E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention |
Fibrilación auricular y síndrome coronario agudo o intervención coronaria percutánea |
|
E.1.1.1 | Medical condition in easily understood language |
atrial fibrillation and heart attacks with a coronary stent placement (PCI = percutaneous coronary intervention) OR after having elective PCI for chest pain. |
fibrilación auricular y ataques al corazón con una colocación de stent coronario (ICP = intervención coronaria percutánea) o después de tener una ICP opcional para el dolor de pecho. |
|
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 | 19.0 |
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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051592 |
E.1.2 | Term | Acute coronary syndrome |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065608 |
E.1.2 | Term | Percutaneous coronary intervention |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
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 determine if apixaban is noninferior to VKA (INR target range 2.0-3.0) on the combined endpoint of ISTH major and clinically relevant non-major bleeding in patients with NVAF who develop ACS or undergo PCI with planned concomitant P2Y12 inhibitor therapy.
- To determine if anticoagulant plus single antiplatelet therapy with a P2Y12 inhibitor is superior to anticoagulant plus dual antiplatelet therapy with a P2Y12 inhibitor and aspirin on the combined outcome of ISTH major and
clinically relevant non-major bleeding in patients with NVAF who develop ACS or undergo PCI with planned concomitant P2Y12 inhibitor therapy. |
• Determinar si apixabán es no inferior al AVK (intervalo del objetivo de CIN de 2,0 a 3,0) en cuanto al criterio de valoración combinado de hemorragia grave y hemorragia no grave pero clínicamente relevante según la ISTH en pacientes con FANV que presenten un SCA o precisen una ICP con tratamiento concomitante programado con un inhibidor de P2Y12.
• Determinar si el anticoagulante más el tratamiento antiagregante plaquetario simple con un inhibidor de P2Y12 es superior al tratamiento antiagregante plaquetario doble con un inhibidor de P2Y12 y aspirina en cuanto al resultado combinado de hemorragia grave y hemorragia no grave pero clínicamente relevante según la ISTH en pacientes con FANV que presenten un SCA o precisen una ICP con tratamiento anticoagulante concomitante. |
|
E.2.2 | Secondary objectives of the trial |
To compare apixaban and VKA (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who develop ACS or undergo PCI, with respect to:
- Superiority on major or clinically relevant non-major (CRNM) bleeding
- Death, stroke, myocardial infarction, stent thrombosis, or urgent revascularization
- Re-hospitalization (time to first re-hospitalization) for any cause
To compare aspirin and aspirin placebo (with concomitant P2Y12 inhibitor therapy), in patients with NVAF who develop ACS or undergo PCI with respect to:
- Death, stroke, myocardial infarction, stent thrombosis, or urgent revascularization
- Re-hospitalization (time to first re-hospitalization) for any cause |
Comparar apixabán y AVK (con tratamiento concomitante con un inhibidor de P2Y12), en pacientes con FANV que presenten un SCA o precisen una ICP, con respecto a:
• Superioridad en cuanto a hemorragia grave o no grave pero clínicamente relevante (NGCR).
• Muerte, ictus, infarto de miocardio, trombosis de endoprótesis o revascularización urgente.
• Re-hospitalización (tiempo hasta la primera re-hospitalización) por cualquier causa.
Comparar aspirina y placebo de aspirina (con tratamiento concomitante con un inhibidor de P2Y12), en pacientes con FANV que presenten un SCA o precisen una ICP, con respecto a:
• Muerte, ictus, infarto de miocardio, trombosis de endoprótesis o revascularización urgente.
• Re-hospitalización (tiempo hasta la primera re-hospitalización) por cualquier causa. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent.
2. Target Population
a) Males and females 18 years of age (or age of majority) or older with either active or a
history of non-valvular atrial fibrillation or flutter with the planned or existing use of an
oral anticoagulant for prophylaxis of thromboembolism.
b) Must have had an acute coronary syndrome (ST-elevation myocardial infarction
[STEMI], non-ST-elevation myocardial infarction [NSTEMI], or unstable angina), within
the prior 14 days
c) Planned use of an approved P2Y12 inhibitor for at least 6 months.
3. Subject Re-enrollment:
a) This study does permit the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (screen failure).
4. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
b) Women must not be breastfeeding
c) WOCBP must agree to use effective contraception for the duration of treatment with study drugs plus
i. 33 days for patients on apixaban
ii. 40 days for patients on warfarin
d) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. |
1. Firma del consentimiento informado por escrito
a) Se proporcionará un consentimiento informado por escrito a los pacientes
2.Población Objetivo
a) Mujeres y hombres de 18 años de edad (o mayores de edad) con presencia activa o antecedentes de fibrilación o aleteo auricular no valvular que estén usando o tengan previsto usar un anticoagulante oral para la prevención de tromboembolias
b) Haber tenido un síndrome coronario agudo (infarto de miocardio con elevación del ST [IMCEST], infarto de miocardio sin elevación del ST [IMSEST] o angina inestable) en los 14 días anteriores
c)Tener previsto el uso de un inhibidor aprobado del P2Y12 durante al menos seis meses
3. Reclutamiento de Pacientes:
a) Este estudio permite el reclutamiento de pacientes que hayan discontinuado el estudio debido a un fallo previo al tratamiento (fracaso de seleccion).
4. Edad y capacidad reproductiva
a) Las mujeres en edad fértil (MEF) deben obtener un resultado negativo en una prueba de embarazo en suero u orina (sensibilidad mínima de 25 UI/l o unidades equivalentes de hCG) realizada en las 24 horas previas al inicio de la administración del fármaco del estudio.
b)Las mujeres no deben estar dando el pecho
c)Las MEF deben estar de acuerdo en usar métodos anticonceptivos eficaces durante el tratamiento con medicamentos del estudio además de
i. 33 días para los pacientes tratados con apixaban
ii. 40 días para los pacientes tratados con warfarina
d) Los varones con azoospermia y las MEF que no tengan en ningún momento actividad heterosexual están exentos de los requisitos sobre anticonceptivos. Sin embargo, las MEF deben seguir haciéndose pruebas de embarazo como se describe en esta sección.
Los investigadores deben insistir a las MEF y a los varones que mantengan relaciones sexuales con MEF en la importancia de la prevención del embarazo y las consecuencias de un embarazo imprevisto. Los investigadores deben aconsejar a las MEF y a los varones que mantengan relaciones sexuales con MEF sobre el uso de métodos |
|
E.4 | Principal exclusion criteria |
- Conditions other than atrial fibrillation that require chronic anticoagulation (eg, prosthetic mechanical heart valve)
- Severe renal insufficiency (serum creatinine > 2.5 [221 micromol/L] or a calculated creatinine clearance < 30 mL/min
- Patients with any history of intracranial hemorrhage
- Any contraindications to warfarin, apixaban, to intended P2Y12 inhibitors or to aspirin
- Patients who have or will undergo coronary arterial bypass graft (CABG) for their index
ACS event
- Patients with known ongoing bleeding
- Patients with known coagulopathies |
• Trastornos distintos de la fibrilación auricular que precisen tratamiento crónico con anticoagulantes (por ejemplo, prótesis valvular mecánica).
• Insuficiencia renal grave (creatinina sérica > 2,5 [221 micromol/l] o aclaramiento calculado de la creatinina < 30 ml/min
• Pacientes con antecedentes de hemorragia intracraneal
• Cualquier contraindicación para recibir warfarina, apixabán, inhibidores de P2Y12 programados o aspirina
• Injerto de derivación aortocoronaria (IDAC) reciente o previsto por el episodio de SCA de referencia
• Pacientes con hemorragia persistente conocida
• Pacientes con coagulopatías conocidas |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints (safety):
The primary endpoint for apixaban versus VKA is
- ISTH major or CRNM bleeding
The primary endpoint for aspirin versus placebo is
- ISTH major or CRNM bleeding |
Criterios de valoración principales (seguridad):
El criterio de valoración principal para la comparación de apixabán con AVK es
• Hemorragia grave o NGCR según la ISTH
El criterio de valoración principal para la comparación de aspirina con placebo es
• Hemorragia grave o NGCR según la ISTH |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
A blinded assessment of the primary endpoint event rate will be performed after 50% of subjects have completed the study (please refer to Protocol section 8.1). |
Se realizará una evaluación enmascarada de la tasa de episodios del criterio de valoración principal después de que el 50% de los sujetos haya finalizado el estudio (por favor refiérase a la sección 8.1 del Protocolo). |
|
E.5.2 | Secondary end point(s) |
The secondary endpoint for apixaban versus VKA includes
- Superiority on major or CRNM bleeding
- The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent revascularization
- First re-hospitalization for any cause
The secondary endpoint for aspirin versus placebo includes
- The composite endpoints of death, stroke, myocardial infarction, stent thrombosis, urgent revascularization
- First re-hospitalization for any cause |
Los criterios de valoración secundarios para la comparación de apixabán con AVK son:
• Superioridad en cuanto a hemorragia grave o NGCR
• Resultados combinados de muerte, ictus, infarto de miocardio, trombosis de endoprótesis o revascularización urgente.
• Primera rehospitalización por cualquier causa.
Los criterios de valoración secundarios para la comparación de aspirina con placebo son
• Resultados combinados de muerte, ictus, infarto de miocardio, trombosis de endoprótesis o revascularización urgente.
• Primera rehospitalización por cualquier causa. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Protocol section 8.1 |
Por favor refiérase a la sección 8.1 del Protocolo. |
|
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 | Yes |
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) | 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 | No |
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 | Yes |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 253 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Croatia |
Czech Republic |
Denmark |
Germany |
Hungary |
India |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Norway |
Peru |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
Spain |
Sweden |
Switzerland |
Ukraine |
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
|
LVLS |
Ultima visita del ultimo paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |