Pulsed Field Ablation (PFA) Versus Anti-Arrhythmic Drug (AAD) Therapy as a First Line Treatment for Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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The purpose of this study is to establish the safety and effectiveness of pulsed field ablation as a first-line ablation treatment for subjects with persistent atrial fibrillation as compared to subjects who received an initial treatment with anti-arrhythmic drugs.

Detailed Description
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This is a prospective, randomized, multi-center, global, pivotal Investigational device exemption (IDE) study. Subjects with persistent atrial fibrillation will be randomized to either pulsed field ablation (PFA) or Versus Anti-Arrhythmic Drug (AAD) treatment. Subjects randomized to PFA treatment will undergo percutaneous ablative pulmonary vein isolation (PVI) and left atrial posterior wall isolation (PWI) using the FARAWAVE™ PFA Catheter (first-line ablation cohort). Subjects randomized to AAD treatment will be prescribed and monitored in accordance with local clinical practice and already established guideline-directed therapy for patients with persistent atrial fibrillation (AF). Cardioversion is recommended during the initiation of antiarrhythmic drugs for subjects who are not in sinus rhythm. In the case of clinical inefficacy, the AAD dose will be up-titrated to the maximum tolerated dose. Thereafter, a change to a second or to a third AAD should be undertaken, insofar as the subject remains within the blanking period, with the goal to completely suppress AF episodes ≥ 30 seconds in duration. It is advisable to perform cardioversion with each dose titration or when changing the AAD regimen. If AAD treatment is proven to be ineffective or intolerable outside of the blanking period, subjects can undergo subsequent ablation therapy and be considered part of the delayed ablation cohort.

Official Title
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A Prospective Randomized Multicenter Global Study Comparing Pulsed Field Ablation (PFA) Versus Anti-Arrhythmic Drug (AAD) Therapy as a First Line Treatment for Persistent Atrial Fibrillation

Conditions
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Persistent Atrial Fibrillation

Intervention / Treatment
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* Device: FARAPULSE™ Pulsed Field Ablation (PFA) System
* Drug: Anti-Arrhythmic Drug (AAD): Flecainide, Sotalol, Propafenone, and Dofetilide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age ≥ 18 years of age, or older if specified by local law 2. Have symptomatic persistent AF, confirmed by both: Documentation, within 180 days of randomization, or treatment assignment for roll-in subjects, of either: i. A 24-hour continuous ECG recording (from any regulatory cleared rhythm monitoring device) confirming continuous AF, OR ii. Two ECGs (from any regulatory cleared rhythm monitoring device) showing continuous AF taken at least 7 days apart Documentation, such as physician note, of persistent continuous AF for > 7 days and ≤ 365 days 3. Willing and capable of providing informed consent 4. Willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center 5. Willing to receive LUX-Dx™ insertable cardiac monitor (ICM) during the study or already has a LUX-Dx™ ICM that was inserted ≤ 6 months of consent Exclusion Criteria: 1. Over the 6 months preceding enrollment, more than 7-day history of therapeutic AAD use (Class I or III), or ≥ 24 hours amiodarone, except for pill-in-the-pocket AAD use, which is permitted. Or, treated with AAD > 6 months preceding enrollment and experienced AAD failure (adverse drug effects or frequent AF episodes) 2. Any of the following atrial conditions: Left atrial (LA) anteroposterior diameter ≥ 5.5 cm, or, if LA diameter not available, non-indexed volume >100 ml, as documented by physician note or imaging (Note: if both values are available, only the LA diameter will be used to confirm eligibility criteria) Any prior atrial endocardial, epicardial or surgical ablation procedure for arrhythmia, other than right sided cavotricuspid isthmus ablation or for right sided supraventricular tachycardia Current atrial myxoma Any PV abnormality, stenosis, or stenting (common