| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Valvular Atrial Fibrillation (NVAF) |
| Fibrilación auricular no valvular (FANV) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Abnormal and irregular, often rapid heart rate with no evidence of moderate or severe damage of the heart valves |
| Ritmo cardíaco anormal e irregular, a menudo rápido, sin evidencia de daño moderado o grave de las válvulas del corazón |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to compare the exposure (based on average concentration at steady state (Cav), minimum concentration in plasma (Cmin), and anti-factor Xa [anti-FXa]) of edoxaban 75 mg once daily (QD) dose to edoxaban 60 mg QD dose in NVAF anticoagulant-naïve patients with CHADS2 score of ≥ 2 and CrCL > 100 mL/min (as calculated by the Cockcroft-Gault formula) treated for up to 12 months. |
| El Objetivo principal es comparar la exposición (en función de la concentración media en situación de equilibrio [Cmed], concentración mínima en plasma [Cmín] y anti-factor Xa [anti-FXa]) de una dosis de 75 mg de edoxabán una vez al día (1 v/d) con la dosis de 60 mg de edoxabán 1 v/d en pacientes con FANV que no han sido tratados anteriormente con anticoagulantes, con una puntuación CHADS2 ≥ 2 y ACr > 100 ml/min (según se calcula mediante la fórmula de Cockcroft-Gault), tratados durante un periodo de hasta 12 meses |
|
| E.2.2 | Secondary objectives of the trial |
-Provide an assessment of exposure based on a validated anti-FXa assay using edoxaban calibrators and controls and edoxaban concentration based on liquid chromatography/tandem mass spectrometry;
-Provide an overall assessment of the patients’ coagulation state based on the PD biomarkers: intrinsic FX, prothrombin time (PT) and activated partial prothromboplastin time ( aPTT);
-Investigate the relationship between exposure Proprietary and Confidential
4 (anti-FXa activity, edoxaban concentrations) and PD biomarkers (intrinsic FX, PT, aPTT).
-Evaluate stroke/transient ischemic attack (TIA) and systemic embolic events (SEE);
-Evaluate the net clinical outcome (composite of stroke/TIA, SEE, myocardial infarction (MI), cardiovascular death, major bleeding);
-Evaluate the incidence of major (including intracranial) and Clinically Relevant Non-Major [CRNM]) bleeding;
-Evaluate the incidence of stroke/ TIA and SEE excluding haemorrhagic stroke. |
Proporcionar una evaluación de la exposición basada en un ensayo anti-FXa validado mediante calibradores y controles de edoxabán y concentración de edoxabán en función de la cromatografía líquida/espectrometría de masas en tándem y general del estado de coagulación del paciente en función de los biomarcadores FD: FX intrínseco, tiempo de protrombina (TP) y tiempo de protromboplastina parcial activada (TTPa)
Estudiar la relación entre la exposición (actividad anti-FXa, concentraciones de edoxabán) y los biomarcadores FD (FX intrínseco, TP, TTPa)
Evaluar los accidentes cerebrovasculares/accidentes isquémicos transitorios (AIT) y acontecimientos embólicos sistémicos (AES)
Evaluar el resultado clínico neto (compuesto por accidente cerebrovascular/AIT, AES, infarto de miocardio [IM], muerte cardiovascular, hemorragia grave) y la incidencia de hemorragia grave (incluida intracraneal) y no grave clínicamente relevante (NGCR)
Evaluar la incidencia de accidente cerebrovascular/AIT y AES |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients older than the minimum legal adult age (country specific) who have signed an informed consent form for the study;
2. History of non-valvular AF documented by any electrical tracing (routine 12-lead electrocardiogram [ECG], Holter monitor [continuous ECG recording] rhythm strip, intracardiac electrogram, or pacemaker [PM] or implantable cardiac defibrillator [ICD] interrogation) within the prior 12 months and for which anticoagulation therapy is indicated and planned for the duration of the study;
3. Patient’s with creatinine clearance (CrCL) > 100 mL/min as measured by the Cockcroft-Gault formula. This criterion must be confirmed by a test result from the study central laboratory prior to randomization;
4. Patient has a CHADS2 score of ≥ 2 at the time of randomization;
5. Patient’s weight is > 60 Kg on the day of randomization;
6. Patient is considered as “anticoagulant naïve” if he/she has never received any oral anticoagulant therapy (VKA or non-VKA oral anticoagulant) in the past or has not received any oral anticoagulant within 30 days prior to randomization. |
1. Pacientes de ambos sexos mayores de la edad legal mínima (específica del país) que hayan firmado el formulario de consentimiento informado del estudio.
2. Antecedentes de FA no valvular documentada por un registro eléctrico (electrocardiograma de 12 derivaciones de rutina [ECG], tira de ritmo del monitor Holter [registro continuo de ECG], electrocardiograma intracardíaco o lecturas del marcapasos [MP] o del desfibrilador cardíaco implantable [DCI]) en los 12 meses previos y para los que se indica y planifica tratamiento con anticoagulantes durante todo el estudio.
3. Pacientes con aclaramiento de creatinina (ACr) > 100 ml/min determinado mediante la fórmula de Cockcroft-Gault. Este criterio debe confirmarse mediante un resultado analítico del laboratorio central del estudio antes de la aleatorización.
4. Pacientes con una puntuación CHADS2 ≥ 2 en el momento de la aleatorización.
5. Peso del paciente > 60 kg el día de la aleatorización.
6. Pacientes no tratados anteriormente con anticoagulantes (definido como no haber recibido nunca anticoagulantes o con INR < 2 en el momento de la aleatorización si están tomando antagonistas de la vitamina K [AVK] o no haber recibido una dosis terapéutica de ningún anticoagulante oral directo [ACOD]) durante al menos 3 días consecutivos antes del día de la selección. |
|
| E.4 | Principal exclusion criteria |
1. Patients with moderate or severe mitral stenosis, mitral valve rheumatic disease, unresected atrial myxoma, or a mechanical heart valve (patients with bioprosthetic heart valves and/or valve repair can be included) and/or other conditions, such as pulmonary embolism, considered to be a formal indication for conventional anticoagulation;
However patients with AF and valvular heart diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease are allowed in the study as long as they are of non-rheumatic nature
2. Patients with acute myocardial infarction, acute coronary syndrome, or percutaneous coronary intervention within the previous 30 days, or ischemic stroke within the previous 7 days; subjects with ischemic stroke more than 7 days prior to randomization can be included provided there is no evidence of haemorrhagic transformation
3. Patients with any contraindication to anticoagulant agents;
4. Patients with conditions associated with high risk of bleeding such as a past history of intracranial (spontaneous or traumatic), spontaneous intraocular, spinal, retroperitoneal or intra-articular bleeding; overt gastrointestinal 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;
5. Patients receiving dual antiplatelet therapy (eg, aspirin plus thienopyridine such as clopidogrel, prasugrel, or ticagrelor) or anticipated to receive such therapy;
6. Patients receiving prohibited concomitant medications (fibrinolytics, non-study anticoagulants), chronic oral or parenteral Non-Aspirin/Non-Steroidal Anti-Inflammatory Drugs (NSAID) use for ≥ 4 days/week;
7. Patients that are either receiving or are planned to receive the following oral P-gp inhibitors concomitantly: ciclosporine, dronedarone, erythromycin, or ketoconazole (topical formulations of ketoconazole or erythromycin are allowed);
8. Patients with severe hepatic impairment or hepatic disease associated with coagulopathy (eg, acute hepatitis, chronic active hepatitis, cirrhosis);
9. Patients with known liver disease and with a combination of alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) and total bilirubin (TBL) > 1.5 x ULN;
10. Patients with hemoglobin < 10 g/dL or platelet count < 100,000 cells/mcL or white blood cell count < 3000 cells/mcL;
11. Patients with planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
12. Patients who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period;
13. Women of childbearing potential not using proper contraceptive measures, and women who are pregnant or breast feeding;
Note: Childbearing potential without proper contraceptive measures (ie, 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);
14. Patients 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 < 12 months.
15. Patients who are unlikely to comply with the protocol (eg, unable to swallow tablets whole uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study);
16. Patients with a known drug or alcohol dependence within the past 12 months as judged by the Investigator;
17. Patients with any condition that, in the opinion of the Investigator, would place the patient at increased risk of harm if he/she participated in the study. |
1. Pacientes con estenosis mitral moderada o grave, enfermedad reumática de la válvula mitral, mixoma auricular no resecado o válvula cardíaca mecánica (puede incluirse a pacientes con válvulas cardíacas bioprotésicas y/o con reparación de válvula), y/u otras afecciones, como embolia pulmonar, consideradas una indicación formal de la anticoagulación convencional.
No obstante, se permite la participación en el estudio de pacientes con FA y enfermedad cardíaca valvular, como prolapso de la válvula mitral, regurgitación mitral y valvulopatía aórtica, siempre y cuando no sean de naturaleza reumática.
2. Pacientes con infarto de miocardio agudo, síndrome coronario agudo, intervención coronaria percutánea en los 30 días previos o accidente cerebrovascular isquémico en los 7 días previos; puede incluirse a pacientes con accidente cerebrovascular isquémico más de 7 días antes de la aleatorización, siempre que no haya evidencias de transformación hemorrágica.
