Clinical Trials Register

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:	Completed
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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-000058-21

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

CLOSURE-AF-DZHK16

A.4.1

Sponsor's protocol code number

CLOSURE-AF-DZHK16

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03463317

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1194-4541

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinik für Kardiologie, Angiologie und Intensivmedizin - Deutsches Herzzentrum der Charité - Campus Benjamin Franklin
B.5.2	Functional name of contact point	Studienzentrale
B.5.3	Address:
B.5.3.1	Street Address	Hindenburgdamm 30
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	12203
B.5.3.4	Country	Germany
B.5.6	E-mail	closure-af@dzhk.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ACETYLSALICYLIC ACID
D.3.4	Pharmaceutical form	Gastro-resistant tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.3	Other descriptive name	ASA, ASS
D.3.9.4	EV Substance Code	SUB12730MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	CLOPIDOGREL
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOPIDOGREL
D.3.9.1	CAS number	744256-69-7
D.3.9.3	Other descriptive name	CLOPIDOGREL BESILATE
D.3.9.4	EV Substance Code	SUB30714
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DABIGATRAN
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DABIGATRAN
D.3.9.3	Other descriptive name	DABIGATRAN ETEXILATE MESILATE
D.3.9.4	EV Substance Code	SUB27581
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RIVAROXABAN
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.4	EV Substance Code	SUB29263
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	APIXABAN
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	APIXABAN
D.3.9.4	EV Substance Code	SUB25425
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	EDOXABAN
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EDOXABAN
D.3.9.1	CAS number	480449-71-6
D.3.9.3	Other descriptive name	EDOXABAN TOSYLATE
D.3.9.4	EV Substance Code	SUB35059
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 7
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PHENPROCOUMON
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PHENPROCOUMON
D.3.9.1	CAS number	435-97-2
D.3.9.4	EV Substance Code	SUB09781MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 8
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	WARFARIN
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	WARFARIN
D.3.9.3	Other descriptive name	WARFARIN SODIUM
D.3.9.4	EV Substance Code	SUB05128MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Atrial Fibrillation with high risk of stroke and bleeding

Vorhofflimmern mit hohen Schlaganfall- und Blutungsrisiko

E.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

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).

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.2.2

Secondary objectives of the trial

Not applicable.

Nicht zutreffend.

E.2.3

Trial contains a sub-study

E.3

Principal 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) or negative SARS-CoV-2 rapid antigen test (no longer than 24 hours prior to randomization)

- 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) oder negativer SARS-CoV-2 Antigen-Schnelltest (nicht älter als 24 Stunden vor Randomisierung)

E.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(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*, 60*, 72* and 84* months, EOS* (*phone visits).

Die Patienten werden bei den Visiten nach 7 Tagen*, 30 Tagen*, 3, 6*, 12, 18*, 24, 36*, 48*, 60*, 72* und 84* Monaten, EOS* (*Telefon-Visiten) auf den primären Endpunkt hin untersucht/ befragt.

E.5.2

Secondary 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)
- Changes in modified Rankin Scale (mRS)

Secondary safety endpoint(s):
- Device-related complications until day 7 or discharge and total follow-up time
- Device thrombus/fracture/erosion/infection/embolization
- Pericardial effusion
- Procedure related death
- Technical and procedural success of device implantation (see also protocol chapter 4.2.4)
- Peri-procedural outcomes at 7 days or discharge and 30 calendar days after implantation (see also protocol chapter 4.2.4)
- Additionally, the total number of SAEs will be analyzed

- 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
- Veränderungen im modified Rankin Scale (mRS)

Sekundäre Sicherheitsendpunkte:
- Device-bedingte Komplikationen bis Tag 7 oder bis Entlassung und Gesamtnachbeobachtungszeit
- Thrombus / Fraktur / Erosion / Infektion / Embolisierung am LAA-Okkluder
- Perikarderguss
- Prozedur bedingter Tod
- Technischer und prozeduraler Erfolg der LAA-Okkluder-Implantation (siehe Protokoll Kapitel 4.2.4)
- Periprozedurale Ergebnisse nach 7 Tagen oder bei Entlassung und 30 Kalendertagen nach Implantation (siehe Protokoll Kapitel 4.2.4)
- Zusätzlich wird die Gesamtzahl der SAEs analysiert

E.5.2.1

Timepoint(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*, 60*, 72* and 84* months, EOS* (*phone visits).

Die Patienten werden bei den Visiten nach 7 Tagen*, 30 Tagen*, 3, 6*, 12, 18*, 24, 36*, 48*, 60*, 72* und 84* Monaten, EOS* (*Telefon-Visiten) auf den primären Endpunkt hin untersucht/ befragt.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

270

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

700

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

970

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 treatment no longer has to take place in the trial site, and can also be carried out by a cardiologist in private practice.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-30

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