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    Summary
    EudraCT Number:2013-000768-27
    Sponsor's Protocol Code Number:BAY59-7939/16573
    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:2014-11-27
    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 number2013-000768-27
    A.3Full title of the trial
    Multicenter, randomized, double-blind, double-dummy, active-comparator, event-driven, superiority phase III study of secondary prevention of stroke and prevention of systemic embolism in patients with a recent Embolic Stroke of Undetermined Source (ESUS), comparing rivaroxaban 15 mg once daily with aspirin 100 mg (NAVIGATE ESUS)
    Estudio de superioridad, fase III, multicéntrico, aleatorizado, doble-ciego , doble simulación, con comparador activo y dirigido por eventos , que compara rivaroxaban 15 mg en una toma diaria con aspirina 100 mg, en la prevención secundaria de accidente cerebrovascular y embolia sistémica en pacientes que han sufrido un accidente cerebrovascular embólico de etiología indeterminada (ACEI) (NAVIGATE ESUS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rivaroxaban versus Aspirin in secondary prevention of stroke and prevention of systemic embolism in patients with recent embolic stroke of undetermined source (ESUS)
    Rivaroxaban comparado a Aspirina en la prevención secundaria de ictus y embolia sistémica en pacientes con reciente accidente cerebrovascular embólico de origen indeterminado
    A.3.2Name or abbreviated title of the trial where available
    Secondary prevention of stroke in patients with ESUS
    A.4.1Sponsor's protocol code numberBAY59-7939/16573
    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 SponsorBayer HealthCare AG
    B.1.3.4CountryGermany
    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 supportBayer HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team/Ref:"EU CTR"/ Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034.900102372
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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 Xarelto 15 mg film-coated tablets
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    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 nameRivaroxaban 15 mg
    D.3.2Product code BAY 59-7939
    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 INNRIVAROXABAN
    D.3.9.1CAS number 366789-02-8
    D.3.9.2Current sponsor codeBAY 59-7939
    D.3.9.4EV Substance CodeSUB29263
    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 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.2.1.1.1Trade name Aspirin 100 mg
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Vital GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAspirin
    D.3.4Pharmaceutical form Gastro-resistant 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 INNACETYLSALICYLIC ACID
    D.3.9.1CAS number 50-78-2
    D.3.9.3Other descriptive nameACETYLSALICYLIC ACID
    D.3.9.4EV Substance CodeSUB12730MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGastro-resistant 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
    Embolic stroke of undetermined source (ESUS)
    Accidente cerebrovascular embólico de etiología indeterminada
    E.1.1.1Medical condition in easily understood language
    Stroke
    Ictus
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10014498
    E.1.2Term Embolic stroke
    E.1.2System Organ Class 10029205 - Nervous system 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 efficacy objective is to evaluate whether rivaroxaban is superior to aspirin in reducing the risk of recurrent stroke and systemic embolism in patients with a recent ESUS.
    El objetivo de eficacia primario es evaluar si rivaroxabán es superior a Aspirina a la hora de reducir el riesgo de accidente cerebrovascular (ACV) y embolia sistémica recurrentes en pacientes que han sufrido recientemente un ACEI
    E.2.2Secondary objectives of the trial
    The secondary efficacy objective is to evaluate whether rivaroxaban is superior to aspirin in reducing cerebrovascular events, cardiovascular events, and mortality in patients with a recent ESUS.

    The safety objective is to document the incidence of clinically relevant bleeding.
    El objetivo de eficacia secundario es evaluar si rivaroxabán es superior a Aspirina a la hora de reducir los acontecimientos cerebrovasculares, los acontecimientos cardiovasculares y la mortalidad en pacientes que han sufrido recientemente un ACEI

    El objetivo de seguridad es documentar la incidencia de hemorragias clínicamente importantes
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Two optional sub-studies (described in Section 14.1 of the protocol) will be conducted at selected sites:

    1. MRI sub-study
    The primary objective of this substudy is to determine the effect of rivaroxaban compared with aspirin on MRI-defined covert infarcts in individuals with a recent ESUS. Secondary objectives will be to determine the effect of rivaroxaban compared to aspirin for reducing covert and clinical infarcts (i.e. all incident infarcts), the progression of volume of white matter hyperintensities (WMH), functional decline (SAGE), and cognitive decline (DSS, MoCA) in the patients with recent ESUS enrolled in this sub-study.

    2. Biomarker sub-study
    Biomarker samples will be collected to promote, facilitate, and improve individualized healthcare by better understanding/predicting ESUS, recurrent stroke, and associated diseases as well as treatment response. Specifically, the intention is to establish ESUS as a distinct clinical entity in which propensity to coagulation is critical, both as a marker of ESUS and as a risk factor for recurrent stroke.
    Se han previsto dos subestudios ( descritos en la sección 14.1 del Protocol)que se llevarán a cabo en centros seleccionados

    1. Subestudio de IRM

    El objetivo principal de este subestudio es determinar el efecto de rivaroxabán en comparación con Aspirina en los infartos encubiertos definidos mediante IRM en individuos con ACEI reciente. Los objetivos secundarios serán determinar el efecto de rivaroxabán comparado con Aspirina para reducir los infartos encubiertos y clínicos (es decir, todos los infartos nuevos), la progresión del volumen de hipersensibilidades de la materia blanca (HMB), el declive funcional (SAGE) y el declive cognitivo (DSS, MoCA) en los pacientes con ACEI reciente incluidos en este subestudio.

