-steroidal anti inflammatory drugs (NSAID) on ≥4 days/week (use of NSAIDs via other routes is not restricted)
11. Subjects with active liver disease or persistent (confirmed by repeat assessments at least a week apart) elevation of liver enzymes/bilirubin:
― Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2 times the upper limit of normal (ULN)
― Total bilirubin (TBL) ≥1.5 times the ULN (subjects whose elevated TBL is due to known Gilbert’s syndrome may be included in the study)
― Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
12. Subjects with kidney failure (calculated creatinine clearance [CrCL] <15 mL/min).
13. Subjects with hemoglobin <10 g/dL or platelet count <100,000 cells/µL or white blood cell (WBC) count <3000 cells/µL.
14. Subjects with pre-planned invasive diagnostic or therapeutic procedures/interventions (other than endoscopy) during the study period in which bleeding is anticipated.
15. Participation in any other interventional trial (subjects who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period).
16. Previous randomization in this study.
17. Female subjects of childbearing potential without using adequate contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least 3 months prior to the start of this study [Visit 1]). Females taking oral contraceptives
should have been on therapy for at least 3 months. Adequate contraceptives include hormonal intra-uterine devices, hormonal contraceptives (oral, depot, patch or injectable), and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.
18. Pregnant or breast-feeding subjects.
19. Subjects with the following diagnoses or situations:
- Active cancer undergoing chemotherapy, radiation or major surgery within the next 5 months
- Significant active/uncontrolled concurrent medical illness
- Life expectancy <6 months.
20. Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study).
21. Subjects with a known drug or alcohol dependence within the past 12 months prior to randomization as judged by the Investigator.
22. Subjects with any condition that, in the opinion of the Investigator, would place the subject at increased risk of harm if he/she participated in the study.
23. Planned procedure using laser catheter ablation or other forms of catheter ablation different from RF or cryoballoon (i.e. high intensity focused ultrasound [HIFU], microwaves, hot balloon, etc) |
1.FA considerada de naturaleza transitoria o reversible ( iocarditis, tras una cirugía, trastornos electrolíticos, tirotoxicosis, neumonía, anemia grave, etc.)
2.Pte.después de un ictus, o con un acontecimiento tromboembólico sistémico en los 6 m. ant.a la aleatorización
3.Pte.con un trombo en el apéndice auricular izq. (AAI), la aurícula izq.(AI), el ventrículo izq. (VI), o la aorta, o una masa intracardiaca
4.Pte.con infarto de miocardio (IM) en los 2 meses ante. a la aleatorización o una cirugía de derivación aortocoronaria (CABG) en los 3 m.anteriores a la aleatorización
5.Pte.con signos hemorragia, antecedentes de hemorragia clínicamente relevante de acuerdo con la ISTH, o afecciones asociadas a un alto riesgo de hemorragia como antecedentes de hemorragia intracraneal (espontánea o traumática), o hemorragia espontánea intraocular, espinal, retroperitoneal o intraarticular; hemorragia gastrointestinal (GI) evidente o úlcera activa el año anterior;traumatismo grave reciente, cirugía mayor o biopsia de un órgano profundo; endocarditis infecciosa activa; hipertensión no controlada (tensión arterial [TA] superior a 170/100 mmHg);o trastorno hemorrágico, incluido un trastorno hemorrágico o de coagulación hereditario o adquirido, conocido o sospechoso, en los 12 meses ant. a aleatorización
6.Pte. válvulas cardiacas mecánicas, pacientes con estenosis mitral de moderada a grave y pacientes con implante reciente de una válvula cardiaca bioprotésica (en los 3 meses anteriores a la aleatorización), con o sin FA.
7.Pte.con antecedentes de inclusión/exclusión del apén. auricular izq. (mediante cirugía o mediante un proced.)
8.Pte.con contraindicaciones para el tratamiento con edoxabán, AVK, heparina de bajo peso molecular o heparina
9.Pte.que reciben antiplaquetario dual (TAPD, aspirina y un antagonista de P2Y12) o tienen previsto recibir un trat. antiplaquetario dual durante el estudio.
10.Pte.requieren el uso crónico de medicamentos afectan a la hemostasia, tales como dosis más altas de aspirina (ácido acetilsalicílico [ASA]) (está permitido el uso de ASA a dosis de hasta 100 mg al día) o uso oral o parenteral crónico de antiinflamatorios no esteroideos (AINE) que no contengan aspirina ≥4 días/semana (no se limita el uso de AINE administrados por otras vías)
11.Pte.enfermedad hepática activa o aumento (confirmado en análisis repetidos con un intervalo mínimo de una semana) de las enzimas hepáticas/bilirrubina:
Alanina-aminotransferasa (ALAT) o aspartato-aminotransferasa (ASAT) ≥2 veces el límite superior de la normalidad (LSN)
Bilirrubina total (BT) ≥1,5 veces el LSN (se puede incluir a pacientes con aumentos de la bilirrubina total que se sabe que son debidos al síndrome de Gilbert)
Enfermedad hepática asociada a coagulopatía y riesgo de hemorragia clínicamente relevante
12.Pte.con insuficiencia renal (aclaramiento de creatinina [CrCL] calculado <15 ml/min)
13.Pte.con hemoglobina <10 g/dl o recuento de plaquetas <100 000 células/µl o recuento de leucocitos <3000 células/µl
14.Pte.con intervenciones o procedimientos diagnósticos o terapéuticos invasivos previamente programados (excepto endoscopia) durante el periodo del estudio espera hemorragia.
15.Participación en cualquier ensayo intervencionista (pacientes que recibieron algún medicamento o dispositivo en investigación en los 30 días anteriores a la aleatorización, o que tienen previsto recibir dicho tratamiento en investigación durante estudio)
16.Aleatorización previa en este estudio
17.Mujeres fértiles no utilizan anticonceptivos (mujer fértil aquella que no lleva al menos un año posmenopáusica, o que no está quirúrgicamente esterilizada, o que no se ha sometido a una histerectomía al menos 3 meses antes de comenzar este estudio [visita 1]). Las mujeres q.toman anticonceptivos orales deben llevar 3 meses recibiendo el tratamiento. Los anticonceptivos adecuados incluyen los dispositivos intrauterinos hormonales, los anticonceptivos hormonales (orales, de liberación lenta, parches o inyectables) y métodos de doble barrera preservativos o diafragmas con gel o espuma espermicida
18.Mujeres embarazadas o en periodo de lactancia
19.Pte. con los siguientes diagnósticos o en las siguientes situaciones:Cáncer activo en tratamiento con quimioterapia, radiación o cirugía mayor en los próximos 5 m.
Enfermedad médica simultánea activa/no controlada.Esperanza de vida <6 meses.
20.Pte.con baja probabilidad de cumplir con el protocolo (p. ej., actitud no cooperativa, incapacidad acudir visitas y/o por otro motivo, el investigador poco probable completen el estudio).
21.Pte.drogodependientes o alcoholismo en los 12 meses ant. aleat.
22.Pte.con cualquier afección que investigador, que el paciente corriera mayor riesgo de sufrir daños.
23.Proced. programado ablación con catéter de láser u otras formas de ablación con catéter que no sean RF o crioablación con balón (ultrasonido focalizado de alta intensidad [HIFU], microondas, balón caliente, etc.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined), and Major Bleeding (ISTH definition), analyzed as time to first occurrence of any component.
