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    Summary
    EudraCT Number:2017-000058-21
    Sponsor's Protocol Code Number:CLOSURE-AF-DZHK16
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2017-08-28
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-000058-21
    A.3Full title of the trial
    Left atrial appendage CLOSURE in patients with Atrial Fibrillation at high risk of stroke and bleeding compared to medical therapy: a prospective randomized clinical trial
    Perkutaner Verschluss des linken Vorhofohres bei Patienten mit Vorhofflimmern und hohem Schlaganfall- und Blutungsrisiko im Vergleich zur medikamentösen Standardtherapie: eine prospektive, randomisierte klinische Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Left atrial appendage CLOSURE in patients with heart arrhythmia at high risk of stroke and bleeding compared to medical therapy.
    Verschluss des linken Herzohres bei Patienten mit Herzarrhythmie und hohem Schlaganfall- und Blutungsrisiko im Vergleich zur medikamentösen Standardtherapie.
    A.3.2Name or abbreviated title of the trial where available
    CLOSURE-AF-DZHK16
    CLOSURE-AF-DZHK16
    A.4.1Sponsor's protocol code numberCLOSURE-AF-DZHK16
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03463317
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1194-4541
    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 SponsorCharité – Universitätsmedizin Berlin, Campus Benjamin Franklin
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDeutsches Zentrum für Herz-Kreislauf-Forschung e.V.
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik für Kardiologie, Studienzentrale
    B.5.2Functional name of contact pointDr. Johannes J. Hartung
    B.5.3 Address:
    B.5.3.1Street AddressHindenburgdamm 30
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code12203
    B.5.3.4CountryGermany
    B.5.4Telephone number4930450513706
    B.5.6E-mailclosure-af@dzhk.de
    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.2.1.2Country 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 nameACETYLSALICYLIC ACID
    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.3.9.3Other descriptive nameASA, ASS
    D.3.9.4EV Substance CodeSUB12730MIG
    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.2.1.2Country 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 nameCLOPIDOGREL
    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 INNCLOPIDOGREL
    D.3.9.1CAS number 744256-69-7
    D.3.9.3Other descriptive nameCLOPIDOGREL BESILATE
    D.3.9.4EV Substance CodeSUB30714
    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 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 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 nameDABIGATRAN
    D.3.4Pharmaceutical form Capsule, hard
    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 INNDABIGATRAN
    D.3.9.3Other descriptive nameDABIGATRAN ETEXILATE MESILATE
    D.3.9.4EV Substance CodeSUB27581
    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 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 nameRIVAROXABAN
    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.3.9.4EV Substance CodeSUB29263
    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 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 nameAPIXABAN
    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 INNAPIXABAN
    D.3.9.4EV Substance CodeSUB25425
    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: 6
    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 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 nameEDOXABAN
    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 480449-71-6
    D.3.9.3Other descriptive nameEDOXABAN TOSYLATE
    D.3.9.4EV Substance CodeSUB35059
    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: 7
    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 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 namePHENPROCOUMON
    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 INNPHENPROCOUMON
    D.3.9.1CAS number 435-97-2
    D.3.9.4EV Substance CodeSUB09781MIG
    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: 8
    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 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 nameWARFARIN
    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
    D.3.9.3Other descriptive nameWARFARIN SODIUM
    D.3.9.4EV Substance CodeSUB05128MIG
    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
    Atrial Fibrillation with high risk of stroke and bleeding
    Vorhofflimmern mit hohen Schlaganfall- und Blutungsrisiko
    E.1.1.1Medical condition in easily understood language
    Atrial Fibrillation (a heart arrhytmia) with high risk of stroke and bleeding
    Vorhofflimmern (eine Arrhythmie des Herzens) mit hohen Schlaganfall- und Blutungsrisiko
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    Study goal is to determine the clinical benefit of a strategy of percutaneous catheter‐based left atrial appendage (LAA) closure in patients with NVAF at high risk of stroke (CHA2DS2‐VASc Score ≥2) and bleeding as compared to best medical care (including a non-vitamin K antagonist oral anticoagulant [NOAC] if patient is eligible).
