AMPLATZER™ Amulet™ LAA Occluder Trial

Study Overview
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Brief Summary
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The Amulet™ device will be evaluated for safety and efficacy by demonstrating its performance is non-inferior to the commercially available WATCHMAN® left atrial appendage closure device in patients with non-valvular atrial fibrillation. Patients who are eligible for the trial will be randomized to receive either the Amulet device or the WATCHMAN device and will be followed for 5 years after device implant.

Detailed Description
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The Amulet IDE trial is a prospective, randomized, multi-center active control worldwide trial, designed to evaluate the safety and effectiveness of the AMPLATZER™ Amulet™ Left Atrial Appendage Occluder. Subjects will be randomized in a 1:1 ratio between the Amulet left atrial appendage (LAA) occlusion device (treatment) or a Boston Scientific WATCHMAN® LAA closure device (Control). The trial will be conducted at up to 150 sites worldwide. All enrolled subjects will follow the protocol-required tests and assessments at each scheduled follow-up visit.

Official Title
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AMPLATZER™ Amulet™ Left Atrial Appendage Occluder Randomized Controlled Trial

Conditions
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Stroke

Intervention / Treatment
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* Device: Amulet Left Atrial Appendage Occluder
* Device: WATCHMAN Left Atrial Appendage Closure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Documented paroxysmal, persistent, or permanent non-valvular atrial fibrillation (AF) and the patient has not been diagnosed with rheumatic mitral valvular heart disease At high risk of stroke or systemic embolism defined as CHADS2 score ≥ 2 or a CHA2DS2-VASc score of ≥ 3 Has an appropriate rationale to seek an alternative to warfarin or other anticoagulation medication Deemed by investigator to be suitable for short term warfarin therapy but deemed unable to take long term oral anticoagulation, following the conclusion of shared decision making (see inclusion criteria #6) Deemed suitable for LAA closure by a multidisciplinary team of medical professionals (including an independent non-interventional physician) involved in the formal and shared decision- making process, and by use of an evidence-based decision tool on oral anticoagulation (final determination must be documented in the subject's medical record) Able to comply with the required medication regimen post-device implant Able to understand and willing to provide written informed consent to participate in the trial Able and willing to return for required follow-up visits and examinations Exclusion Criteria: Requires long-term oral anticoagulation therapy for a condition other than atrial fibrillation Contraindicated for or allergic to aspirin, clopidogrel, or warfarin use Indicated for chronic P2Y12 platelet therapy inhibitor Is considered at high risk for general anesthesia, in the opinion of the investigator, and/or based on past adverse reaction(s) requiring medical intervention or which resulted in prolongation of hospital stay (criterion is only applicable where general anesthesia is planned for the study procedure). Has undergone atrial septal defect (ASD) repair or has an ASD closure device present Has undergone patent foramen ovale (PFO) repair or has a PFO closure device implanted Implanted with a mechanical valve prosthesis Has any of the customary contraindications for a percutaneous catheterization procedure (e.g. subject is too small to accommodate the transesophageal echocardiogram (TEE/TOE) probe or required catheters, or subject has active infection or bleeding disorder) Stroke or transient ischemic attack (TIA) within 90 days prior to randomization or implant procedure (as applicable) Underwent any cardiac or non-cardiac intervention or surgery within 30 days prior to randomization, or intervention or surgery is planned within 60 days after implant procedure (e.g. cardioversion, ablation, cataract surgery, etc.) Myocardial infarction (MI) within 90 days prior to randomization New York Heart Association Class IV Congestive Heart Failure Left ventricular ejection Fraction (LVEF) ≤30% Symptomatic carotid artery disease (defined as >50% stenosis with symptoms of ipsilateral transient or visual TIA evidenced by amaurosis fugax, ipsilateral hemispheric TIAs or ipsilateral stroke); if subject has a history of carotid stent or endarterectomy the subject is eligible if there is <50% stenosis Reversible cause of AF (i.e. secondary thyroid disorders, acute alcohol intoxication, trauma, recent major surgical procedures) History of idiopathic or recurrent venous thromboembolism Left atrial appendage is obliterated or surgically ligated Thrombocytopenia or anemia requiring transfusions Hypersensitivity to any portion of the device material or individual components of either the Amulet or Boston Scientific LAA closure device (e.g. nickel allergy) Actively enrolled or plans to enroll in a concurrent clinical study in which the active treatment arm may confound the results of this trial Subject is pregnant or pregnancy is planned during the course of the investigation Active endocarditis or other infection producing bacteremia Subject has had a transient case of AF (i.e. never previously detected, provoked/induced by surgical or catheter manipulations, etc.) Subjects with severe renal failure (estimated glomerular filtration rate <30ml/min/1.73m²) Subject whose life expectancy is less than 2 years Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical trial or to comply with follow up requirements, or impact the scientific soundness of the clinical trial results. Echocardiographic Exclusion Criteria: Intracardiac thrombus visualized by echocardiographic imaging Existing circumferential pericardial effusion >2mm Significant mitral valve stenosis (i.e. mitral valve area <1.5 cm^2) High risk PFO, defined as an atrial septal aneurysm (excursion > 15mm or length ≥ 15mm; excursion defined as maximal protrusion of the atrial septal aneurysm [ASA] beyond the plane of the atrial septum) or large shunt (early, within 3 beats and/or substantial passage of bubbles i.e. ≥ 20) Complex atheroma with mobile plaque of the descending aorta and/or aortic arch Cardiac tumor LAA anatomy cannot accommodate either a Boston Scientific LAA closure device or Amulet device, as per manufacturer's Instructions for Use (IFU). (i.e. the LAA anatomy and sizing must be appropriate for both devices in order to be enrolled in the trial. This is applicable to all roll-in and randomized subjects). Placement of the device would interfere with any intracardiac or intravascular structure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amulet<br>Amulet left atrial appendage occluder | Device: Amulet Left Atrial Appendage Occluder<br>* Transcatheter left atrial appendage closure<br>|