and middle PVs are admissible) Current left atrial thrombus 3. Any of the following cardiovascular conditions: History of sustained ventricular tachycardia or any ventricular fibrillation AF that is secondary to electrolyte imbalance, thyroid disease, alcohol, or other reversible / non-cardiac causes Current or anticipated pacemaker, implantable cardioverter defibrillator or cardiac resynchronization therapy devices, interatrial baffle, atrial septal patch, atrial septal defect closure device, or patent foramen ovale occluder Valvular disease that is any of the following: i. Symptomatic, ii. Causing or exacerbating congestive heart failure, iii. Associated with abnormal left ventricular (LV) function or hemodynamic measurements Hypertrophic cardiomyopathy Cardiac amyloidosis Any prosthetic heart valve, ring or repair including balloon aortic valvuloplasty Any inferior vena cava (IVC) filter, known inability to obtain vascular access or other contraindication to femoral access Rheumatic heart disease Congenital heart disease with any clinically significant residual anatomic or conduction abnormality Awaiting cardiac transplantation or other cardiac surgery within the next 12 months 4. Any of the following conditions identified during screening assessments Heart failure associated with New York Heart Association (NYHA) Class IV Left Ventricle Ejection Fraction (LVEF) < 40% Uncontrolled hypertension (Systolic Blood Pressure > 160 mmHg or Diastolic Blood Pressure > 95 mmHg on two (2) BP measurements during screening 5. Any of the following events 90 days prior to randomization (or Index procedure for roll-in subjects): Myocardial infarction (MI), unstable angina or coronary intervention Cardiac surgery Heart failure hospitalization Pericarditis or symptomatic pericardial effusion Gastrointestinal bleeding Stroke, TIA, or intracranial bleeding Non-neurologic thromboembolic event Carotid stenting or endarterectomy 6. Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis 7. Contraindication to, or unwillingness to use, systemic anticoagulation, AADs (Class I and III, excluding amiodarone which is not allowed during the study), and PFA treatment 8. Unwillingness to receive, or unable to tolerate, a subcutaneous, chronically inserted LUX-Dx™ ICM device 9. Women of childbearing potential who are pregnant, lactating, not using a reliable form of contraception, or who are planning to become pregnant during the anticipated study period 10. Body Mass Index (BMI) > 45 11. Solid organ or hematologic transplant, or currently being evaluated for a transplant 12. Any prior history or current evidence of hemi-diaphragmatic paralysis or paresis 13. Severe lung disease, or any lung disease involving abnormal blood gases or requiring supplemental oxygen 14. Severe pulmonary hypertension during screening assessment 15. Renal insufficiency if an estimated glomerular filtration rate (eGFR) is < 30 mL / min / 1.73 m2, or with any history of renal dialysis or renal transplant 16. Active malignancy at enrollment (other than cutaneous basal cell or squamous cell carcinoma) 17. Clinically significant gastrointestinal problems involving the esophagus or stomach including severe or erosive esophagitis, uncontrolled gastric reflux, gastroparesis, esophageal candidiasis or active gastroduodenal ulceration 18. Known active systemic infection 19. Known positive test for Coronavirus Disease 2019 (COVID-19) and disease not clinically resolved 20. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior to randomization (or Index procedure for roll-in subjects) 21. Untreated diagnosed obstructive sleep apnea with apnea hypopnea index classification of severe (>30 pauses per hour) 22. Predicted life expectancy less than one (1) year 23. Currently enrolled in another investigational study or registry that would directly interfere with this study, except when the subject is participating in a mandatory governmental registry, or a purely observational registry with no associated treatments; each instance must be brought to the attention of the Sponsor to determine eligibility 24. Health conditions that, in the investigator's medical opinion, would prevent participation in the study, interfere with assessment or therapy, significantly raise the risk of study participation, or modify outcome data or its interpretation 25. Has operational LUX-Dx ICM that was inserted more than 6 months prior to enrollment 26. Has operational ICM other than a LUX-Dx ICM and does not express a willingness to receive a LUX-Dx ICM for the study 27. Individuals who may require an ablation, besides the PV and PW, in the left atrium including, but not limited to, those with Left-Sided Atrioventricular Reentrant Tachycardia (AVRT), Left-Sided Atrial Tachycardia (AT), or Atypical Left-Sided Atrial Flutter.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pulsed Field Ablation (PFA)<br>Pulsed Field Ablation (PFA) is used as the initial treatment for subjects with persistent atrial fibrillation (AF) | Device: FARAPULSE™ Pulsed Field Ablation (PFA) System<br>* Subjects will undergo a pulsed field ablation procedure using the FARAPULSE™ Pulsed Field Ablation (PFA) System for the isolation of pulmonary veins and posterior wall.<br>|
| Active Comparator: Anti-Arrhythmic Drug (AAD)<br>Anti-Arrhythmic Drug (AAD) is used as the initial treatment for subjects with persistent atrial fibrillation (AF) | Drug: Anti-Arrhythmic Drug (AAD): Flecainide, Sotalol, Propafenone, and Dofetilide<br>* Anti-Arrhythmic Drugs (AADs) including, Flecainide, Sotalol, Propafenone, and Dofetilide will be prescribed and monitored in accordance with local clinical practice and already established guideline-directed therapy for patients with persistent atrial fibrillation (AF).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of intent to treat subjects, randomized to PFA with PFA System inserted into body, during index procedure or repeat PFA procedure during blanking period, with device or procedure-related Composite Adverse Events that is serious. | Composite Adverse Events are defined as follows: Day 0 through Day 7: Gastric motility / pyloric spasm disorders Heart block Myocardial infarction Peripheral or organ thromboembolism Pulmonary edema Stroke/ Cerebrovascular accident (CVA) Transient ischemic attack (TIA) Unresolved phrenic nerve palsy / paresis Vascular access complications Day 0 through Day 30: Cardiac tamponade / perforation Cardiovascular or pulmonary adverse event Death Pericarditis Day 0 through Month 12 Atrio-esophageal fistula Pulmonary vein stenosis | 12-Months | 
| Rate of intent to treat subjects with treatment success from the pulse field ablation treatment and Anti-Arrhythmic Drug treatment. | Rate of Intent to Treat subjects with Treatment Success through Month 12 assessment PFA Treatment Arm: Acute Success - Isolation of all attempted pulmonary veins and left atrial posterior wall with PFA system Chronic Success: Freedom from amiodarone use and after the blanking period through the Month-12 assessment occurrence of: Occurrence ≥ 1 hour of asymptomatic or ≥ 30 seconds of symptomatic Atrial Fibrillation (AF), Atrial Flutter (AFL), or Atrial Tachycardia (AT) Any re-ablation for AF, AFL, or AT Any electrical cardioversion for AF, AFL, or AT Any Class I or III AAD use AAD Treatment Arm: Acute Success - Ablation not performed during the blanking period Chronic Success - Freedom from amiodarone use and after the blanking period through the Month 12 assessment of occurrence of: Detectable occurrence ≥ 1 hour of asymptomatic or ≥ 30 seconds of symptomatic AF, AFL, or AT Electrical cardioversion for AF, AFL, or AT Any ablation for AF, AFL, or AT | 12-Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Atrial fibrillation burden between the pulsed field ablation and anti-arrhythmic drug arm, as measured by the LUX-Dx Insertable Cardiac Monitor and defined as the proportion of time an individual spends in AF during a period (expressed as a percentage). | Atrial Fibrillation (AF) burden, as measured by the LUX-Dx Insertable Cardiac Monitor (ICM) between the 2 randomized groups: Pulsed Field Ablation (PFA) as initial treatment for subjects with persistent AF Anti-Arrhythmic Drug (AAD) as initial treatment for subjects with persistent AF AF Burden is defined as the proportion of time an individual spends in AF during a period (expressed as a percentage). | 12, 24, and 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulsed Field Ablation, Atrial Fibrillation, Heart Diseases, Persistent Atrial Fibrillation, Insertable Cardiac Monitor, Cardiovascular Diseases