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    Summary
    EudraCT Number:2016-003930-26
    Sponsor's Protocol Code Number:DU176B-C-U4001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-04-10
    Trial 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 number2016-003930-26
    A.3Full title of the trial
    Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation – In Atrial Fibrillation. ENVISAGE TAVI-AF
    Edoxaban vs. el tratamiento estándar y sus efectos en los resultados clínicos de pacientes que se han sometido a una cirugía de implante de válvula aórtica transcatéter - en fibrilación auricular
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Edoxaban Treatment Versus VKA in patients with AF undergoing TAVI Procedure in Atrial Fibrillation.
    Tratamiento con Edoxaban vs. tratamiento con antagonistas de la Vitamina K en pacientes que se han sometido a una cirugía de implante de válvula aórtica transcatéter en fibrilación auricular
    A.3.2Name or abbreviated title of the trial where available
    ENVISAGE TAVI-AF
    ENVISAGE TAVI-AF
    A.4.1Sponsor's protocol code numberDU176B-C-U4001
    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 pointMarlen Casabona-Rojas
    B.5.3 Address:
    B.5.3.1Street Address2 Hilton Court
    B.5.3.2Town/ cityParsippany,
    B.5.3.3Post codeNJ 07054
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 973 944 2367
    B.5.5Fax number+1 973 944 2680
    B.5.6E-mailmcasabona-ro@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 Yes
    D.2.1.1.1Trade name Lixiana 60 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameedoxaban
    D.3.2Product code DU-176b
    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
    D.3.9.1CAS number 480449-70-5
    D.3.9.3Other descriptive nameEDOXABAN
    D.3.9.4EV Substance CodeSUB32701
    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.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 Yes
    D.2.1.1.1Trade name Lixiana 30 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameedoxaban
    D.3.2Product code DU-176b
    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
    D.3.9.1CAS number 480449-70-5
    D.3.9.3Other descriptive nameEDOXABAN
    D.3.9.4EV Substance CodeSUB32701
    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 Yes
    D.2.1.1.1Trade name Lixiana 15 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderDaiichi Sankyo Europe GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameedoxaban
    D.3.2Product code DU-176b
    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
    D.3.9.1CAS number 480449-70-5
    D.3.9.3Other descriptive nameEDOXABAN
    D.3.9.4EV Substance CodeSUB32701
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameacenocumarol
    D.3.2Product code vitamin K antagonist (VKA)
    D.3.4Pharmaceutical form 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 INNACENOCOUMAROL
    D.3.9.1CAS number 152-72-7
    D.3.9.4EV Substance CodeSUB05211MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 4
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 namewarfarin
    D.3.2Product code vitamin K antagonist (VKA)
    D.3.4Pharmaceutical form 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 INNwarfarin sodium
    D.3.9.1CAS number CAS 129-06-6
    D.3.9.3Other descriptive nameWARFARIN SODIUM
    D.3.9.4EV Substance CodeSUB05128MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 10
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation after transcatheter aortic valve implantation (TAVI)
    Pacientes con fibrilación auricular (FA) e indicación de anticoagulación oral crónica (AOC) después de un implante de válvula aórtica transcatéter (IVAT)
    E.1.1.1Medical condition in easily understood language
    Patients with atrial fibrillation (AF) after transcatheter aortic valve implantation (a catheter based procedure where a new valve is placed in the location of the old and narrowed aortic valve)
    Pacientes con fibrilación auricular después de un implante de válvula aórtica transcatéter (procedimiento por catéter donde una válvula es colocada en la ubicación de la válvula antigua y estrechada)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    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
    2.1.1. Co-Primary Objectives
    •To assess the effect of Edoxaban versus vitamin K antagonist (VKA) on net adverse clinical events (NACE), i.e., the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition).
    •To assess the effect of Edoxaban versus VKA on major bleeding (ISTH definition).
    • Evaluar el efecto de Edoxaban en comparación con antagonistas de la vitamina K (AVK) en acontecimientos clínicos adversos netos (net adverse clinical events, NACE), es decir, el compuesto de muerte por cualquier causa, el infarto de miocardio (IM), el accidente cerebrovascular isquémico, la tromboembolia sistémica (SEE), la trombosis valvular y el sangrado significativo (definición de la Sociedad Internacional de Trombosis y Hemostasia [International Society on Thrombosis and Haemostasis, ISTH]).