| Active Comparator: WATCHMAN (Control)<br>WATCHMAN left atrial appendage closure device | Device: WATCHMAN Left Atrial Appendage Closure<br>* Transcatheter left atrial appendage closure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Endpoint: Composite Endpoint Rate of Procedure-related Complications, or All-cause Death or Major Bleeding (Defined as Type 3 or Greater Based on the Bleeding Academic Research Consortium (BARC) Definition) (Non-inferiority Analysis) | Procedure related complications are adverse events adjudicated by the Clinical Events Committee (CEC), as procedure related and requiring either invasive surgical or percutaneous intervention. All-cause deaths (cardiovascular or non-cardiovascular) were assessed. Major Bleeding Type 3a: Any transfusion with overt bleeding Overt bleeding+Hb drop of ≥ 3 to < 5 g/dL (provided Hb drop is related to bleed) Type 3b: Overt bleeding+Hb drop ≥ 5 g/dL (provided Hb drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for (Watchman) Bleeding requiring intravenous vasoactive drugs Type 3c: Intracranial hemorrhage including subdural hemorrhages Subcategories confirmed by autopsy/imaging/lumbar puncture Intraocular bleed compromising vision Type 5a: Probably fatal bleeding Type 5b: Definite fatal bleeding | At 12-months | 
| Primary Effectiveness Endpoint: Composite Rate of Ischemic Stroke or Systemic Embolism (Non-inferiority Analysis) | Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Systemic Embolism: Acute vascular insufficiency or occlusion of the extremities or any non-central nervous system (non-CNS) organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism (e.g. trauma, atherosclerosis, or instrumentation). When there is presence of prior peripheral artery disease, angiographic or surgical or autopsy evidence is required to show abrupt arterial occlusion. | At 18-months | 
| Mechanism of Action Primary Endpoint: Rate of Device Closure, by the Echocardiography Core Lab (Non-inferiority Analysis) | Device closure (defined as residual jet around the device ≤ 5 mm) at the 45-day visit documented by transesophageal echocardiogram (TEE/TOE) defined by Doppler flow was assessed. | At 45-days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Rate of All Stroke, Systemic Embolism, or Cardiovascular/Unexplained Death (Non-inferiority Analysis) | Stroke: An acute episode of focal or global neurological dysfunction caused by the brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Systemic Embolism: Acute vascular insufficiency/occlusion of the extremities/any non-CNS organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism (trauma/atherosclerosis/instrumentation). When there is presence of prior peripheral artery disease, angiographic/surgical/autopsy evidence is required to show abrupt arterial occlusion. Cardiovascular/unexplained death includes: Death due to proximate cardiac cause Death caused by non-coronary/non-CNS vascular conditions Death from vascular CNS causes All procedure-related deaths Sudden/unwitnessed death Death of unknown cause | At 18-months | 
| Rate of Major Bleeding (Superiority Analysis) | Major bleeding rate defined as Type 3 or greater based on the Bleeding Academic Research Consortium (BARC) definition was assessed Type 3a: Any transfusion with overt bleeding Overt bleeding+Hb drop of ≥ 3 to < 5 g/dL (provided Hb drop is related to bleed) Type 3b: Overt bleeding+Hb drop ≥ 5 g/dL (provided Hb drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for (Watchman) Bleeding requiring intravenous vasoactive drugs Type 3c: Intracranial hemorrhage including subdural hemorrhages Subcategories confirmed by autopsy/imaging/lumbar puncture Intraocular bleed compromising vision Type 5a: Probably fatal bleeding: bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging Type 5b: Definite fatal bleeding: bleeding that is directly observed or confirmed on autopsy | At 18-months | 
| Superiority Test of Primary Safety Endpoint: Composite Endpoint Rate of Procedure-related Complications, or All-cause Death or Major Bleeding (Defined as Type 3 or Greater Based on the Bleeding Academic Research Consortium (BARC) Definition) | Procedure related complications are adverse events adjudicated by the Clinical Events Committee (CEC), as procedure related and requiring either invasive surgical or percutaneous intervention. All-cause deaths (cardiovascular or non-cardiovascular) were assessed. Major Bleeding Type 3a: Any transfusion with overt bleeding Overt bleeding+Hb drop of ≥ 3 to < 5 g/dL (provided Hb drop is related to bleed) Type 3b: Overt bleeding+Hb drop ≥ 5 g/dL (provided Hb drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for (Watchman) Bleeding requiring intravenous vasoactive drugs Type 3c: Intracranial hemorrhage including subdural hemorrhages Subcategories confirmed by autopsy/imaging/lumbar puncture Intraocular bleed compromising vision Type 5a: Probably fatal bleeding Type 5b: Definite fatal bleeding | At 12-months | 
| Superiority Test of Primary Effectiveness Endpoint: Composite Rate of Ischemic Stroke or Systemic Embolism | Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue. Systemic Embolism: Acute vascular insufficiency or occlusion of the extremities or any non-central nervous system (non-CNS) organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism (e.g. trauma, atherosclerosis, or instrumentation). When there is presence of prior peripheral artery disease, angiographic or surgical or autopsy evidence is required to show abrupt arterial occlusion. | At 18-months | 
| Superiority Test of Primary Mechanism of Action Endpoint: Rate of Device Closure, by the Echocardiography Core Lab | Device closure (defined as residual jet around the device ≤ 5 mm) at the 45-day visit documented by transesophageal echocardiogram (TEE/TOE) defined by Doppler flow was assessed. | At 45-days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-valvular atrial fibrillation, Left Atrial Appendage