    Ziel der Studie ist es, den klinischen Nutzen des perkutanen, katheter-basierten Vorhofsohrverschlusses bei Patienten mit nicht-valvulärem Vorhofflimmern (NVAF) mit hohem Schlaganfallrisiko (CHA2DS2‐VASc Score ≥2) sowie hohem Blutungsrisiko zu bestimmen im Vergleich zur medikamentösen Standardtherapie (einschließlich eines [Nicht-Vitamin K] oralen Antikoagulans [(N)OAK], wenn möglich).
    E.2.2Secondary objectives of the trial
    Not applicable.
    Nicht zutreffend.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed Written Informed Consent
    - Documented atrial fibrillation (paroxysmal, persistent, long-standing persistent or permanent)
    - CHA2DS2VASc-Score ≥2
    - High risk of bleeding under oral anticoagulation or contraindication for (N)OAC therapy, in particular patients with at least one of the following conditions:
    *HAS-BLED-Score ≥3
    *Prior intracranial/intraspinal bleed, intraocular bleed compromising vision (BARC: type 3c)
    *Hemorrhagic/bleeding complication fulfilling BARC type 3a or 3b: gastrointestinal tract, genitourinary tract or respiratory tract bleeding, where the patient is considered to be at a persistently increased risk of bleeding, e.g. the cause of bleeding cannot be successfully eliminated
    *Chronic kidney disease with eGFR 15-29 ml/min/1.73 m2
    * Any recurrent bleeding making chronic anticoagulation not feasible
    - Subject eligible for an LAA occluder device
    - Age ≥18 years
    - Willing and capable of providing informed consent, participating in all associated study activities
    - negative SARS-CoV-2 PCR test (no longer than 48 hours prior to randomization in outpatients or not older than 14 days in continuously hospitalized patients without signs of COVID-19 infection)
    - Unterschriebene schriftliche Einwilligungserklärung
    - Dokumentiertes Vorhofflimmern (paroxysmal, persistent, permanent)
    - CHA2DS2VASc-Score ≥2
    - Hohes Risiko für das Auftreten von Blutungen unter oraler Antikoagulation oder bestehende Kontraindikation für eine (N)OAK-Therapie, insbesondere Patienten mit mindestens einem der folgenden Zustände:
    *HASBLED-Score ≥3
    *Stattgehabte intrakraniale/intraspinale Blutung, intraokkuläre Blutung, die die Sehkraft beeinträchtigt (BARC: type 3c)
    *Blutung, die die Kriterien BARC Typ 3a oder 3b erfüllt: Blutungen des Magen-Darm-Trakts, des Urogenitaltrakts oder der Atemwege, bei denen weiterhin ein erhöhtes Blutungsrisiko besteht, da z.B. die Ursache der Blutung nicht erfolgreich beseitigt werden konnte
    *Chronische Niereninsuffizienz mit einer eGFR 15-29 ml/min/1.73m2
    * Jede rezidivierende Blutung, die eine dauerhafte Antikoagulation ausschließt
    - Patienten, die für den katheterinterventionellen Vorhofohrverschluss geeignet sind
    - Alter ≥ 18 Jahre
    - Einwilligungsfähiger Patient, der in der Lage ist und gewillt ist, an allen Studienaktivitäten teilzunehmen
    - Negativer SARS-CoV-2 PCR Test (nicht älter als 48 Stunden vor Randomisierung bei ambulant behandelten Patienten oder nicht älter als 14 Tage bei kontinuierlich stationären Patienten ohne COVID-19 Symptomen)
    E.4Principal exclusion criteria
    - Absolute contraindication to acetylsalicylic acid
    - Comorbidities other than AF requiring chronic (N)OAC therapy, e.g. mechanical heart valve prosthesis
    - Symptomatic carotid disease (if not treated)
    - Complex aortic atheroma with mobile plaque (Kronzon classification grade V)
    - Heart transplant
    - Active infection or symptoms suggestive of COVID-19 infection or active endocarditis or other infections resulting in bacteremia
    - Cardiac Tumor
    - Severe liver failure (Child–Pugh class C or liver failure with coagulopathy)
    - Severe renal failure (GFR <15 ml/min/1.73m2 or current requirement for dialysis (defined as current, regular renal replacement therapy performed at least weekly (including hemodialysis and peritoneal dialysis) within the last 30 days))
    - Pregnancy or breastfeeding
    - For female patients of reproductive potential: Unwilling to agree to use a highly effective method of contraception (Pearl index <1) throughout the study period
    - Subject with participation in another interventional clinical trial during this study or within 30 days before entry into this trial.
    - Known terminating disease with life expectancy <1 year (including those with end-stage heart failure)
    - Subjects, who are committed to an institution due to binding official or court order
    - Subject who is dependent on the Site, the Site Investigator, any sub-investigator, his/her representative and/or the sponsor
    - Persons who are not proficient in the German language
    - Unstable/ not fully recompensated acute heart failure corresponding to NYHA class III and/or IV
    -Subject with known antiphospholipid syndrome
    - Absolute Kontraindikationen für Acetylsalicylsäure
    - Weitere Komorbiditäten, die einer dauerhaften (N)OAK Behandlung bedürfen, z.B. mechanische Herzklappenprothesen
    - Symptomatische Carotisstenose (falls unbehandelt)
    - Komplexes Aortenatherom mit mobiler Plaque (Kronzon Klassifikation Grad V)
    - Herztransplantation
    - Aktive Infektion oder Symptome, die auf eine COVID-19 Infektion hinweisen oder aktive Endokarditis oder andere Infektionen, die zu Bakteriämie führen
    - Herztumore
    - Schwere Leberinsuffizienz (Child-Pugh Stadium C oder Lebererkrankungen in Verbindung mit einer Koagulopathie)
    - Schwere Niereninsuffizienz (GFR <15 ml/min/1.73m2 oder aktuelle Dialysepflicht (definiert als aktuelle regelmäßige, mindestens wöchentliche Durchführung eines Nierenersatzverfahrens (einschließlich Hämodialyse und Peritonealdialyse) innerhalb der letzten 30 Tage))
    - Schwangerschaft oder Stillen
    - Bei gebärfähige Frauen: Keine Bereitschaft eine zuverlässige Verhütungsmethode(Pearl Index <1) während des gesamten Studienzeitraums an verwenden
    - Teilnahme an einer anderen interventionellen klinischen Studie während dieser Studie oder innerhalb von 30 Tagen vor dem Eintritt in diese Studie
    - Bekannte Krankheit mit einer Lebenserwartung <1 Jahr (einschließlich derjenigen mit Herzinsuffizienz im Endstadium)
    - Personen, die aufgrund behördlicher oder gerichtlicher Anordnung in einer Anstalt untergebracht wurden
    - Personen, die von der Prüfstelle, dem Prüfer und / oder den Prüfärzten sowie deren Vertretern und / oder vom Sponsor abhängig sind
    - Personen, die kein Deutsch beherrschen
    - Instabile/ nicht vollständig rekompensierte akute Herzinsuffizienz entsprechend der NYHA Klassifikation III und/oder IV
    - Personen mit bekanntem Antiphospholipid-Syndrom
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint (net clinical benefit)
    Survival time free of the composite of:
    - Stroke (including ischemic or hemorrhagic stroke)
    - Systemic embolism
    - Major bleeding (BARC type 3‐5)
    - Cardiovascular or unexplained death
    Primärer Endpunkt (net clinical benefit)
    Kombinierte Überlebenszeit frei von:
    - Schlaganfall (ischemisch oder haemorrhagisch)
    - systemische Embolie
    - schwere Blutung (BARC type 3‐5)
    - Kardiovaskulärer oder ungeklärter Tod
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be evaluated for the primary endpoint at follow up visits at
    7 days*, 30 days*, 3, 6*, 12, 18*, 24, 36*, 48* and 60* months (*phone visits).