3. Pacientes con cualquier contraindicación a agentes anticoagulantes.
4. Pacientes con afecciones asociadas con un riesgo elevado de hemorragia, como antecedentes de hemorragia intracraneal (espontánea o traumática), intraocular, medular, retroperitoneal o intraarticular espontánea; hemorragia gastrointestinal evidente o úlcera activa durante el año anterior; traumatismo grave reciente, cirugía mayor o biopsia de órgano profundo en los 10 días previos; endocarditis infecciosa activa; hipertensión no controlada (tensión arterial [TA] por encima de 170/100 mmHg) o trastorno hemorrágico, incluido trastorno hemorrágico o de coagulación hereditario o adquirido, conocido o sospechado.
5. Pacientes que estén recibiendo tratamiento antiplaquetario doble (p. ej., ácido acetilsalicílico más tienopiridina como clopidogrel, prasugrel o ticagrelor) o programados para recibir dicho tratamiento.
6. Pacientes que estén recibiendo medicación concomitante prohibida (fibrinolíticos, anticoagulantes que no sean del estudio), uso crónico por vía oral o parenteral de fármacos antiinflamatorios que no sean ácido acetilsalicílico/no esteroideos (AINE) durante ≥ 4 días/semanas.
7. Pacientes que estén recibiendo o tengan programado recibir concomitantemente los siguientes inhibidores de gp-P orales: ciclosporina, dronedarona, eritromicina o ketoconazol (están permitidas las formulaciones tópicas de ketoconazol o eritromicina).
8. Pacientes con insuficiencia hepática grave o enfermedad hepática asociada con coagulopatía (p. ej., hepatitis aguda, hepatitis activa crónica, cirrosis).
9. Pacientes con enfermedad hepática conocida y con una combinación de alanina aminotransferasa (ALT)/aspartato aminotransferasa (AST) > 2 veces el límite superior de la normalidad (LSN) y bilirrubina total (BLT) > 1,5 veces el LSN.
10. Pacientes con hemoglobina < 10 g/dl o recuento de plaquetas < 100 000 células/μl o recuento de leucocitos < 3000 células/μl.
11. Pacientes con procedimientos invasivos programados (excepto la endoscopia de rutina) o cirugías programadas en las que se prevé hemorragia durante el periodo del estudio.
12. Pacientes que hayan recibido cualquier fármaco o dispositivo en investigación en los 30 días anteriores a la aleatorización o que planeen recibir dicho tratamiento en investigación durante el periodo del estudio.
13. Mujeres en edad fértil que no utilicen medidas anticonceptivas adecuadas y que estén embarazadas o en periodo de lactancia.
Nota: Estar en edad fértil y no utilizar métodos anticonceptivos adecuados (es decir, un método anticonceptivo con una tasa de fracaso < 1 % durante el transcurso del estudio, incluido el periodo de observación). Estos métodos anticonceptivos, de acuerdo con la nota orientativa sobre estudios preclínicos de seguridad para la realización de ensayos en humanos para industrias farmacéuticas (CPMP/ICH/286/95, modificación) incluyen el uso sistemático y correcto de hormonas que contienen implantes e inyectables, anticonceptivos orales combinados, dispositivos intrauterinos con hormonas, esterilización quirúrgica, abstinencia sexual y vasectomía de la pareja masculina.
14. Pacientes con los siguientes diagnósticos o situaciones:
Cáncer activo, que se someterán a tratamiento con quimioterapia, radioterapia o cirugía mayor en los próximos 3 meses.
Enfermedad o infección clínica concurrente activa significativa.
Esperanza de vida < 12 meses.
15. Pacientes que probablemente no cumplirán con el protocolo (p. ej., incapaces de tragar los comprimidos enteros debido a una actitud poco cooperativa, con imposibilidad de regresar para visitas posteriores y/o que el investigador considere que probablemente no completarán el estudio por cualquier otro motivo).
16. Pacientes con dependencia conocida al alcohol o las drogas en los últimos 12 meses a criterio del investigador.
17. Pacientes con cualquier enfermedad que, a criterio del investigador, pondría al paciente en un riesgo mayor de sufrir daño si participase en el estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PK/PD Endpoints:
-edoxaban concentration (CAV, Cmin);
-anti-FXa;
-intrinsic FX, PT, aPTT. |
Criterios de valoración FC/FD:
-Concentración de edoxabán (Cmed, Cmín).
-Anti-FXa.
-FX intrínseco, PT, TTPa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 2, 4, 6 and 9. |
| Visita 2, 4, 6, y 9 |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
-composite of stroke/transient ischemic attack (TIA) and SEE (ischemic stroke, hemorrhagic stroke, TIA, and SEE). |
Criterios de valoración de la eficacia:
-Criterios compuestos de accidente cerebrovascular/accidente isquémico transitorio (AIT) y AES (accidente cerebrovascular isquémico, accidente cerebrovascular hemorrágico, AIT y AES). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout study duration |
| A lo largo de la duración del estudio |
|
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 236 |
| 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 |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
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