| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stroke and thromboembolism prevention in patients with non-valvular atrial fibrillation (NVAF) undergoing planned electrical cardioversion. |
Prevención de accidentes cerebrovasculares y de
tromboembolia en pacientes con fibrilación auricular no valvular (FANV) que se sometan a cardioversión eléctrica programada |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of development of clots in patients with an abnormal heartbeat condition called atrial fibrillation undergoing cardioversion; a procedure that converts the abnormal heartbeat to normal. |
| Prevención en formación de coágulos en pacientes con ritmo cardiaco anormal llamado fibrilación auricular sometido cardioversión; procedimiento que convierte el ritmo cardiaco anormal a la normal. |
|
| 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 | 16.1 |
| 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:
Compare the incidences of the composite endpoints of stroke, systemic
embolic event (SEE), myocardial infarction (MI) and cardiovascular (CV)
mortality between the edoxaban group and the enoxaparin/warfarin
group from randomization to end of follow up (FU).
Primary Safety Objective:
Compare the incidence of the composite endpoints of major and clinically-relevant non-major (CRNM) bleeding between the edoxaban group and the enoxaparin/warfarin group from the first administration of study drug to end of treatment + 3 days.
|
El objetivo principal de eficacia de este estudio es:
- Comparar las incidencias de las combinaciones de criterios de valoración de accidente cerebrovascular, episodio de embolia sistémica (EES), infarto de miocardio (IM) y mortalidad cardiovascular (CV) entre el grupo de edoxabán y el grupo de enoxaparina/warfarina desde la
aleatorización hasta el final del seguimiento.
El objetivo principal de seguridad de este estudio es:
- Comparar la incidencia de las combinaciones de criterios de valoración de hemorragia importante y no importante pero clínicamente relevante (clinically-relevant non-major, CRNM) entre el grupo de edoxabán y el grupo de enoxaparina/warfarina desde la primera administración del medicamento del estudio hasta el final del tratamiento + 3 días. |
|
| E.2.2 | Secondary objectives of the trial |
| Compare the incidences of the composite endpoints of stroke, systemic embolic event (SEE), myocardial infarction (MI), cardiovascular (CV) mortality and major bleedings between the edoxaban group and the enoxaparin/warfarin group from randomization to end of FU. |
Comparar las incidencias de las combinaciones de criterios de valoración de accidente cerebrovascular, EES, IM, mortalidad CV y hemorragias importantes entre el grupo de edoxabán y el grupo de enoxaparina/warfarina desde la aleatorización hasta el final del
seguimiento |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed ICF;
2. Male or female subjects older than the minimum legal adult age (country specific);
3. Ongoing AF lasting for at least 48 hours but <= 12 months;
Ongoing AF at the time of randomization should be confirmed by any electrical tracing (eg, routine 12-lead electrocardiogram (ECG), Holter monitor rhythm strip, intracardiac electrogram, or pacemaker) prior to randomization. Duration and proof of AF during the previous 12 months can be confirmed by any electrical tracing or a recording in the subject?s medical records (eg, medical chart, hospital discharge summary);
4. Subject is planned for electrical cardioversion;
Subjects with AF following a cardiac surgical procedure will be allowed in the study providing that they meet all the other inclusion criteria AND the time from the surgery to randomization is no less than 30 days. The Investigator will be responsible for assessment of risks relevant to the cardioversion procedure in such subjects. |
1. Formulario de consentimiento informado firmado.
2. Hombres o mujeres mayores de la edad adulta legal mínima (específica de cada país).
3. FA en curso de al menos 48 horas de evolución, pero <= 12 meses.
- La FA en curso en el momento de la
aleatorización debe estar confirmada
mediante algún registro eléctrico (p. ej., electrocardiograma [ECG] de
12 derivaciones convencional, tira de
ritmo de monitorización Holter,
electrograma intracardiaco o lecturas de marcapasos) antes de la aleatorización.
La duración y la prueba de FA durante
los 12 meses previos se puede confirmar mediante algún registro eléctrico o un registro en los historiales médicos del sujeto (p. ej., gráficas médicas, informe del alta hospitalaria).
4. El sujeto tiene una cardioversión eléctrica programada.
- Los sujetos con FA tras una intervención quirúrgica cardíaca (incluida ablación por catéter) podrán participar en el
estudio siempre que cumplan todos los
demás criterios de inclusión Y que el
tiempo desde la intervención hasta la
aleatorización no sea inferior de 30 días.
