The Fourth Left Atrial Appendage Occlusion Study (LAAOS-4)

• ClinicalTrials.gov Identifier: NCT05963698
• Recruitment Status: Recruiting
• First Posted: July 27, 2023
• Last Update Posted: December 18, 2023
• Sponsor: Hamilton Health Sciences Corporation
• Collaborators: McMaster University; Population Health Research Institute; Boston Scientific Corporation
• Information provided by (Responsible Party): Hamilton Health Sciences Corporation

Study Description

Brief Summary:

LAAOS-4 aims to determine if catheter-based endovascular left atrial appendage occlusion prevents ischemic stroke or systemic embolism in participants with atrial fibrillation, who remain at high risk of stroke, despite receiving ongoing treatment with oral anticoagulation.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation; Stroke, Ischemic; Systemic Embolism	Device: WATCHMAN device	Not Applicable

Detailed Description:

LAAOS-4 is a multicentre, prospective, open-label, randomized controlled trial with blinded assessment of endpoints (PROBE) to determine if catheter-based endovascular left atrial appendage occlusion prevents ischemic stroke or systemic embolism in participants with atrial fibrillation, who remain at high risk of stroke, despite receiving ongoing treatment with oral anticoagulation.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 4000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized Controlled Trial
• Masking: Single (Outcomes Assessor)
• Masking Description: Events Adjudication Committee is blinded to intervention assignment.
• Primary Purpose: Treatment
• Official Title: The Fourth Left Atrial Appendage Occlusion Study (LAAOS-4)
• Actual Study Start Date: November 30, 2023
• Estimated Primary Completion Date: September 1, 2029
• Estimated Study Completion Date: December 1, 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: WATCHMAN device; Participants will undergo endovascular left atrial appendage occlusion with the WATCHMAN device	Device: WATCHMAN device; Participants will undergo endovascular left atrial appendage occlusion with the WATCHMAN device
No Intervention: Standard Care; Participants will receive local, standard medical care

Outcome Measures

Primary Outcome Measures :

1. Ischemic stroke or systemic embolism [ Time Frame: The study duration is event-driven. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]

   The primary efficacy variable is the time from randomization to first occurrence of any of the components of the composite outcome (adjudicated) over the duration of follow-up, including:

   • Ischemic stroke (Strokes of undetermined etiology will be treated as ischemic stroke)
   • Systemic embolism

Secondary Outcome Measures :

1. All-cause stroke or systemic embolism [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]

   Secondary efficacy outcomes will be evaluated in a hierarchical fashion only when the primary outcome meets statistical significance in the specified order:

   Time from randomization to first occurrence of all-cause stroke or systemic embolism

2. All-cause stroke, systemic embolism, or transient ischemic attack (TIA) [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to first occurrence of all-cause stroke, systemic embolism or transient ischemic attack (TIA)
3. Montreal Cognitive Assessment (MoCA) Score [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Proportion of participants with a decrease of two or more points on the MoCA score at either year 2 or end of study
4. New disabling ischemic strokes [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to first occurrence of disabling ischemic strokes with modified Rankin Score (mRS) >2, measured at 90 days post-stroke
5. Cardiovascular mortality [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to cardiovascular mortality
6. All-cause mortality [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to all-cause mortality

Other Outcome Measures:

1. Non-procedural Major Bleeding [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Proportion of participants with non-procedural Major Bleeding (International Society on Thrombosis and Haemostasis (ISTH) definition; excluding WATCHMAN-related bleeding within 14 days of implant)
2. Hospitalization for any cause [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to first occurrence of hospitalization for any cause
3. Heart failure hospitalization or emergency department/clinic visit for intensification of heart failure related therapy [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to first occurrence of heart failure hospitalization or emergency department/clinic visit for intensification of heart failure related therapy
4. Myocardial Infarction [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Time from randomization to first occurrence of Myocardial Infarction (4th Universal definition)
5. Device and procedural-related outcomes: Device-related thrombus [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Proportion of participants with device-related thrombus (thrombus formed on the surface of the WATCHMAN device)
6. Device and procedural-related outcomes: Incomplete left atrial appendage (LAA) closure [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Proportion of participants with incomplete LAA closure
7. Device and procedural-related outcomes: Peri-procedural major bleeding [ Time Frame: Will be evaluated once primary outcome meets statistical significance. The primary analysis will be performed through study completion, once 265 primary efficacy endpoint events have occurred (an estimated average follow-up of 4 years). ]
   Proportion of participants with peri-procedural major bleeding (ISTH definition; within 14 days following the procedure)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. (a) Persistent or permanent atrial fibrillation OR (b) Paroxysmal atrial fibrillation in participants with a history of ischemic stroke or systemic embolism
2. Increased risk of stroke, defined as a CHA2DS2-VASc stroke risk score of ≥ 4. [Note: the acronym CHA2DS2-VASc stands for congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female).]
3. Treatment with oral anticoagulants (Vitamin K agonist or factor Xa inhibitor) for at least 90 days prior to enrollment, AND no documented plan to discontinue treatment with oral anticoagulants for the expected duration of the trial.

Exclusion Criteria:

1. Age < 18 years
2. Current left atrial appendage thrombus
3. Prior left atrial appendage occlusion or removal (surgical or percutaneous)
4. Prior percutaneous atrial septal defect or patent foramen ovale closure
5. Prior atrial fibrillation ablation unless evidence of recurrent qualifying atrial fibrillation present at least 30 days following ablation
6. Planned atrial fibrillation ablation within 90 days of enrollment
7. Individuals being treated with direct thrombin inhibitors
8. Women of childbearing potential unless they agree to employ effective birth control methods throughout the study
9. Anticipated life-expectancy of < 2 years
10. Patient unable or willing to give informed consent

Contacts and Locations

Contacts

Contact: Program Director; 905-521-2100; LAAOS-4@phri.ca

Locations

United States, Arkansas

Arrhythmia Research Group; Recruiting

Jonesboro, Arkansas, United States, 72401

Contact: Cary Ball 870-316-8181 cball@dnairresearch.com

Principal Investigator: Devi Nair, MD

Canada, Ontario

Hamilton Health Sciences Corp; Recruiting

Hamilton, Ontario, Canada, L8L 2X2

Sponsors and Collaborators

Hamilton Health Sciences Corporation

McMaster University

Population Health Research Institute

Boston Scientific Corporation

Investigators

• Principal Investigator: Jeff Healey; Hamilton Health Sciences Corporation

More Information

• Responsible Party: Hamilton Health Sciences Corporation
• ClinicalTrials.gov Identifier: NCT05963698
• Other Study ID Numbers: LAAOS-4
• First Posted: July 27, 2023
• Last Update Posted: December 18, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by Hamilton Health Sciences Corporation:

WATCHMAN; Left Atrial Appendage (LAA); LAA Device; Left Atrial Appendage Occlusion

Additional relevant MeSH terms:

Ischemic Stroke; Atrial Fibrillation; Embolism; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Embolism and Thrombosis; Vascular Diseases; Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases