Persistent Atrial Fibrillation
Conditions
Brief summary
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).
Interventions
DEVICEPhase 1: FARAPULSE Ablation System
PHASE 1: Pulsed Field Ablation to isolate the Pulmonary Veins and Posterior Wall using the FARAPULSE Ablation System.
DEVICEPhase 2: FARAPULSE Ablation System
PHASE 2: Pulsed Field Ablation to isolate the Pulmonary Veins, Posterior Wall and Cavo-Tricuspid Isthmus using the FARAPULSE Ablation System.
Sponsors
Boston Scientific Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\[PHASE 1\] -------------------------------------------- Inclusion Criteria: 1. Age ≥ 18 years of age, or older if specified by local law 2. 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 3. Subjects who are willing and capable of providing informed consent 4. Subjects who are willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center
Exclusion criteria
1. Any of the following atrial conditions: 1. 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) 2. Any prior atrial endocardial, epicardial or surgical ablation procedure for arrhythmia, other than right sided cavotricuspid isthmus ablation or for right sided SVT 3. Current atrial myxoma 4. Any PV abnormality, stenosis, or stenting (common and middle PVs are admissible) 5. Current left atrial thrombus 2. 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 3. Any of the following conditions at baseline (Section7.5): 1. Heart failure associated with NYHA Class III or IV 2. LVEF \< 40% 3. Uncontrolled hypertension (SBP \> 160 mmHg or DBP \> 95 mmHg on two (2) BP measurements at baseline assessment 4. Any of the following events within 90 days of the Consent Date: 1. Myocardial infarction (MI), unstable angina or coronary intervention 2. Any cardiac surgery 3. Heart failure hospitalization 4. Pericarditis or symptomatic pericardial effusion 5. Gastrointestinal bleeding 6. Stroke, TIA, or intracranial bleeding 7. Any non-neurologic thromboembolic event 8. Carotid stenting or endarterectomy 5. Thrombocytosis, thrombocytopenia, disorder of blood clotting or bleeding diathesis 6. Contraindication to, or unwillingness to use, systemic anticoagulation 7. Patients who have not been on anticoagulation therapy for at least 4 weeks prior to the ablation procedure 8. 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 9. 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: 1. Body Mass Index (BMI) \> 42.0 2. Solid organ or hematologic transplant, or currently being evaluated for a transplant 3. Any prior history or current evidence of hemi-diaphragmatic paralysis or paresis. 4. Severe lung disease, pulmonary hypertension, or any lung disease involving abnormal blood gases or requiring supplemental oxygen 5. 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 6. Active malignancy or history of treated malignancy within 24 months of enrollment (other than cutaneous basal cell or squamous cell carcinoma) 7. Clinically significant gastrointestinal problems involving the esophagus or stomach including severe or erosive esophagitis, uncontrolled gastric reflux, gastroparesis, esophageal candidiasis or active gastroduodenal ulceration 8. Active systemic infection 9. 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) 10. Predicted life expectancy less than one (1) year 11. 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: 1. Age ≥ 18 years of age, or older if specified by local law 2. 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 3. Subjects who are willing and capable of providing informed consent 4. Subjects who are willing and capable of participating in all testing associated with this clinical investigation at an approved clinical investigational center
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Safety Endpoint (PSE): Event Rate of Safety Events Post Procedure | Phase 1 Index Procedure through 360 Days | Phase 2 Index Procedure through 90 Days (per protocol Primary Safety Endpoint requirements) | Phase 1: Through 7 Days: * 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 Through 30 Days: * Cardiac tamponade / perforation * Pericarditis Through 360 Days Post-Procedure: * PV stenosis * Atrio-esophageal fistula Phase 2 Through 7 Days: * 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 Through 30 Days: * Death * Cardiac tamponade / perforation * Pericarditis * Any PFA system related PFA procedure-related cardiovascular or pulmonary adverse event Through 90 Days: * PV stenosis * Atrio-esophageal fistula |
| Primary Effectiveness Endpoint: Treatment Success Rate Through Day 360 | Post-Blanking Period: Day 90 through Day 360 | Includes both Acute Procedural Success and Chronic Success through Day 360. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of Persistent AF Chronic Success | Post-Blanking Period: Day 90 through Day 360 | Defined as the freedom from any of the following through the Day 360 Assessment after the Blanking Period, excluding documented CTI-dependent AFL for phase 1 and for Phase 2 excluding documented CTI-dependent AFL if the participant did not have a CTI ablation with a FARAPOINT PFA Catheter: 1. Arrhythmia: Occurrence of any Detectable AF, AFL or AT 2. Re-ablation: Any re-ablation for AF, AFL or AT 3. Cardioversion: Any electrical cardioversion for AF, AFL or AT 4. AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone |
| Rate of Persistent AF Acute Procedural Success | Assessed through Index Ablation Procedure | * 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. * Use of an ablation catheter other than the FARAWAVE Pulse Field Ablation Catheter (i.e., use of a non-study catheter) to achieve Pulmonary Vein Isolation and Posterior Wall Isolation. |
Countries
Belgium, Canada, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects PHASE 1 only
Phase 1: FARAPULSE Ablation System - Pulsed Field Ablation (PFA) to isolate the Pulmonary Veins and Posterior Wall using the FARAWAVE PFA Catheter. | 260 |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects Phase 2 only
Phase 2: FARAPULSE Ablation System - Pulsed Field Ablation (PFA) to isolate the Pulmonary Veins and Posterior Wall using the FARAWAVE PFA Catheter and FARAPOINT PFA Catheter for cavo-tricuspid isthmus (CTI) ablation. | 255 |
| Total | 515 |
Baseline characteristics
| Characteristic | Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Total |
|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 9.3 | 66.2 years STANDARD_DEVIATION 9.3 | 66.4 years STANDARD_DEVIATION 9.3 |
| BMI (kg/m^2) | 30.9 kg/m^2 STANDARD_DEVIATION 5.3 | 30.4 kg/m^2 STANDARD_DEVIATION 5.3 | 30.7 kg/m^2 STANDARD_DEVIATION 5.3 |
| CHA₂DS₂-VASc Score 0 | 21 Participants | 31 Participants | 52 Participants |
| CHA₂DS₂-VASc Score 1 | 46 Participants | 47 Participants | 93 Participants |
| CHA₂DS₂-VASc Score 2 | 68 Participants | 59 Participants | 127 Participants |
| CHA₂DS₂-VASc Score 3 | 65 Participants | 64 Participants | 129 Participants |
| CHA₂DS₂-VASc Score 4 | 37 Participants | 43 Participants | 80 Participants |
| CHA₂DS₂-VASc Score 5 | 16 Participants | 12 Participants | 28 Participants |
| CHA₂DS₂-VASc Score 6 | 1 Participants | 4 Participants | 5 Participants |
| CHA₂DS₂-VASc Score 7 | 1 Participants | 0 Participants | 1 Participants |
| Diastolic Blood Pressure (mmHg) | 77.6 mmHg STANDARD_DEVIATION 10.3 | 77.5 mmHg STANDARD_DEVIATION 10 | 77.5 mmHg STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 245 Participants | 211 Participants | 456 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 45 Participants | 50 Participants |
| Height (cm) | 177.6 cm STANDARD_DEVIATION 10.6 | 175.8 cm STANDARD_DEVIATION 9.7 | 176.7 cm STANDARD_DEVIATION 10.2 |
| LA Diameter (cm) | 4.3 cm STANDARD_DEVIATION 0.6 | 4.3 cm STANDARD_DEVIATION 0.6 | 4.3 cm STANDARD_DEVIATION 0.6 |
| LA Volume (mL) | 65.5 mL STANDARD_DEVIATION 19.3 | 65.1 mL STANDARD_DEVIATION 24.6 | 65.2 mL STANDARD_DEVIATION 23 |
| Left Ventricular Ejection Fraction (%) | 56.6 % blood ejected from the left ventricle STANDARD_DEVIATION 6.7 | 57.2 % blood ejected from the left ventricle STANDARD_DEVIATION 6.9 | 56.9 % blood ejected from the left ventricle STANDARD_DEVIATION 6.8 |
| NYHA Class I | 52 participants | 42 participants | 94 participants |
| NYHA Class II | 63 participants | 44 participants | 107 participants |
| NYHA Class III | 0 participants | 0 participants | 0 participants |
| NYHA Class IV | 0 participants | 0 participants | 0 participants |
| NYHA No Heart Failure | 140 participants | 173 participants | 313 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Report | 5 Participants | 45 Participants | 50 Participants |
| Race/Ethnicity, Customized White | 241 Participants | 209 Participants | 450 Participants |
| Resting Heart Rate (bpm) | 76.8 bpm STANDARD_DEVIATION 18.7 | 74 bpm STANDARD_DEVIATION 18.3 | 75.4 bpm STANDARD_DEVIATION 18.5 |
| Sex: Female, Male Female | 73 Participants | 80 Participants | 153 Participants |
| Sex: Female, Male Male | 182 Participants | 180 Participants | 362 Participants |
| Systolic Blood Pressure (mmHg) | 129.8 mmHg STANDARD_DEVIATION 16.6 | 129.9 mmHg STANDARD_DEVIATION 16.6 | 129.8 mmHg STANDARD_DEVIATION 16.6 |
| Weight (kg) | 98 kg STANDARD_DEVIATION 20.3 | 94.3 kg STANDARD_DEVIATION 19.7 | 96.1 kg STANDARD_DEVIATION 20.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 260 | 2 / 255 |
| other Total, other adverse events | 82 / 260 | 76 / 255 |
| serious Total, serious adverse events | 44 / 260 | 53 / 255 |
Outcome results
Primary
Primary Effectiveness Endpoint: Treatment Success Rate Through Day 360
Includes both Acute Procedural Success and Chronic Success through Day 360.