El investigador será responsable de
evaluar los riesgos relevantes para el
procedimiento de cardioversión en cada sujeto. |
|
| E.4 | Principal exclusion criteria |
1. AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery [unless the duration of AF post-cardiac surgery is > 30 days, refer to inclusion criterion number 4], ionic disturbances, thyrotoxicosis, pneumonia, severe anemia, etc);
2. No evidence of rhythm other than AF on any ECG or any other available recording (including patient?s notes) for more than 12 consecutive months prior to randomization;
3. Subjects with moderate or severe mitral stenosis, mitral valve rheumatic disease, unresected atrial myxoma, or a mechanical heart valve (subjects with bioprosthetic heart valves and/or valve repair can be included) and/or other conditions, such as PE, considered to be formal indication for conventional anticoagulation;
a. However subjects with AF and valvular heart diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease are allowed in the study;
4. Subjects with a history of LAA closure (either by surgery or by a procedure);
5. Known presence of a thrombus in LAA, LA, left ventricle, aorta or intracardial mass;
6. Subjects with acute myocardial infarction (MI), stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention within the previous 30 days or receiving DAPT regardless of when the event has occurred;
7. Subjects with any contraindication to anticoagulant agents;
8. Signs of bleeding or conditions associated with high risk of bleeding including major surgeries or biopsies in the last 10 days;
9. Subjects with 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 within the previous 10 days; 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;
10. Subjects receiving dual antiplatelet therapy (eg, aspirin plus thienopyridine such as clopidogrel, prasugrel or ticagrelor) or anticipated to receive such therapy;
11. Subjects receiving prohibited concomitant medications (fibrinolytics, non-study anticoagulants other than those used as a bridge to/from study drug), chronic oral or parenteral Non-Aspirin/Non-Steroidal Anti-Inflammatory Drugs (NSAID) use for ? 4 days/week;
12. Subjects receiving chronic cyclosporine therapy;
13. Subjects with active liver disease or persistent (confirmed by repeat assessments at least a week apart) elevation of liver enzymes/bilirubin:
ALT or AST ? 2 x ULN;
TBL ? 1.5 x ULN (however, subjects whose elevated TBL is due to known Gilbert?s syndrome may be included in the study);
14. Subjects with renal failure (end stage renal disease, calculated CrCL < 15 mL/min);
15. Subjects with hemoglobin < 10 g/dL or platelet count < 100000 cells/mcL or white blood cell count < 3000 cells/mcL;
16. Subjects with pre-planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
17. 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;
18. Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breast feeding
Note: Childbearing potential without proper contraceptive measures (i.e., a method of contraception with a failure rate < 1 % during the course of the study (including the observational period). These methods of contraception according
to the note for guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner);
19. Subjects with the following diagnoses or situations:
Active cancer undergoing chemotherapy, radiation or major surgery within the next 3 months;
Significant active concurrent medical illness or infection;
Life expectancy < 6 months;
20. Subjects who are unlikely to comply with the protocol (eg, 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 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. |
1. FA considerada temporal o de naturaleza reversible (como miocarditis, tras cirugía [except duración de FA posterior a cirugía cardíaca > 30 días, ver criterio inclusión n.º 4], alteraciones iónicas, tirotoxicosis, neumonía, anemia grave, etc)
2. Ausencia de signos de ritmo aparte de FA en cualquier ECG o cualquier otro registro disponible (inclu notas del paciente) durante + 12
meses consecutivos antes de aleatorización.
3. "S" ( en adelante "S") con estenosis mitral moderada o intensa, valvulopatía mitral reumática, mixoma auricular no resecado o válvula cardíaca mecánica (se pueden incluir "S" con válvulas cardíacas bioprotésicas y/o reparación valvular) y/u otras afecciones, como embolia pulmonar, considerada como una indicación formal para anticoagulación convencional.
a. Sin embargo se permite participación en el estudio de "S" con FA y enfermedades cardíacas valvulares, como prolapso de la válvula mitral, regurgitación mitral y enfermedad valvular aórtica.
