A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in Subjects With Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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The objective of the ADVANTAGE AF Study is to establish the safety and effectiveness of the FARAPULSE Pulsed Field Ablation System (FARAPULSE PFA System) for treatment of drug resistant, symptomatic persistent atrial fibrillation (PersAF).

Official Title
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in Subjects With Persistent Atrial Fibrillation

Conditions
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Persistent Atrial Fibrillation

Intervention / Treatment
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* Device: Phase 1: FARAPULSE Ablation System
* Device: Phase 2: FARAPULSE Ablation System


Participation Criteria
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Eligibility Criteria
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[PHASE 1] -------------------------------------------- Inclusion Criteria: Age ≥ 18 years of age, or older if specified by local law Subjects have symptomatic, documented, drug-resistant, Persistent AF, defined as: a. Documented: at a minimum a physician's note confirming the arrhythmia symptoms and durations AND, within 180 days of Enrollment Date, either: i. A 24-hour continuous ECG recording confirming continuous AF OR ii. Two ECGs from any regulatory cleared rhythm monitoring device showing continuous AF taken at least 7 days apart b. Drug-resistant: effectiveness failure of, intolerance to, or specific contraindication to at least one (1) AAD (Class I or III). c. Persistent: continuous AF for > 7 days and ≤ 365 days Subjects who are willing and capable of providing informed consent Subjects who are willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center Exclusion Criteria: Any of the following atrial conditions: Left atrial anteroposterior diameter ≥ 5.5 cm, or if LA diameter not available, non-indexed volume >100 ml (by MRI, CT or TTE report or physician note) Any prior atrial endocardial, epicardial or surgical ablation procedure for arrhythmia, other than right sided cavotricuspid isthmus ablation or for right sided SVT Current atrial myxoma Any PV abnormality, stenosis, or stenting (common and middle PVs are admissible) Current left atrial thrombus Cardiovascular exclusions - Any of the following CV conditions: a. History of sustained ventricular tachycardia or any ventricular fibrillation b. AF that is secondary to electrolyte imbalance, thyroid disease, alcohol, or other reversible / non-cardiac causes c. Current or anticipated pacemaker, implantable cardioverter defibrillator or cardiac resynchronization therapy devices, interatrial baffle, closure device, patch, or patent foramen ovale occluder, LA appendage closure, device or occlusion, active implantable loop recorder or insertable cardiac monitor at the time of ablation d. Valvular disease that is any of the following: i. Symptomatic ii. Causing or exacerbating congestive heart failure iii. Associated with abnormal LV function or hemodynamic measurements e. Hypertrophic cardiomyopathy f. Any prosthetic heart valve, ring or repair including balloon aortic valvuloplasty g. Any IVC filter, known inability to obtain vascular access or other contraindication to femoral access h. Rheumatic heart disease i. Congenital heart disease with any clinically significant residual anatomic or conduction abnormality j. Awaiting cardiac transplantation or other cardiac surgery within the next 12 months Any of the following conditions at baseline (Section7.5): Heart failure associated with NYHA Class III or IV LVEF < 40% Uncontrolled hypertension (SBP > 160 mmHg or DBP > 95 mmHg on two (2) BP measurements at baseline assessment Any of the following events within 90 days of the Consent Date: Myocardial infarction (MI), unstable angina or coronary intervention Any cardiac surgery Heart failure hospitalization Pericarditis or symptomatic pericardial effusion Gastrointestinal bleeding Stroke, TIA, or intracranial bleeding Any non-neurologic thromboembolic event Carotid stenting or endarterectomy Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis Contraindication to, or unwillingness to use, systemic anticoagulation Patients who have not been on anticoagulation therapy for at least 4 weeks prior to the ablation procedure Women of childbearing potential who are pregnant, lactating, not using medical birth control or who are planning to become pregnant during the anticipated study period 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, including but not limited to: Body Mass Index (BMI) > 42.0 Solid organ or hematologic transplant, or currently being evaluated for a transplant Any prior history or current evidence of hemi-diaphragmatic paralysis or paresis. Severe lung disease, pulmonary hypertension, or any lung disease involving abnormal blood gases or requiring supplemental oxygen 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 Active malignancy or history of treated malignancy within 24 months of enrollment (other than cutaneous basal cell or squamous cell carcinoma) Clinically significant gastrointestinal problems involving the esophagus or stomach including severe or erosive esophagitis, uncontrolled gastric reflux, gastroparesis, esophageal candidiasis or active gastroduodenal ulceration Active systemic infection COVID-19 disease i. Current confirmed, active COVID-19 disease ii. Current positive test for SARS-CoV-2 iii. Confirmed COVID-19 disease not clinically resolved at least 3 months prior to the Consent Date j. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior to the Consent Date k. Untreated diagnosed obstructive sleep apnea with apnea hypopnea index classification of severe (>30 pauses per hour) Predicted life expectancy less than one (1) year Subjects who are currently enrolled in another investigational study or registry that would directly interfere with the current 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 [PHASE 2] -------------------------------------------- Inclusion Criteria: Age ≥ 18 years of age, or older if specified by local law Subjects have symptomatic, documented, drug-resistant, Persistent AF, defined as: a. Documented: at a minimum a physician's note confirming the arrhythmia symptoms and durations AND, within 180 days of Enrollment Date, either: i. A 24-hour continuous ECG recording confirming continuous AF OR ii. Two ECGs from any regulatory cleared rhythm monitoring device showing continuous AF taken at least 7 days apart b. Drug-resistant: effectiveness failure of, intolerance to, or specific contraindication to at least one (1) AAD (Class I or III). c. Persistent: continuous AF for > 7 days and ≤ 365 days Subjects who are willing and capable of providing informed consent Subjects who are willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center Exclusion Criteria: Any of the following atrial conditions: Left atrial anteroposterior diameter ≥ 5.5 cm, or if LA diameter not available, non-indexed volume >100 ml (by MRI, CT or TTE report or physician note) Any prior atrial endocardial, epicardial or surgical ablation procedure for arrhythmia, other than right sided cavotricuspid isthmus ablation or for right sided SVT Current atrial myxoma Any PV abnormality, stenosis, or stenting (common and middle PVs are admissible) Current left atrial thrombus Cardiovascular exclusions - Any of the following CV 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, closure device, patch, or patent foramen ovale occluder, LA appendage closure, device or occlusion, active implantable loop recorder or insertable cardiac monitor at the time of ablation Valvular disease that is any of the following: i. Symptomatic ii. Causing or exacerbating congestive heart failure iii. Associated with abnormal LV function or hemodynamic measurements e. Hypertrophic cardiomyopathy f. Any prosthetic heart valve, ring or repair including balloon aortic valvuloplasty g. Any IVC filter, known inability to obtain vascular access or other contraindication to femoral access h. Rheumatic heart disease i. Awaiting cardiac transplantation or other cardiac surgery within the next 12 months j. Nitroglycerin intolerance: Known adverse drug reaction to nitroglycerin k. Coronary disease: Known severe non-revascularizable coronary disease l. Stents: Pre-existing right coronary artery stent Any of the following conditions at baseline (Section7.5): Heart failure associated with NYHA Class III or IV LVEF < 40% Uncontrolled hypertension (SBP > 160 mmHg or DBP > 95 mmHg on two (2) BP measurements at baseline assessment Ventricular dysfunction: Right ventricular dysfunction Any of the following events within 90 days of the Consent Date: Myocardial infarction (MI), unstable angina or coronary intervention Any cardiac surgery Heart failure hospitalization Pericarditis or symptomatic pericardial effusion Gastrointestinal bleeding Stroke, TIA, or intracranial bleeding Any non-neurologic thromboembolic event Carotid stenting or endarterectomy Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis Contraindication to, or unwillingness to use, systemic anticoagulation Patients who have not been on anticoagulation therapy for at least 4 weeks prior to the ablation procedure Women of childbearing potential who are pregnant, lactating, not using medical birth control or who are planning to become pregnant during the anticipated study period 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, including but not limited to: Body Mass Index (BMI) > 42.0 Solid organ or hematologic transplant, or currently being evaluated for a transplant Any prior history or current evidence of hemi-diaphragmatic paralysis or paresis. Severe lung disease, pulmonary hypertension, or any lung disease involving abnormal blood gases or requiring supplemental oxygen 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 Active malignancy or history of treated malignancy within 24 months of enrollment (other than cutaneous basal cell or squamous cell carcinoma) Clinically significant gastrointestinal problems involving the esophagus or stomach including severe or erosive esophagitis, uncontrolled gastric reflux, gastroparesis, esophageal candidiasis or active gastroduodenal ulceration Active systemic infection COVID-19 disease i. Current confirmed, active COVID-19 disease ii. Current positive test for SARS-CoV-2 iii. Confirmed COVID-19 disease not clinically resolved at least 3 months prior to the Consent Date j. Uncontrolled diabetes mellitus or a recorded HgbA1c > 8.0% in the 90 days prior to the Consent Date k. Untreated diagnosed obstructive sleep apnea with apnea hypopnea index classification of severe (>30 pauses per hour) l. Medication Use: Required use of phosphodiesterase inhibitors within 24 hours of the ablation procedure Predicted life expectancy less than one (1) year Subjects who are currently enrolled in another investigational study or registry that would directly interfere with the current 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 Any of the following congenital conditions: Congenital heart disease: Congenital heart disease with any clinically significant residual anatomic or conduction abnormality Methemoglobinemia: History of known congenital methemoglobinemia G6PD deficiency: History of known G6PD deficiency Contraindication to ICM insertion: Patients who cannot tolerate a subcutaneous, chronically-inserted LUX-Dx device LUX-Dx longevity: Patients with a LUX-Dx device inserted > 6 months prior to enrollment with an estimated longevity of less than 1 year

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pulsed Field Ablation (Phase 1)<br>PHASE 1 only | Device: Phase 1: FARAPULSE Ablation System<br>* PHASE 1: Pulsed Field Ablation to isolate the Pulmonary Veins and Posterior Wall using the FARAPULSE Ablation System.<br>|
| Experimental: Pulsed Field Ablation (Phase 2)<br>PHASE 2 only | Device: Phase 2: FARAPULSE Ablation System<br>* PHASE 2: Pulsed Field Ablation to isolate the Pulmonary Veins, Posterior Wall and Cavo-Tricuspid Isthmus using the FARAPULSE Ablation System.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Rate of Safety Events at 7 days Post Procedure | Death Myocardial infarction Stroke TIA Peripheral or organ thromboembolism Pulmonary edema Unresolved phrenic nerve palsy / paresis Vascular access complications Heart block Gastric motility / pyloric spasm disorders | 7 Days | 
| Phase 1: Rate of Safety Events at 30 days Post Procedure | Cardiac tamponade / perforation Pericarditis | 30 Days | 
| Phase 1: Rate of Safety Events at 12 Months Post Procedure | PV stenosis Atrio-esophageal fistula | 360 Days | 
| Phase 1: Rate of Persistent AF Acute Procedural Success | Using only the FARAWAVE Catheter, Acute Procedural Success is defined as: The isolation of all attempted Pulmonary Veins as clinically assessed at the end of the procedure by entrance block, AND The isolation of the Left Atrial Posterior Wall as clinically assessed at the end of the procedure via interrogation by multipolar diagnostic catheter or 3D electroanatomical mapping | 0 Days | 
| Phase 1: Rate of Persistent AF Chronic Success | Defined as the freedom from any of the following through the Day 360 Assessment after the Blanking Period, excluding documented CTI-dependent AFL: Arrhythmia: Occurrence of any Detectable AF, AFL or AT Re-ablation: Any re-ablation for AF, AFL or AT Cardioversion: Any electrical cardioversion for AF, AFL or AT AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone | 360 Days | 
| Phase 2: Rate of Safety Events at 7 days Post Procedure | Myocardial infarction Stroke Transient Ischemic Attack (TIA) Peripheral or organ thromboembolism Pulmonary edema Unresolved phrenic nerve palsy / paresis Vascular access complications Heart block Gastric motility / pyloric spasm disorders | 7 Days | 
| Phase 2: Rate of Safety Events at 30 days Post Procedure | Death Cardiac tamponade / perforation Pericarditis Any PFA system related PFA procedure-related cardiovascular or pulmonary adverse event | 30 Days | 
| Phase 2: Rate of Safety Events at 90 days Post Procedure | PV stenosis Atrio-esophageal fistula | 90 Days | 
| Phase 2: Rate of Persistent AF Acute Procedural Success | The isolation of all attempted PVs as clinically assessed at the end of the procedure by entrance block performed with or without adenosine testing, AND The isolation of the left atrial PW as clinically assessed at the end of the procedure, performed with or without adenosine testing, via interrogation by multipolar diagnostic catheter or 3D electroanatomical mapping. | 0 Days | 
| Phase 2: Rate of Persistent AF Chronic Success | Defined as the freedom from any of the following through the Day 360 Assessment after the Blanking Period, excluding documented CTI-dependent AFL: Arrhythmia: Occurrence of any Detectable AF, AFL or AT Re-ablation: Any re-ablation for AF, AFL or AT Cardioversion: Any electrical cardioversion for AF, AFL or AT AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone | 360 Days |