    Die Patienten werden bei den Visiten nach 7 Tagen*, 30 Tagen*, 3, 6*, 12, 18*, 24, 36*, 48* und 60* Monaten (*Telefon-Visiten) auf den primären Endpunkt hin untersucht/ befragt.
    E.5.2Secondary end point(s)
    - Primary endpoint events per year
    - Combined endpoint: MACCE (stroke/systemic embolism/cardiovascular death/myocardial infarction)
    - Mortality (including all-cause death, cardiovascular death, non‐ cardiovascular death, peri‐procedural death)
    - Major bleeding (BARC type 3‐5)
    - Systemic embolism
    - Ischemic stroke
    - Hemorrhagic stroke
    - Transient ischemic attack (TIA; defined as neurological deficit of vascular origin lasting ≤24 hours without corresponding brain lesion)
    - Myocardial infarction
    - Hospitalization for bleeding or cardiovascular event
    - Changes in cognitive function assessed by MoCA (= Montreal Cognitive Assessment)
    - Changes in health-related quality of life (EQ-5D-5L)

    Secondary safety endpoint(s):
    - Device thrombus/fracture/erosion
    - Vascular access related complications requiring intervention
    - Procedure related death
    - Technical and procedural success of device implantation
    - Post-procedure infection rate
    - Peri-procedural outcomes at 7 and 30 calendar days after implantation
    - Primäre Endpunktereignisse pro Jahr
    - Kombinierter Endpunkt: MACCE (Schlaganall/systemische Embolie/kardiovaskulärer Tod/Myokardinfarkt)
    - Mortalität (inkl. Tod jeder Ursache, kardiovaskulärer Tod, nicht-kardiovaskulärer Tod, peri-prozeduraler Tod)
    - Schwere Blutung (BARC type 3‐5)
    - Systemische Embolie
    - Ischämischer Schlaganfall
    - Hämorrhagischer Schlaganfall
    - Transitorischer ischämischer Angriff (TIA, definiert als neurologisches Defizit vaskulären Ursprungs, ≤24 Stunden, ohne entsprechende Hirnläsion)
    - Myokardinfarkt
    - Veränderungen der kognitiven Funktion, beurteilt durch MoCA (= Montreal Cognitive Assessment)
    - Veränderungen der Lebensqualität, beurteilt durch EQ-5D-5L

    Sekundäre Sicherheitsendpunkte:
    - Thrombus / Fraktur / Erosion am LAA-Okkluder
    - Gefäßzugangskomplikationen, die einer Intervention bedürfen
    - Prozedur bedingter Tod
    - Technischer und prozeduraler Erfolg der LAA-Okkluder-Implantation
    - Postprozedurale Infektionsrate
    - Periprozedurale Ergebnisse nach 7 und 30 Kalendertagen nach Implantation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be evaluated for the primary endpoint at follow up visits at
    7 days*, 30 days*, 3, 6*, 12, 18*, 24, 36*, 48* and 60* months (*phone visits).
    Die Patienten werden bei den Visiten nach 7 Tagen*, 30 Tagen*, 3, 6*, 12, 18*, 24, 36*, 48* und 60* Monaten (*Telefon-Visiten) auf den primären Endpunkt hin untersucht/ befragt.
    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 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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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 concerned65
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 regular study end is defined as the time until the 467th event is adjudicated as primary endpoint by the Clinical Event Committee .
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 455
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1057
    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 state1512
    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)
    After termination of the study, patients will continue to receive the same treatment.
    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 Decision2017-11-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-01
    P. End of Trial
    P.End of Trial StatusRestarted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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