    • Evaluar el efecto de Edoxaban en comparación con AVK en sangrados significativos (definición de la ISTH).
    E.2.2Secondary objectives of the trial
    To compare Edoxaban with VKA with regards below efficacy endpoints:
    •NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major and minor bleeding per TIMI definitions
    •NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (Bleeding Academic Research Consortium [BARC] 3 or 5 definition)
    •NACE defined as composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis and major & moderate bleeding [GUSTO] definition
    To compare Edoxaban with VKA with regards below safety endpoints:
    •Major bleeding (defined by TIMI [major & minor], BARC 3 or 5, GUSTO [moderate & severe]
    •Major & Clinically Relevant Non-Major (CRNM) bleeding (defined by ISTH, TIMI, BARC 2, 3 or 5, GUSTO)
    •Clinically Relevant Non-Major bleeding (defined by ISTH, TIMI, BARC 2, GUSTO)
    •Intracranial hemorrhage, Life-threatening bleeding, Fatal major bleeding (ISTH definition)
    For full list, refer to Protocol
    Comparar Edoxaban con AVK con respecto a los siguientes criterios de valoración de eficacia:
    •NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y menor, según las definiciones de TIMI
    •NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición 3ó5 BARC)
    •NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y moderado (definición de GUSTO)
    Comparar Edoxaban con AVK respecto a los siguientes criterios de valoración de seguridad:
    •Sangrado significativo (definido según TIMI [significativo y menor], BARC 3ó5, GUSTO [moderado y grave])
    •Sangrado significativo y no significativo clínicamente relevante
    Consulte el protocolo para la revision de la lista completa
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must satisfy all of the following criteria to be included in the study:
    1. Successful transfemoral TAVI with any approved/marketed device (other access routes may only be used if they become standard of care with a proven superior outcome and after written approval of this study’s Executive Committee); success is defined as:
    a. Correct positioning of a single prosthetic heart valve into the proper anatomical location
    b. Presence of all 3 conditions post TAVI
    I. Mean aortic valve gradient <20 mm Hg
    ii. Peak transvalvular velocity <3.0 m/s
    iii. Aortic valve regurgitation of 2 or less
    c. No overt stroke
    d. No uncontrolled bleeding at time of randomization
    2. Indication for chronic OAC
    a. Pre-existing atrial fibrillation (AF)
    b. New onset AF (> 30 seconds documented by ECG recording)
    3. Provision of signed informed consent
    4. Age ≥18 years
    Los pacientes deben cumplir todos los siguientes criterios para que se les incluya en el estudio:
    1. IVAT transfemoral exitoso (solo se pueden utilizar otras vías de acceso si se convierten en tratamiento estándar con un resultado superior comprobado y después de la aprobación por escrito del Comité Ejecutivo de este estudio) con cualquier dispositivo aprobado/comercializado; éxito se define como:
    a.Ubicación correcta de una sola válvula cardíaca prostética en el lugar anatómico adecuado
    b.Presencia de las 3 afecciones posteriores a un IVAT
    i.Gradiente promedio de la válvula aórtica <20 mm Hg
    ii.Velocidad transvalvular pico <3,0 m/s
    iii.Insuficiencia de la válvula aórtica de 2 o menos
    c.Ningún accidente cerebrovascular evidente
    d.Ningún sangrado no controlado al momento de la aleatorización
    2.Indicación de AOC crónicos
    a.Fibrilación auricular (FA) documentada preexistente
    b.Aparición reciente de FA (>30 segundos, documentada por registro ECG)
    3.Entrega de consentimiento informado firmado
    4.Edad ≥18 años
    E.4Principal exclusion criteria
    1. History of life-threatening or major bleeding event ≥ BARC 3b definitions within the last year
    2. Other conditions with a high risk of bleeding
    o This may include but is not limited to: active peptic ulcer or upper gastrointestinal (GI) bleeding within last 3 months prior to randomization, malignancy at high risk of bleeding, recent unresolved brain or spinal injury, spinal or ophthalmic surgery (within the last 3 months prior to randomization), any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities.
