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    Summary
    EudraCT Number:2016-001795-30
    Sponsor's Protocol Code Number:DU176b-C-E314
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-10-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-001795-30
    A.3Full title of the trial
    Evaluation of Edoxaban in Anticoagulant Naïve Patients with Non-Valvular Atrial Fibrillation (NVAF) and high Creatinine Clearance
    Evaluación de edoxabán en pacientes con fibrilación auricular no valvular (FANV) y aclaramiento de creatinina elevado que no han sido tratados anteriormente con anticoagulantes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Edoxaban in Anticoagulant Naïve patients with normal renal function who are suffering from abnormal and irregular, often rapid heart rate defined as Atrial Fibrillation with no evidence of moderate or severe damage of the heart valves.
    Evaluación de Edoxabán en pacientes no tratados previamente anticoagulante con función renal normal que sufren de ritmo cardíaco anormal e irregular, a menudo rápida definido como la fibrilación auricular, sin evidencia de daño moderado o grave de las válvulas del corazón.
    A.4.1Sponsor's protocol code numberDU176b-C-E314
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDaiichi Sankyo, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDaiichi Sankyo, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo, Inc.
    B.5.2Functional name of contact pointClinical Trial Information Contact
    B.5.3 Address:
    B.5.3.1Street Address399 Thornall Street
    B.5.3.2Town/ cityEdison
    B.5.3.3Post codeNJ 08837
    B.5.3.4CountryUnited States
    B.5.4Telephone number0034670063444
    B.5.6E-maileu_cta@dsi.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDU176b
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEDOXABAN (as anhydrous free form)
    D.3.9.1CAS number 480449-71-6
    D.3.9.3Other descriptive nameEDOXABAN TOSYLATE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB182369
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDU176b
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEDOXABAN (as anhydrous free form)
    D.3.9.1CAS number 480449-71-6
    D.3.9.3Other descriptive nameEDOXABAN TOSYLATE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB182369
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDU176b
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEDOXABAN (as anhydrous free form)
    D.3.9.1CAS number 480449-71-6
    D.3.9.3Other descriptive nameEDOXABAN TOSYLATE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB182369
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-Valvular Atrial Fibrillation (NVAF)
    Fibrilación auricular no valvular (FANV)
    E.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10003658
    E.1.2Term Atrial fibrillation
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    Visit 2, 4, 6 and 9.
    Visita 2, 4, 6, y 9
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA236
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 589
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 572
    F.4.2.2In the whole clinical trial 600
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard Care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-12-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-09
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