E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial Fibrillation |
Fibrilación auricular |
|
E.1.1.1 | Medical condition in easily understood language |
Atrial Fibrillation |
Fibrilación auricular |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053468 |
E.1.2 | Term | Anticoagulant therapy |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 evaluate that the oral FXIa inhibitor BAY 2433334 when compared to apixaban leads to a lower incidence of bleeding in participants with AF |
Evaluar que el inhibidor del FXIa de administración por vía oral BAY 2433334 en comparación con apixabán conduce a una menor incidencia de hemorragia en participantes con FA |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participant must be 45 years of age or older at the time of signing the informed consent. 2. Participant with AF documented by ECG evidence with • CHA2DS2-VASc score ≥ 2 if male or CHA2DS2-VASc score ≥ 3 if female • Indication for treatment with an oral anticoagulant in • any participant currently not treated with an oral anticoagulant (e.g. treatment naïve) or alternatively, • participant on a NOAC in case of at least one bleeding risk feature (history of a prior bleed within the last 12 months requiring medical attention and / or moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically indicated antiplatelet therapy with ASA ≤ 100 mg) |
1. El participante debe tener una edad igual o superior a 45 años en el momento de firmar el consentimiento informado. 2. Participante con FA confirmada por ECG con: • Puntuación en la escala CHA2DS2-VASc ≥2 para los varones o CHA2DS2-VASc ≥3 para las mujeres. • Indicación de tratamiento con un anticoagulante de administración por vía oral en: •cualquier participante que no esté recibiendo tratamiento actualmente con un anticoagulante de administración por vía oral (p. ej., sin tratamiento previo) o, por otra parte, •participante en tratamiento con un NACO en caso de al menos una manifestación de riesgo de hemorragia (antecedentes de hemorragia previa en los últimos 12 meses que requirió atención médica, y/o disfunción renal moderada con TFGe 30-50 ml/min, y/o tratamiento actual con antiagregantes plaquetarios por indicación clínica con AAS ≤100 mg). |
|
E.4 | Principal exclusion criteria |
1. Mechanical heart valve prosthesis 2. Any degree of rheumatic mitral stenosis or moderate-to-severe, non-rheumatic mitral stenosis 3. Atrial fibrillation due to a reversible cause, participants in sinus rhythm after successful ablation, or plan for cardioversion or ablation during study conduct 4. Stroke within the last 30 days of screening 5. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) at randomization 6. Active bleeding; known bleeding disorder 7. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or hepatic insufficiency classified as Child-Pugh B or C, or ALT/AST > 2.5 x the upper limit of normal, measured between screening and randomization 8. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, calculated by Modification of Diet in Renal Disease (MDRD) formula, determined between screening and randomization 9. Major surgery during the last 30 days or planned major surgery or intervention within study period (e.g. carotid endarterectomy, coronary artery bypass grafting) 10. Known allergy, intolerance or hypersensitivity to either of the study interventions (active substance or excipients) 11. Any contraindication for the use of an anticoagulant or listed in the local labeling for apixaban 12. Requirement for chronic anticoagulation (for a different indication than AF e.g. mechanical heart valve or cardiac thrombus) or antiplatelet therapy (up to 100 mg ASA is allowed). Anticipated need for chronic (more than 4 weeks) therapy with NSAIDs 13. Treated with a Vitamin K antagonist in the 30 days prior to screening 14. Concomitant use of any of the following therapies within 14 days (or at least five half-lives of the active substance whatever is longer) before randomization and first study intervention administration: • Strong inhibitors of cytochrome P450 isoenzyme 3A4 (CYP3A4) e.g. human immunodeficiency virus protease inhibitors, systemically used azole-antimycotic agents, clarithromycin or telithromycin • Strong inducers of CYP3A4, e.g. phenytoin, carbamazepine, phenobarbital, rifampicin or St. John’s wort. 15. Women of childbearing potential (women are considered of childbearing potential if they are not surgically sterile or postmenopausal, defined as amenorrhea for > 12 months). Male participants not willing to use condoms when sexually active with a woman of childbearing potential |