Major Bleeding (ISTH definition), analyzed as time to first occurrence of Major Bleeding. |
Combinación de muerte por cualquier causa, ictus (isquémico, hemorrágico o indeterminado) y hemorragia mayor (ISTH), analizada como el tiempo hasta la primera aparición de cualquiera de los componentes
Hemorragia mayor (ISTH), analizada como el tiempo hasta la primera aparición de hemorragia mayor |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All adjudicated endpoints are analyzed as time to first occurrence of any of its components |
| Todas las variables adjudicadas se analizan como el tiempo hasta la primera aparición de cualquiera de sus componentes |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
• Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined, according to alternative definition (see Protocol Section 7.4.2 for details) and Major Bleeding (ISTH definition)
• Composite of stroke (ischemic, hemorrhagic, or undetermined) SEE, and CV mortality
• Composite of stroke (ischemic, hemorrhagic, or undetermined) SEE, and all-cause mortality
• Composite of stroke (ischemic, hemorrhagic, or undetermined) and TIA
• Stroke (ischemic, hemorrhagic, or undetermined)
• Stroke (ischemic)
• Stroke (hemorrhagic)
• Stroke (undetermined)
• SEE
• TIA
• Fatal stroke (ischemic, hemorrhagic, or undetermined)
• Non-fatal stroke (ischemic, hemorrhagic, or undetermined)
• Disabling stroke (ischemic, hemorrhagic, or undetermined)
• Non-disabling stroke (ischemic, hemorrhagic, or undetermined)
Safety:
• Major Bleeding (defined by TIMI, BARC (2 or higher))
• Major and Clinically Relevant Non-Major (CRNM) Bleeding (ISTH definition)
• CRNM Bleeding (ISTH definition)
• Minor Bleeding (ISTH definition)
• Any Bleeding
• ICH
• Life-threatening bleeding
• Fatal Major Bleeding (ISTH definition)
• Non-fatal Major Bleeding (ISTH definition)
• Fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
• Non-fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
• Safety parameters such as AEs, SAEs, laboratory parameters, ECG and vital signs. |
Eficacia
• Combinación de muerte por cualquier causa, ictus (isquémico, hemorrágico o indeterminado, según una definición alternativa ver Protocolo 7.4.2) ) y hemorragia mayor (definición de la ISTH)
• Combinación de ictus (isquémico, hemorrágico o indeterminado), AES y mortalidad CV
• Combinación de ictus (isquémico, hemorrágico o indeterminado), AES y mortalidad por cualquier causa
• Combinación de ictus (isquémico, hemorrágico o indeterminado) y AIT
• Ictus (isquémico, hemorrágico o indeterminado)
• Ictus (isquémico)
• Ictus (hemorrágico)
• Ictus (indeterminado)
• AES
• AIT
• Ictus mortal (isquémico, hemorrágico o indeterminado)
• Ictus no mortal (isquémico, hemorrágico o indeterminado)
• Ictus discapacitante (isquémico, hemorrágico o indeterminado
• Ictus no discapacitante (isquémico, hemorrágico o indeterminado)
Seguridad
• Hemorragia mayor (definida como TIMI, BARC (2 o más )
• Hemorragia mayor y hemorragia no mayor clínicamente relevante (definición de la ISTH)
• Hemorragia no mayor (definición de la ISTH)
• Hemorragia menor (definición de la ISTH)
• Cualquier hemorragia
• (HIC)
• Parámetros relevantes de la investigación de resultados económicos de la salud
• Hemorragia mayor mortal (definición de la ISTH)
• Hemorragia mayor mortal (definida según TIMI, BARC [2 o más])
• Hemorragia mayor no mortal (definida según TIMI, BARC [2 o más])
• Parámetros de seguridad tales como AA, AAG, parámetros de laboratorio, ECG y constantes vitales |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All adjudicated endpoints are analyzed as time to first occurrence of any of its components |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Taiwan |
| United Kingdom |
|
| 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
|
| All randomized subjects will have a contact planned 30-35 days after the EOT visit, to collect data on targeted concomitant medications, SAEs, and other AESI. The final contact is the post-treatment follow-up visit scheduled at 30-35 days after the EOT visit. The study is deemed completed as soon as the final contact of the last subject is performed in all centers and in all participating countries. |
| Habrá un contacto planeado con sujetos aleatorizados entre 30-35 días después de Visita de Fin de Ensayo, para recopilar datos de medicaciones concomitantes específicas, A. A. Graves y otros A.A. de Especial Interés. El último contacto es visita de Seguimiento post-tratamiento programada entre 30-35 días después de visita de Fin de Ensayo. El Ensayo se considerará finalizado se haya llevado a cabo el contacto final del último paciente en todos los centros y en todos los países participantes. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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