| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Device-detected sub-clinical atrial fibrillation |
| Fibrilación auricular subclínica detectada por un dispositivo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sub-clinical atrial fibrillation detected by pacemaker, ICD or loop recorder |
| Fibrilación auricular subclínica detectada por un marcapasos, un ICD o un monitor cardíaco implantable (ICM) |
|
| 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.1.3 | 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, when compared to aspirin, will reduce the incidence of stroke and systemic embolism in patients with sub-clinical atrial fibrillation (SCAF). |
| Determinar si el uso de apixabán en pacientes con SCAF reducirá la incidencia de ictus y embolia sistémica en comparación con la aspirina en pacientes con fibrilación auricular subclínica detectada por un dispositivo |
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate the safety of apixaban compared to aspirin with respect to major bleeding in patients with device-detected sub-clinical atrial fibrillation. |
| Demostrar la seguridad de apaxibán en comparación don aspirina en relación a hemorragia importante en pacientes con fibrilación auricular subclínica detectada por un dispositivo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF
2. At least one episode of device-detected SCAF ? 6 minutes in duration (atrial rate > 175/min if an atrial lead is present), but no single episode > 24 hours in duration at any time prior to enrollment. SCAF requires electrogram confirmation (at least one episode) unless ? 6 hours in duration
3. Age ? 18 years
4. CHADS2-VASc score of ? 4 |
1. Marcapasos o desfibrilador permanentes (con o sin
resincronización) o monitor cardíaco implantable capaces de
detectar SCAF
2. Al menos un episodio de SCAF detectado por el dispositivo de 6
minutos o más de duración (Frecuencia auricular > 175/min si hay
un cable auricular presente), pero sin ningún episodio individual >
24 horas de duración en cualquier momento antes de la selección.
SCAF requiere confirmación mediante electrograma (al menos un
episodio) salvo que sea de ≥ 6 horas de duración
3. Edad ≥ 18 años
4. Puntuación CHA2DS2-VASc ≥ 4 |
|
| E.4 | Principal exclusion criteria |
1. Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ? 6 minutes, with or without clinical symptoms
2. Mechanical valve prosthesis, recent (within past 6 months) deep vein thrombosis or pulmonary embolism or other condition requiring treatment with an anticoagulant
3. Allergy to aspirin or apixaban
4. Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 ?mol/L] or a calculated creatinine clearance < 25 ml/min)
5. Serious bleeding in the last 6 months or at high risk of bleeding (this includes, but is not limited to: prior intracranial hemorrhage, active peptic ulcer disease, clinically significant thrombocytopenia or anemia, recent stroke within past 10 days, documented hemorrhagic tendencies or blood dyscrasias)
6. Moderate to severe hepatic impairment
7. Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors)
8. Meets criteria for requiring lower dose of apixaban AND also has ongoing need for strong inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin)
9. Ongoing need for strong dual inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John's wort)
10. Received an investigational drug in the past 30 days
11. Participants considered by the investigator to be unsuitable for the study for any of the following reasons:
? Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment
? Unwilling to attend study follow-up visits
? Life expectancy less than 2 years due to concomitant disease
12. Women who are pregnant, breast-feeding or of child-bearing potential without an acceptable form of contraception in place (sterilization, abstinence or other method with less than 1% failure rate) |
1. Fibrilación auricular clínica documentada por ECG de superficie
(ECG de 12 derivaciones, Telemetría, Holter) de ≥ 6 minutos de
duración, con o sin síntomas clínicos
2. Prótesis de válvula mecánica, trombosis venosa profunda o
embolia pulmonar recientes (en el plazo de los últimos 6 meses) u
otra afección que requiere tratamiento con un anticoagulante
3. Alergia a la aspirina o al apixabán
4. Insuficiencia renal grave (creatinina sérica > 2,5 mg/dl [221
μmol/L] o aclaramiento de creatinina calculado < 25 ml/min)
5. Sangrado grave en los últimos 6 meses o con alto riesgo de
sangrado (esto incluye, por ejemplo: hemorragia intracraneal
previa, enfermedad de úlcera péptica activa, trombocitopenia o
anemia clínicamente significativas, ictus reciente en los últimos
10 días, tendencias hemorrágicas o discrasias sanguíneas
documentadas)
6. Insuficiencia hepática de moderada a grave
7. Necesidad continua de tratamiento combinado con aspirina y
clopidogrel (u otra combinación de dos inhibidores de plaquetas)
8. Cumple con los criterios para requerir una dosis más baja de
apixabán Y también tiene una necesidad continua de inhibidores
potentes tanto de CYP3A4 como de P-glicoproteína (por ejemplo,
ketoconazol, itraconazol, ritonavir o claritromicina)
9. Necesidad continua de inductores duales potentes tanto de
CYP3A4 como de P-glicoproteína (por ejemplo, rifampicina,
carbamazepina, fenitoína, hierba de San Juan)
10. Haber recibido un fármaco en investigación en los últimos 30
días
11. Participantes que el investigador considere que no son
adecuados para el estudio por cualquiera de los siguientes
motivos:
No conformes con el tratamiento con aspirina o apixabán o que
se prevé tendrán un mal cumplimiento del tratamiento
farmacológico en estudio.
No dispuestos a asistir a las visitas de seguimiento del estudio
Expectativa de vida de menos de 2 años debido a una
enfermedad concomitante
12. Mujeres embarazadas, en período de lactancia o en edad fértil
sin una forma adecuada de anticoncepción (esterilización,
abstinencia u otro método con una tasa de fracaso inferior al 1%) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy outcome is a composite of stroke and systemic embolism.
The primary safety outcome will be the occurrence of clinically overt major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria:
1. Fatal bleeding
2. Symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial or intramuscular with compartment syndrome, and/or
3. Bleeding causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells. |
La variable de seguridad primaria será el hecho de una hemorragia importante clínicamente
manifiesta según lo definido por los criterios de ISTH:
1. Hemorragia fatal, o
2. Hemorragia sintomática en un área u órgano crítico, como intracraneal, intraespinal,
intraocular, retroperitoneal, intraarticular o pericárdica, o intramuscular con síndrome
compartimental, y/o
3. Hemorragia que provoca una caída en el nivel de hemoglobina de 2 g/dl o más, o que
conduce a la transfusión de dos o más unidades de sangre entera o glóbulos rojos. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time to first event during the study follow-up period. The study will be event driven and will continue until 248 primary events have occurred, which is anticipated with average patient follow-up of 36 months. |
| Tiempo hasta el primer evento durante el periodo de seguimiento del estudio. El estudio estará determinado por eventos y continuará hasta que se hayan producido 248 eventos primarios, que se prevé se producirán cuando el seguimiento promedio del paciente sea de aproximadamente 36 meses. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints include:
1. Ischemic stroke
2. Myocardial infarction
3. Vascular death
4. Total death (vascular and non-vascular)
5. Composite of stroke, myocardial infarction, systemic embolism and total death
6. Composite of stroke, myocardial infarction, systemic embolism, total death and major bleeding |
Las variables secundarias incluirán:
1. Ataque isquémico
2. Infarto de miocardio
3. Muerte vascular
4. Muerte total (vascular y no vascular)
5. Compuesto de ictus, infarto de miocardio, embolia sistémica y muerte total
6. Compuesto de ictus, infarto de miocardio, embolia sistémica, muerte total y hemorragia
importante |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints of evaluation will every six months for the duration of study (estimated to be an average 36 months of follow-up). |
| Evaluaciones cada seis meses para la duración total del estudio (se estiman 36 meses de 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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| Switzerland |
| 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
|
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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