1. Prótesis mecánica valvular cardíaca 2. Cualquier grado de estenosis mitral reumática o estenosis mitral no reumática moderada o grave 3. Fibrilación auricular debida a una causa reversible, los participantes en ritmo sinusal después de una ablación satisfactoria o plan de cardioversión o ablación durante la realización del estudio 4. Ictus en los últimos 30 días respecto a la selección 5. Hipertensión no controlada (presión arterial sistólica ≥160 mmHg o presión arterial diastólica ≥100 mmHg) en el momento de la aleatorización 6. Hemorragia activa; trastorno hemorrágico conocido 7. Hepatopatía significativa conocida (p. ej., hepatitis aguda, hepatitis crónica activa, cirrosis) o insuficiencia hepática clasificada como Child-Pugh B o C (ver apartado 10.6), o ALT/AST >2,5 veces el límite superior de la normalidad, medido entre la selección y la aleatorización 8. Tasa de filtración glomerular estimada (TFGe) <30 ml/min/1,73 m2, calculada mediante la fórmula del estudio Modification of Diet in Renal Disease (MDRD, Modificación de la dieta en la enfermedad renal), determinada entre la selección y la aleatorización 9. Cirugía mayor durante los últimos 30 días o intervención o cirugía mayor programadas dentro del período de estudio (por ejemplo, endarterectomía carotídea, revascularización coronaria) 10. Alergias, intolerancias o hipersensibilidades conocidas a cualquiera de las intervenciones del estudio (principio activo o excipientes) 11. Cualquier contraindicación para el uso de un anticoagulante o que figure en la ficha técnica local del apixabán 12. Requisito de tratamiento crónico con anticoagulantes (para una indicación diferente a la FA, por ejemplo, válvula cardíaca mecánica o trombo cardíaco) o tratamiento con antiagregantes plaquetarios (se permiten hasta 100 mg de AAS). Necesidad prevista de tratamiento crónico (más de 4 semanas) con AINE 13. Se ha recibido tratamiento con un antagonista de la vitamina K en los 30 días previos a la selección 14. Uso concomitante de cualquiera de los siguientes tratamientos en los 14 días (o al menos cinco semividas del principio activo, lo que sea más largo) previos a la aleatorización y la primera administración de la intervención del estudio: • Inhibidores potentes de la isoenzima 3A4 del citocromo P450 (CYP3A4), por ejemplo, inhibidores de la proteasa del virus de la inmunodeficiencia humana, antimicóticos azólicos utilizados sistémicamente, claritromicina o telitromicina • Inductores potentes de CYP3A4, por ejemplo, fenitoína, carbamazepina, fenobarbital, rifampicina o hierba de San Juan 15. Mujeres en edad fértil (se considera que una mujer se encuentra en edad fértil si no se ha sometido a esterilización quirúrgica o es posmenopáusica, definida como >12 meses de amenorrea). Participantes varones que no están dispuestos a usar preservativos cuando sean sexualmente activos con una mujer en edad fértil |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Composite of ISTH major and clinically relevant non-major bleeding |
Combinación de hemorragias graves y de hemorragias no graves clínicamente relevantes según la International Society on Thrombosis and Hemostasis (ISTH, Sociedad Internacional de Trombosis y Hemostasia) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Visit 2 (randomization visit) until Visit 7 (safety follow-up visit) |
Desde la Visita 2 (aleatorización) hasta la Visita 7 (visita de seguimiento de seguridad) |
|
E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints: • All bleeding • ISTH major bleeding • ISTH clinically relevant non-major bleeding • ISTH minor bleeding |
Criterios secundarios de valoración de la seguridad: • todas las hemorragias • hemorragia grave según la ISTH • hemorragia no grave clínicamente relevante según la ISTH • hemorragia leve según la ISTH |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Visit 2 (randomization visit) until Visit 7 (safety follow-up visit) |
Desde la Visita 2 (aleatorización) hasta la Visita 7 (visita de seguimiento de seguridad) |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Con doble enmascaramiento, de determinación de dosis |
Double dummy - Dose-finding |
|
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 | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 87 |
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 |
Czech Republic |
France |
Hungary |
Italy |
Japan |
Latvia |
Netherlands |
Spain |
Sweden |
Switzerland |
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 |
Última visita 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 | 4 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 7 |