Time frame: Post-Blanking Period: Day 90 through Day 360
Population: Note: Phase 1 includes all Non-Roll in Treatment subjects. Phase 2 includes Non-Roll in Treatment subjects who received an Insertable Cardiac Monitor for arrhythmia recurrence monitoring.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Primary Effectiveness Endpoint: Treatment Success Rate Through Day 360 | 63.5 Percentage of participants |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Primary Effectiveness Endpoint: Treatment Success Rate Through Day 360 | 73.4 Percentage of participants |
Primary
Primary Safety Endpoint (PSE): Event Rate of Safety Events Post Procedure
Phase 1: Through 7 Days: * 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 Through 30 Days: * Cardiac tamponade / perforation * Pericarditis Through 360 Days Post-Procedure: * PV stenosis * Atrio-esophageal fistula Phase 2 Through 7 Days: * 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 Through 30 Days: * Death * Cardiac tamponade / perforation * Pericarditis * Any PFA system related PFA procedure-related cardiovascular or pulmonary adverse event Through 90 Days: * PV stenosis * Atrio-esophageal fistula
Time frame: Phase 1 Index Procedure through 360 Days | Phase 2 Index Procedure through 90 Days (per protocol Primary Safety Endpoint requirements)
Population: Adverse Events reported for subjects were reviewed and adjudicated for meeting Safety Endpoint criteria by an independent physician Clinical Events Committee.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Primary Safety Endpoint (PSE): Event Rate of Safety Events Post Procedure | 2.3 Percentage of participants |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Primary Safety Endpoint (PSE): Event Rate of Safety Events Post Procedure | 2.4 Percentage of participants |
Post Hoc
Freedom From Documented Symptomatic Recurrence and Intervention
Freedom from symptomatic recurrence and intervention is Chronic Treatment Success, as defined for the Primary Effectiveness Endpoint, but excluding failure due to asymptomatic detectable AF, AFL, or AT.
Time frame: Post-Blanking Period: Day 90 through Day 360
Population: Note: Freedom from Documented Symptomatic Recurrence and Intervention was a post-hoc analysis for the Phase 1 cohort and a pre-specified analysis for the Phase 2 cohort.~Note: Phase 1 includes all Non-Roll in Treatment subjects. Phase 2 includes Non-Roll in Treatment subjects who received an Insertable Cardiac Monitor for arrhythmia recurrence monitoring.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Freedom From Documented Symptomatic Recurrence and Intervention | 85.3 Percentage of participants |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Freedom From Documented Symptomatic Recurrence and Intervention | 81.0 Percentage of participants |
Other Pre-specified
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. * Use of an ablation catheter other than the FARAWAVE Pulse Field Ablation Catheter (i.e., use of a non-study catheter) to achieve Pulmonary Vein Isolation and Posterior Wall Isolation.
Time frame: Assessed through Index Ablation Procedure
Population: Note: Phase 1 includes all Non-Roll in Treatment subjects. Phase 2 includes Non-Roll in Treatment subjects who received an Insertable Cardiac Monitor for arrhythmia recurrence monitoring.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Rate of Persistent AF Acute Procedural Success | 99.6 Percentage of participants |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Rate of Persistent AF Acute Procedural Success | 99.6 Percentage of participants |
Other Pre-specified
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 for phase 1 and for Phase 2 excluding documented CTI-dependent AFL if the participant did not have a CTI ablation with a FARAPOINT PFA Catheter: 1. Arrhythmia: Occurrence of any Detectable AF, AFL or AT 2. Re-ablation: Any re-ablation for AF, AFL or AT 3. Cardioversion: Any electrical cardioversion for AF, AFL or AT 4. AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone
Time frame: Post-Blanking Period: Day 90 through Day 360
Population: Note: Phase 1 includes all Non-Roll in Treatment subjects. Phase 2 includes Non-Roll in Treatment subjects who received an Insertable Cardiac Monitor for arrhythmia recurrence monitoring.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pulsed Field Ablation (Phase 1) Non-Roll In Treatment Subjects | Rate of Persistent AF Chronic Success | 64.2 Percentage of participants |
| Pulsed Field Ablation (Phase 2) Non-Roll In Treatment Subjects | Rate of Persistent AF Chronic Success | 73.4 Percentage of participants |