4. "S"con antecedentes de oclusión de orejuela auricular izquierda (mediante cirugía o procedimiento)
5. Presencia conocida de trombo en la LAA, aurícula izquierda, ventrículo izquierdo, aorta o masa intracardiaca
6. "S"con infarto de miocardio agudo, accidente cerebrovascular, síndrome coronario agudo o intervención coronaria percutánea en 30 días previos o reciben tto con antiagregantes plaquetarios doble con independen de cuándo se produjo el acontecimiento
7. "S"con alguna contraindicación para fármacos anticoagulantes
8. Signos de hemorragia o afecciones asociadas a elevado riesgo de hemorragia, inclu cirugías mayores o biopsias en últimos 10 días
9. "S"con problemas asociados con riesgo elevado de hemorragia, como antecedentes de hemorragia intracraneal (espontánea o traumática), hemorragia espontánea intraocular, medular, retroperitoneal o intraarticular; hemorragia gastrointestinal evidente o úlcera activa durante año anterior; traumatismo grave reciente, cirugía mayor o biopsia de órgano profundo en 10 días previos; endocarditis infecciosa activa; hipertensión no controlada (presión arterial [PA] superior a 170/100 mmHg); o trastorno hemorrágico, incluido trastorno hemorrágico o coagulación hereditario o adquirido, conocido o sospechado
10. "S"que reciben tto con antiagregantes plaquetarios doble (p. ej., AA más tienopiridina, como clopidogrel, prasugrel o ticagrelor) o "S" que se prevé q recibirán ese tipo de tto
11. "S"que reciben medicamentos concomitantes prohibidos (anticoagulantes fibrinolíticos fuera del estudio distintos de utilizados como puente con el MI), antiinflamatorios no esteroideos (AINE)/distintos del AA crónicos orales o parenterales durante >= 4 días/semana
12. "S"que reciban tto crónico con ciclosporina
13. "S"con enfermedad hepática activa o aumento persistente (confirmado por evaluaciones repetidas con al menos una semana de diferencia) de enzimas hepáticas o bilirrubina: Alanina transaminasa o aspartato transaminasa >=2 veces el límite superior de la normalidad (LSN) Bilirrubina total (BLT) >= 1,5 veces el LSN ( podrán incluirse "S" con BLT elevada por síndrome de Gilbert)
14. "S"con insuficiencia renal (enfermedad renal en estadio terminal, CrCL calculado < 15 ml/min)
15. "S"con hemoglobina < 10 g/dl o recuento de plaquetas < 100.000 células/mcl o recuento de leucocitos < 3000 células/mcl
16. "S" con intervenciones invasivas previa programadas (Exc.endoscopia de rutina) o cirugías que prevea hemorragia durante el estudio
17. "S" que hayan recibido cualquier fármaco o dispositivo en investigación en 30 días previos a aleatorización o planeen recibir dicha tto durante el estudio
18. Mujeres en edad fértil sin medidas anticonceptivas adecuadas, y embarazadas o en lactancia
Nota: En edad fértil sin medidas anticonceptivas adecuadas (es decir, método anticonceptivo con tasa de fracaso < 1 % durante todo el estudio [incl p.observación]) Estos métodos según nota orientativa sobre estudios preclínicos de seguridad para la realización de ensayos de productos farmacéuticos en humanos (CPMP/ICH/286/95, modificada) incluyen uso coherente y correcto de implantes e inyectables con hormonas, anticonceptivos orales combinados, dispositivos intrauterinos hormonales, esterilización quirúrgica, abstinencia sexual y vasectomía en pareja masculina
19. "S" con siguientes diagnósticos o situaciones: Cáncer activo sometido a quimioterapia, radiación o cirugía mayor en 3 meses previos
Enfermedad o infección concomitante activa significativa Esperanza de vida < 6 meses
20. "S" que probablemente no cumplirán con protocolo (p.ej., actitud poco cooperativa, imposibilidad de regresar para visitas posteriores y/o que el Inv. considere poco probable que completen el estudio por otro motivo)
21. "S" con dependencia conocida al alcohol o drogas en últimos 12 meses, a criterio del Inv
22. "S" con cualquier enfermedad que, a criterio del Inv., pondría al sujeto en mayor riesgo de daño si participara en el estudio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
- Stroke, SEE, MI and CV mortality
Primary safety endpoint
- Major or CRNM bleedings |
Criterios principales de valoración de la eficacia
- Accidente cerebrovascular, EES, IM y mortalidad CV
Criterios principales de valoración de la seguridad
- Hemorragias importantes y CRNM |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
TEE-Guided Stratum: Day -3 (randomisation) to Day 58 (discontinuation visit/follow up)
Non-TEE-Guided Stratum: Day -21 (randomisation) to Day 58 (discontinuation visit/follow up) |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoint
? All-cause mortality
Secondary safety endpoints
? All bleedings |
Criterios secundarios de valoración de la eficacia
- Mortalidad por cualquier causa
Criterios secundarios de valoración de la seguridad
- Cualquier hemorragia |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
TEE-Guided Stratum: Day -3 (randomisation) to Day 58 (discontinuation visit/follow up)
Non-TEE-Guided Stratum: Day -21 (randomisation) to Day 58 (discontinuation visit/follow up) |
Estrato guiado por ETE: Día -3 ( Aleatorización ) a Día 58 ( Visita de
interrupción/ seguimiento)
Estrato no guiado por ETE: Día -21 ( Aleatorización ) a Día 58 ( Visita de
interrupción/ seguimiento) |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| 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 | 199 |
| 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 |
| Bulgaria |
| Canada |
| Denmark |
| France |
| Italy |
| Austria |
| Netherlands |
| Romania |
| Sweden |
| Czech Republic |
| Germany |
| Hungary |
| Spain |
| Israel |
| Poland |
| Russian Federation |
| Ukraine |
| 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
|
| Last subject last follow up. |
| últimos seguimiento del último paciente. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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