    3. Other known bleeding diatheses
    4. Serious unresolved periprocedural complications
    5. Hypersensitivity or contraindications to Edoxaban, VKA, ASA, and/or P2Y12 antagonists
    6. Concomitant treatment with other antithrombotic agents, ASA > 100 mg/day, fibrinolytic therapy, or chronic (> 4 days/week) use of nonsteroidal antiinflammatory drugs (NSAIDs)
    7. Requirement for dual-antiplatelet therapy (DAPT) within 1 month prior to randomization
    8. Treatment with other investigational drugs or devices within 30 days before enrollment or planned use of investigational drugs or devices during the study
    For full list of Exclusion criteria: Refer to Protocol, section: 4.2
    1. Antecedentes de sangrado significativo o potencialmente mortal ≥ BARC 3b en el año anterior
    2. Otras afecciones con alto riesgo de sangrado
    Esto puede incluir, entre otros: úlcera péptica activa con sangrado gastrointestinal (GI) superior en los últimos 3 meses antes de la aleatorización, neoplasia maligna con alto riesgo de sangrado, lesión cerebral o de la columna vertebral reciente no resuelta, cirugía de la columna vertebral u oftalmológica reciente (en los últimos 3 meses antes de la aleatorización), cualquier hemorragia intracraneal, várices esofágicas conocidas o presuntas, malformaciones arteriovenosas, aneurismas vasculares, o anomalías vasculares intraespinales o intracerebrales significativas.
    3. Otra diátesis hemorrágica conocida
    En relación con el procedimiento
    4. Complicaciones graves no resueltas en relación con el procedimiento
    En relación con el medicamento
    5. Hipersensibilidad o contraindicación a Edoxaban, AVK, AAS, y/o antagonistas de P2Y12
    6. Tratamiento concomitante con otros agentes antitrombóticos (AAS) >100 mg/día, terapia fibrinolítica o uso crónico (>4 días/semana) de fármacos antiinflamatorios no esteroideos (nonsteroidal anti-inflammatory drugs, NSAID)
    7. Necesidad de recibir terapia antiplaquetaria dual (DAPT) en el plazo de 1 mes antes de la aleatorización
    8. Tratamiento con otros fármacos o dispositivos en investigación en los 30 días anteriores a la al reclutamiento o uso planificado de fármacos o dispositivos en investigación durante el estudio

    Para lista completa de criterios de exclusion: Consulte el Protocolo, sección 4.2
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:
    • NACE, ie, the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (ISTH definition)
    Primary safety endpoint:
    • Major bleeding (ISTH definition)
    Criterio de valoración principal de la eficacia:
    •NACE, es decir, el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición de la ISTH)

    Criterio de valoración principal de la seguridad:
    •Sangrado significativo (definición de la ISTH)
    E.5.1.1Timepoint(s) of evaluation of this end point
    First occurrence of any component.
    Primera aparición de cualquier componente.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    • NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (TIMI definition)
    • NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding ([BARC 3 or 5 definition)
    • NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major and moderate bleeding (GUSTO definition)
    • Stroke (ischemic, hemorrhagic, or undetermined)
    • Stroke (ischemic)
    • Stroke (hemorrhagic)
    • Stroke (undetermined)
    • Fatal stroke (ischemic, hemorrhagic, or undetermined)
    • Non-fatal stroke (ischemic, hemorrhagic, or undetermined)
    • SEE
    • Myocardial Infarction
    • Valve thrombosis

    Secondary Safety Endpoints
    • Major bleeding (defined by TIMI [major and minor], BARC 3 or 5, GUSTO [moderate and severe])
    • Major and Clinically Relevant Non-Major (CRNM) bleeding (defined by ISTH, TIMI, BARC 2, 3 or 5, GUSTO)
    • Clinically Relevant Non-Major bleeding (defined by ISTH, TIMI, BARC 2, GUSTO)
    • Minor Bleeding (defined by ISTH, TIMI [minimal], BARC 1 [non-actionable], GUSTO)
    • Any bleeding
    • Intracranial hemorrhage
    • Life-threatening bleeding
    • Fatal major bleeding (ISTH definition)
    • Non-fatal major bleeding (ISTH definition)
    • All-cause mortality
    • Cardiovascular mortality
    • Safety parameters such as (serious) adverse events, laboratory parameters, ECG and vital signs
    Comparar Edoxaban con AVK con respecto con los siguientes criterios de valoración de eficacia:
    • NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y menor, según las definiciones de trombosis en infarto de miocardio (TIMI)
    • NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición 3 o 5 del Consorcio de Investigación Académica en Sangrado [Bleeding Academic Research Consortium, BARC])
    • NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y moderado (definición de Utilización global de estreptocinasa y activador tisular del plasminógeno para arterias ocluidas [Global Utilization of Streptokinase And Tissue Plasminogen Activator For Occluded arteries, GUSTO])
    • Accidente cerebrovascular (isquémico, hemorrágico, o no determinado)
    • Accidente cerebrovascular (isquémico)
    • Accidente cerebrovascular (hemorrágico)
    • Accidente cerebrovascular (no determinado)
    • Accidente cerebrovascular mortal (isquémico, hemorrágico, o no determinado)
    • Accidente cerebrovascular no mortal (isquémico, hemorrágico, o no determinado)
    • SEE
    • Infarto de miocardio
    • Trombosis valvular
    Comparar Edoxaban con AVK con respecto con los siguientes criterios de valoración de seguridad:
    • Sangrado significativo (definido según TIMI [significativo y menor], BARC 3 o 5, GUSTO [moderado y grave])
    • Sangrado significativo y no significativo clínicamente relevante (Clinically Relevant Non-Major, CRNM) (definido según ISTH, TIMI, BARC 2, 3 o 5, GUSTO)
    • Sangrado no significativo clínicamente relevante (definido según ISTH, TIMI, BARC 2, GUSTO)
    • Sangrado menor (definido según ISTH, TIMI [mínimo], BARC 1 [mínimo], GUSTO)
    • Cualquier sangrado
    • Hemorragia intracraneal
    • Sangrado potencialmente mortal
    • Sangrado significativo mortal (definición de la ISTH)
    • Sangrado significativo no mortal (definición de la ISTH)
    • Mortalidad por cualquier causa
    • Mortalidad cardiovascular
    • Parámetros de seguridad como acontecimientos adversos (graves), parámetros de laboratorio, ECG y signos vitales
    E.5.2.1Timepoint(s) of evaluation of this end point
    All clinical endpoints will be analyzed as time to first occurrence of any of its components.
    Todos los criterios de valoración clínicos se analizarán como el tiempo hasta la primera aparición de cualquiera de sus componentes.
    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 No
    E.6.7Pharmacodynamic No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Antagonista de la vitamina K
    Vitamin K Antagonist
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Austria
    Belgium
    Canada
    France
    Germany
    Italy
    Netherlands
    Spain
    Switzerland
    United Kingdom
    United States
    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
    As an event driven study, the subjects will continue on treatment until the study is stopped due to 320 adjudicated events (from approximately 2500 subject years) will have been reached, or they permanently discontinue from the study (for any reason). Subjects enrolled late in the study may be terminated from the study after a minimum of 6 months on treatment. Subjects will also have a Follow-up Visit approximately 30 days after the EOT Visit.
    Como estudio dirigido por eventos, los sujetos continuarán el tratamiento hasta que el estudio se detenga debido a que se alcancen los 320 eventos adjudicados (aproximadamente 2500 años-sujetos) , o discontinúen permanentemente del estudio (por cualquier razón). Para los últimos pacientes reclutados , la duración mínima del tratamiento será de al menos 6 meses. Los sujetos también tendrán una visita de seguimiento aproximadamente 30 días después de la visita de fin de tratamiento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1120
    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 state110
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 921
    F.4.2.2In the whole clinical trial 1400
    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)
    The subjects on Edoxaban will use the Sponsor provided transition kit to transition from Edoxaban to a VKA. The choice of VKA will be made by the Investigator in consultation with the subject’s personal physician and per local guidelines
    Los sujetos de Edoxaban usarán el kit de transición proporcionado por el Promotor para la transición de Edoxaban a VKA. La elección de VKA será hecha por el Investigador en conjunto con el médico de cabecera del sujeto y por las guías locales.
    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 Decision2017-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-12
    P. End of Trial
    P.End of Trial StatusOngoing
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