    2. Subestudio de biomarcadores

    Se recogerán muestras de biomarcadores en este subestudio exploratorio para fomentar, facilitar y mejorar la asistencia sanitaria individualizada mediante el mejor conocimiento/predicción del ACEI, el ACV recurrente y las enfermedades asociadas así como la respuesta al tratamiento. En concreto, la intención es establecer el ACEI como una entidad clínica distintiva, en el que la predisposición a la coagulación es crucial, como marcador del ACEI y también como factor de riesgo para el ACV recurrente.
    E.3Principal inclusion criteria
    Recent ESUS (between 7 days and 6 months), defined as:
    - Recent ischemic stroke (including transient ischemic attack with positive neuroimaging) visualized by brain imaging that is not lacunar, and
    - Absence of cervical carotid atherosclerotic stenosis >= 50% or occlusion, and
    - No atrial fibrillation after >= 24-hour cardiac rhythm monitoring, and
    - No intra-cardiac thrombus on transthoracic echocardiography, and
    - No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)
    ACEI reciente (entre 7 días y 6 meses), definido como:

    - Accidente cerebrovascular isquémico reciente (incluye accidente isquémico transitorio con neuroimágenes positivas) cuya visualización mediante técnicas de imagen cerebrales indica que no es lagunar, y

    - Ausencia de estenosis ateroesclerótica de las carótidas cervicales >=50 % u oclusión, y

    - Ausencia de fibrilación auricular después de >=24 horas de monitorización del ritmo cardiaco, y

    - Ausencia de trombos intracardiacos en la ecocardiografía transtorácica, y

    - Ausencia de otra causa específica del accidente cerebrovascular (por ejemplo, arteritis, disección, migraña/vasoespasmo, consumo de drogas)
    E.4Principal exclusion criteria
    - Severely disabling stroke (modified Rankin score >=4)
    - Indication for chronic anticoagulation or antiplatelet therapy
    - Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
    - ACV que produce una discapacidad grave (puntuación de Rankin modificada >=4 en la selección).
    - Indicación para el tratamiento crónico anticoagulación o antiagregantes plaquetarios
    - Tasa de filtración glomerular estimada (TFGe) <30 ml/min/1,73 m2
    E.5 End points
    E.5.1Primary end point(s)
    1. Time from randomization to first occurrence of any of the components of the composite outcome (adjudicated), including:
    - Stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging)
    - Systemic embolism

    2. Time from randomization to the first occurrence of major bleeding (International Society on Thrombosis and Haemostasis)
    1. Tiempo desde la aleatorización hasta la aparición de cualquiera de los componentes del resultado compuesto (validado), que son:

    - Accidente cerebrovascular (accidente cerebrovascular isquémico, hemorrágico e indefinido, accidente isquémico transitorio con neuroimágenes positivas)

    - Embolia sistémica

    2. Tiempo desde la aleatorización hasta la aparición de hemorragia grave (International Society on Thrombosis and Haemostasis)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Monitored throughout study
    Monitorizado a lo largo del estudio
    E.5.2Secondary end point(s)
    1. Time from randomization to first occurrence of:
    - Cardiovascular death (including death due to hemorrhage), recurrent stroke, systemic embolism, and myocardial infarction

    2. Time from randomization to first occurrence of:
    - All-cause mortality

    3. Time from randomization to first occurrence of:
    Individual components of the primary and secondary efficacy outcomes (stroke, CV death, and myocardial infarction) as well as ischemic stroke, and disabling stroke (modified Rankin score 4 and 5)

    4. Time from randomization to the first occurrence of life-threatening bleeding

    5. Time from randomization to the first occurrence of clinically relevant non-major bleeding

    6. Time from randomization to the first occurrence of intracranial hemorrhage
    1. Tiempo desde la aleatorización hasta la aparición de:

    Muerte por causas cardiovasculares (incluida la muerte por hemorragia), ACV recurrente, embolia sistémica e IM.

    2. Tiempo desde la aleatorización hasta la aparición de:

    Mortalidad por cualquier causa

    3. Tiempo desde la aleatorización hasta la aparición de los componentes individuales de los resultados primarios y secundarios de la eficacia (ACV, muerte por causas cardiovasculares e IM), así como el ACV isquémico y el ACV incapacitante (puntuación de Rankin modificada de 4 y 5)

    4. Tiempo desde la aleatorización hasta la aparición de hemorragia potencialmente mortal.

    5. Tiempo desde la aleatorización hasta la aparición de hemorragia no grave clínicamente importante

    6. Tiempo desde la aleatorización hasta la aparición de hemorragia intracraneal
    E.5.2.1Timepoint(s) of evaluation of this end point
    Monitored throughout study
    Monitorizado a lo largo del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 Yes
    E.6.12Pharmacoeconomic Yes
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Doble simulación, dirigido por eventos
    Double-dummy, event-driven
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA151
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hungary
    Ireland
    Italy
    Japan
    Korea, Republic of
    Mexico
    Poland
    Portugal
    Russian Federation
    South Africa
    Spain
    Sweden
    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
    The end of the study as a whole will be reached when the final efficacy outcome event has been adjudicated for patients from all participating clinical sites.
    Se alcanzará el final del estudio en su conjunto cuando se haya alcanzado los criterios de valoración de la eficacia para los pacientes de todos los centros clínicos participantes.
    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 months8
    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: 2500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4500
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3020
    F.4.2.2In the whole clinical trial 7000
    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 of care
    Tratamiento standard.
    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 Decision2015-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-15
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