Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44381   clinical trials with a EudraCT protocol, of which   7393   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2017-000058-21
    Trial protocol
    		 DE  
    Global end of trial date
    30 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Feb 2026
    First version publication date
    13 Feb 2026
    Other versions
    Summary report(s)
    		 SAEs-summary_CLOSURE

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLOSURE-AF-DZHK16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03463317
    WHO universal trial number (UTN)
    		 U1111-1194-4541
    Sponsors
    Sponsor organisation name
    Charité Universitaetsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Studienzentrale, Department of Cardiology - Deutsches Herzzentrum der Charité - Campus Benjamin Franklin, +49 030 450513702, closure-af@dzhk.de
    Scientific contact
    Studienzentrale, Department of Cardiology - Deutsches Herzzentrum der Charité - Campus Benjamin Franklin, +49 030 450513702, closure-af@dzhk.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    28 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main 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).
    Protection of trial subjects
    The study was conducted in accordance with the ICH E6 (R2) Guideline for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, German Medicinal Products Act (AMG)), and with the ethical principles that have their origins in the Declaration of Helsinki (version 2013).
    Background therapy
    		 An alternative method for stroke prevention in AF patients is the exclusion of the LAA from systemic circulation, a location that is prone to thrombus formation in patients with AF. This interventional therapy may be especially attractive for the prevention of LAA-mediated thromboembolic events in AF patients with high bleeding risk or bleeding history. .Many AF patients – an estimated 300.000 in Germany - are often left untreated because of safety concerns with (N)OAC due to high bleeding risks and/or after occurrence of bleedings (particularly gastrointestinal or cerebral bleeding). Consequently, there is an increasing need for research to ensure optimal thrombo-prophylaxis in patients with AF to avoid fatal stroke especially in patients with high bleeding risk. Clearly, this illustrates that LAA closure therapy is perceived to be potentially beneficial in AF patients at risk for stroke and bleeding, but that evidence is needed to inform best practice and to ensure that LAA closure devices are used in those patients who need them most. There are no trials directly comparing the efficacy and safety profile of NOACs or best medical care and LAA devices. Therefore, we used indirect comparisons between NOACs and LAA exclusion devices on the basis of the warfarin-controlled trials and the stroke risk (CHADS2 score) of each trial to estimate event rates and relative risk for CLOSURE AF.
    Evidence for comparator
    		 Best medical care: NOAC Drug: Acetylsalicylic acid Drug: Clopidogrel Drug: Dabigatran Drug: Rivaroxaban Drug: Apixaban Drug: Edoxaban Drug: Phenprocoumon Drug: Warfarin
    Actual start date of recruitment
    28 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 888
    Worldwide total number of subjects
    888
    EEA total number of subjects
    888
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    47
    From 65 to 84 years
    720
    85 years and over
    121

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study were conducted at 42 sites in Germany.

    Pre-assignment
    Screening details
    		 3000 AF-patients with high risk of bleeding under oral anticoagulation or contraindication for NOAC were screened and 912 were randomized 1:1 to percutaneous closure of the LAA or best medical care (including (N)OAC when eligible)

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    open label, phase 4 Left Atrial Appendage CLOSURE in Patients With Atrial Fibrillation at High Risk of Stroke and Bleeding Compared to Medical Therapy,

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAA-group
    Arm description
    		 Patients with LAAo implantation with post procedure treatment according to the physicians recommendation with Clopidogrel (ASS); oral anticoagulation is not prescribed in this group
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Routes of administration
    Dosage and administration details
    xxxx

    Arm title
    		 Control-Group
    Arm description
    		 Patients allocated to the best medical care (including a [non-vitamin K] oral anticoagulant [(N)OAC] when eligible) - possible drugs: Drug: Dabigatran Drug: Rivaroxaban Drug: Apixaban Drug: Edoxaban Drug: Phenprocoumon Drug: Warfarin
    Arm type
    		 standard of care

    Investigational medicinal product name
    Acetylsalicylic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg per day . Antithombotic therapy was individualized according to the patient’s bleeding risk and determined by the treating physician.

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg per day, Antithombotic therapy was individualized according to the patient’s bleeding risk and determined by the treating physician.

    Number of subjects in period 1
    		LAA-group Control-Group
    Started
    446
    442
    Completed
    446
    442

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    LAA-group
    Reporting group description
    		 Patients with LAAo implantation with post procedure treatment according to the physicians recommendation with Clopidogrel (ASS); oral anticoagulation is not prescribed in this group

    Reporting group title
    Control-Group
    Reporting group description
    		 Patients allocated to the best medical care (including a [non-vitamin K] oral anticoagulant [(N)OAC] when eligible) - possible drugs: Drug: Dabigatran Drug: Rivaroxaban Drug: Apixaban Drug: Edoxaban Drug: Phenprocoumon Drug: Warfarin

    Reporting group values
    		 LAA-group Control-Group Total
    Number of subjects
    		 446 442 888
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 17 30 47
        From 65-84 years
    		 366 354 720
        85 years and over
    		 63 58 121
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 78.48 ( 6.84 ) 77.29 ( 7.34 ) -
    Gender categorical
    Units: Subjects
        Female
    		 172 171 343
        Male
    		 274 271 545

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    LAA-group
    Reporting group description
    		 Patients with LAAo implantation with post procedure treatment according to the physicians recommendation with Clopidogrel (ASS); oral anticoagulation is not prescribed in this group

    Reporting group title
    Control-Group
    Reporting group description
    		 Patients allocated to the best medical care (including a [non-vitamin K] oral anticoagulant [(N)OAC] when eligible) - possible drugs: Drug: Dabigatran Drug: Rivaroxaban Drug: Apixaban Drug: Edoxaban Drug: Phenprocoumon Drug: Warfarin

    Primary: Survival time free (Events- IIT)

    		 Close Top of page
    End point title
    		 Survival time free (Events- IIT)
    End point description
    Incidence per 100 patients-years 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
    End point type
    Primary
    End point timeframe
    After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.
    End point values
    		 LAA-group Control-Group
    Number of subjects analysed
    446
    442
    Units: number
        cardiovascular deaths
    65
    51
        unexplained deaths
    34
    30
        systemic embolism, stroke, TIA
    21
    18
    Attachments
    		 secondary endpints
    primary endpoint
    Statistical analysis title
    		 Adjusted difference in RMST (years)
    Comparison groups
    LAA-group v Control-Group
    Number of subjects included in analysis
    888
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.441
    Method
    		 adjusted differences
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.01

    Primary: First bleeding stratified by time of first occurence

    		 Close Top of page
    End point title
    		 First bleeding stratified by time of first occurence [1]
    End point description
    End point type
    Primary
    End point timeframe
    overall trial
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since it was not possible to display the primary endpoint in the EudracT database, the data was uploaded separately under charts.
    End point values
    		 LAA-group Control-Group
    Number of subjects analysed
    446
    442
    Units: percent (%)
        bleedings < 3 months
    9
    4
        bleedings < 6 months
    11
    5
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    All over study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.
    Reporting groups
    Reporting group title
    LAA- group
    Reporting group description
    		 A total of 1610 SAE cases occurred in the LLA intervention group, 158 of which were fatal. A detailed overview can be found in the appendix “SAE summary.”

    Reporting group title
    Control-Group
    Reporting group description
    		 A total of 1,483 SAE cases occurred in the Control group, 141 of which were fatal. A detailed overview can be found in the appendix “SAE summary.”

    Serious adverse events
    		 LAA- group Control-Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 446 (0.00%)
    0 / 442 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LAA- group Control-Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    293 / 446 (65.70%)
    280 / 442 (63.35%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 446 (4.93%)
    17 / 442 (3.85%)
         occurrences all number
    25
    23
    Hypotension
         subjects affected / exposed
    16 / 446 (3.59%)
    17 / 442 (3.85%)
         occurrences all number
    16
    18
    Hematoma
         subjects affected / exposed
    28 / 446 (6.28%)
    11 / 442 (2.49%)
         occurrences all number
    33
    12
    superficial thrombophlebitis
         subjects affected / exposed
    12 / 446 (2.69%)
    3 / 442 (0.68%)
         occurrences all number
    12
    3
    Thromboembolic event - related device
         subjects affected / exposed
    14 / 446 (3.14%)
    0 / 442 (0.00%)
         occurrences all number
    14
    0
    General disorders and administration site conditions
    Flu like symptoms
         subjects affected / exposed
    5 / 446 (1.12%)
    4 / 442 (0.90%)
         occurrences all number
    5
    5
    Edema limbs
         subjects affected / exposed
    16 / 446 (3.59%)
    13 / 442 (2.94%)
         occurrences all number
    17
    14
    Fatigue
         subjects affected / exposed
    8 / 446 (1.79%)
    11 / 442 (2.49%)
         occurrences all number
    8
    11
    Exsycosis
         subjects affected / exposed
    4 / 446 (0.90%)
    3 / 442 (0.68%)
         occurrences all number
    4
    3
    Weight loss
         subjects affected / exposed
    3 / 446 (0.67%)
    5 / 442 (1.13%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    15 / 446 (3.36%)
    20 / 442 (4.52%)
         occurrences all number
    16
    24
    Dyspnoea
         subjects affected / exposed
    15 / 446 (3.36%)
    21 / 442 (4.75%)
         occurrences all number
    15
    23
    Pleural effusion
         subjects affected / exposed
    9 / 446 (2.02%)
    9 / 442 (2.04%)
         occurrences all number
    11
    9
    Investigations
    Hemoglobin decreased
         subjects affected / exposed
    3 / 446 (0.67%)
    6 / 442 (1.36%)
         occurrences all number
    3
    6
    CRP increased
         subjects affected / exposed
    8 / 446 (1.79%)
    2 / 442 (0.45%)
         occurrences all number
    8
    2
    Creatine urine increased
         subjects affected / exposed
    6 / 446 (1.35%)
    2 / 442 (0.45%)
         occurrences all number
    7
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    23 / 446 (5.16%)
    13 / 442 (2.94%)
         occurrences all number
    23
    16
    Cardiac disorders
    Chest pain- cardiac
         subjects affected / exposed
    8 / 446 (1.79%)
    12 / 442 (2.71%)
         occurrences all number
    8
    12
    Atrial fibrillation
         subjects affected / exposed
    30 / 446 (6.73%)
    22 / 442 (4.98%)
         occurrences all number
    36
    25
    heart failure
         subjects affected / exposed
    21 / 446 (4.71%)
    21 / 442 (4.75%)
         occurrences all number
    22
    22
    Tachycardia
         subjects affected / exposed
    10 / 446 (2.24%)
    6 / 442 (1.36%)
         occurrences all number
    11
    7
    Nervous system disorders
    cognitive disturbance
    Additional description: dementia
         subjects affected / exposed
    6 / 446 (1.35%)
    12 / 442 (2.71%)
         occurrences all number
    6
    13
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    32 / 446 (7.17%)
    31 / 442 (7.01%)
         occurrences all number
    34
    34
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 446 (1.79%)
    15 / 442 (3.39%)
         occurrences all number
    8
    17
    Gastrointestinal disorders
    Diarrhoe
         subjects affected / exposed
    7 / 446 (1.57%)
    4 / 442 (0.90%)
         occurrences all number
    8
    5
    Abdominal pain upper
         subjects affected / exposed
    14 / 446 (3.14%)
    11 / 442 (2.49%)
         occurrences all number
    14
    12
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    22 / 446 (4.93%)
    20 / 442 (4.52%)
         occurrences all number
    26
    22
    Chronic kidney disease
         subjects affected / exposed
    4 / 446 (0.90%)
    5 / 442 (1.13%)
         occurrences all number
    4
    6
    Urinary retention
         subjects affected / exposed
    4 / 446 (0.90%)
    6 / 442 (1.36%)
         occurrences all number
    4
    6
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    4 / 446 (0.90%)
    4 / 442 (0.90%)
         occurrences all number
    4
    4
    Hypothyroidism
         subjects affected / exposed
    9 / 446 (2.02%)
    4 / 442 (0.90%)
         occurrences all number
    9
    4
    Musculoskeletal and connective tissue disorders
    Back/Flank pain
         subjects affected / exposed
    13 / 446 (2.91%)
    12 / 442 (2.71%)
         occurrences all number
    13
    12
    Pain in extremity
         subjects affected / exposed
    10 / 446 (2.24%)
    11 / 442 (2.49%)
         occurrences all number
    11
    11
    Neck pain
         subjects affected / exposed
    3 / 446 (0.67%)
    3 / 442 (0.68%)
         occurrences all number
    4
    3
    Arthritis
    Additional description: include Arthritis rheumatides
         subjects affected / exposed
    10 / 446 (2.24%)
    10 / 442 (2.26%)
         occurrences all number
    10
    13
    Fracture
         subjects affected / exposed
    12 / 446 (2.69%)
    12 / 442 (2.71%)
         occurrences all number
    12
    13
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    5 / 446 (1.12%)
    5 / 442 (1.13%)
         occurrences all number
    5
    7
    COVID-19-Infection
         subjects affected / exposed
    34 / 446 (7.62%)
    35 / 442 (7.92%)
         occurrences all number
    36
    35
    Upper respiratory infection
         subjects affected / exposed
    9 / 446 (2.02%)
    7 / 442 (1.58%)
         occurrences all number
    9
    8
    Urinary Tract Infection
         subjects affected / exposed
    40 / 446 (8.97%)
    23 / 442 (5.20%)
         occurrences all number
    46
    28
    Metabolism and nutrition disorders
    Hyperuricemia
         subjects affected / exposed
    4 / 446 (0.90%)
    0 / 442 (0.00%)
         occurrences all number
    5
    0
    Hyperkalemia
         subjects affected / exposed
    10 / 446 (2.24%)
    7 / 442 (1.58%)
         occurrences all number
    11
    9
    Hypokalemia
         subjects affected / exposed
    14 / 446 (3.14%)
    17 / 442 (3.85%)
         occurrences all number
    18
    20
    Hyperglycemia
         subjects affected / exposed
    20 / 446 (4.48%)
    7 / 442 (1.58%)
         occurrences all number
    22
    8

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2021
    - change protocol V2.0, update SmPCs, risk-benefit, change of PI

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/40946883
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sat Feb 14 01:06:57 CET 2026 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA