A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in Subjects With Persistent Atrial Fibrillation
Phase: NA
Conditions: Persistent Atrial Fibrillation
Sponsor: Boston Scientific Corporation

Form/Template 90702637_Rev/Ver AU 
Confidential 
ADVANTAGE AF Study, 92836802, Rev/Ver H 
 
 
 
 
 
 
 
 
 
A Prospective Single Arm Open Label Study of the  
FARAPULSE Pulsed Field Ablation System in  
Subjects with Persistent Atrial Fibrillation 
 
The ADVANTAGE AF Study 
92836802 
PF106 
CLINICAL INVESTIGATION PLAN 
 
G220079 
NCT 05443594 
 
Sponsored By 
Boston Scientific Corporation 
 
Sponsored By 
Boston Scientific Corporation 
4100 Hamline Ave N. 
St. Paul, MN 55112 
 
and 
 
Boston Scientific International S.A.  
Le Val Saint-Quentin 
2 rue René Caudron 
78960 Voisins le Bretonneux, France 
 
 
This protocol contains confidential information for use by the Investigators and their designated 
representatives participating in this clinical investigation. The protocol should be held confidential 
and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
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Form/Template 90702637_Rev/Ver AU 
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Contact Information 
Role 
Contact  
Boston Scientific 
Corporation (BSC) 
Clinical Contact 
 
 
Boston Scientific Corporation 
4100 Hamline Ave N. 
St. Paul, MN 55112 
USA 
  
 
 
Boston Scientific Corporation 
4100 Hamline Ave N. 
St. Paul, MN 55112 
USA 
 
 
 
     Green Square 
     Lambroekstraat 5D 
     1831 Diegem (Brussels) 
     Belgium 
 
Coordinating Principal 
Investigator(s) 
Vivek Reddy, MD, Principal Investigator 
Mount Sinai Hospital 
 
 
 
 
 
Executive Steering 
Committee 
Edward Gerstenfeld, MD 
Moussa Mansour, MD 
Andreas Metzner, MD 
Devi Nair, MD 
Andrea Natale, MD 
Walid Saliba, MD 
Boris Schmidt, MD 
Philipp Sommer, MD 
Atul Verma, MD 
Vendors / Labs / 
External Organizations 
A list of vendors / laboratories / external organizations involved in the 
trial is maintained by the Sponsor.  
 
 
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Form/Template 90702637_Rev/Ver AU 
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Original Release: February 24, 2022 
Current Version:  August 20, 2024 
 
Revision 
Version 
Protocol 
Date 
Template # 
Version 
Section(s) 
Modified 
Summary of Changes 
Justification for Modification 
A 
February 
24, 2022 
90702637, 
Version AP 
N/A 
Original issue 
N/A 
B 
May 10, 
2022 
90702637, 
Version AQ 
Throughout 
Modifications according to initial 
FDA IDE review, application # 
G220079, 8 April 2022 
Modifications according to initial 
FDA IDE review, application # 
G220079, 8 April 2022 
C 
June 28, 
2022 
90702637, 
Version AQ 
Sections 1, 2.2, 
7.6.2.5, 17.1, 
17.4 and 17.6 
Modifications according to 
G220079/A001 Interactive request, 
June 21, 2022 and follow-up FDA 
teleconference June 23, 2022 
Modifications according to 
G220079/A001 Interactive request, 
June 21, 2022 and follow-up FDA 
teleconference June 23, 2022. 
D 
July 28, 
2022 
90702637, 
Version AQ 
Throughout 
Modification to reflect the 
FARASTAR Generator supplement 
A specific investigational generator 
compatible for both FARAWAVE and 
FARAPOINT will be used for the 
study.  
D 
July 28, 
2022 
90702637, 
Version AQ 
Throughout 
Modifications to allow a 
commercially available RF catheter to 
be used for CTI ablation and increase 
the total study and Roll-In Subject 
sample size  
Flexibility to conduct the study and 
treat the targeted arrhythmia for the 
study without a dependency on the 
FARAPOINT PFA Catheter but allow 
the option to add the catheter later 
E 
November 
10, 2022 
90702637, 
Version AQ 
Throughout 
Modifications to remove 
FARAPOINT,associated components 
and associated endpoints 
Modification according to FDA IDE 
Supplement, application #G220079, 
Nov 2022 
E 
November 
10, 2022 
90702637, 
Version AQ 
Section 2 
Modifications to reflect the systems 
used in the different geographies 
Commercial system will be used 
under the study specific IFUs in 
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Form/Template 90702637_Rev/Ver AU 
Confidential 
ADVANTAGE AF Study, 92836802, Rev/Ver H 
  
Revision 
Version 
Protocol 
Date 
Template # 
Version 
Section(s) 
Modified 
Summary of Changes 
Justification for Modification 
geographies where the system is 
approved, Investigational system will 
be used in North America 
E 
November 
10, 2022 
90702637, 
Version AQ 
Sections 8.1 
Modification to primary safety 
endpoint performance goal and 
sample size : increase from 219 
Subjects to 258 treatment subjects – 
increase in stie number from 40 to 53 
Answer to Study Design 
Consideration 1. From FDA 
correspondence, 24 Jun 2022 
F 
August 9, 
2023 
90702637, 
Version AR 
Throughout 
Updated reference to Phase 1 of the 
trial in Protocol synopsis; Added 
Appendix A for ADVANTAGE AF 
Phase 2 protocol 
Modifications to incorporate 
ADVANTAGE Phase 2 
F 
August 9, 
2023 
90702637, 
Version AR 
7.6.2.2, 7.6.2.3 
Administrative corrections 
Reference errors corrected 
G 
August 18, 
2023 
90702637, 
Version AR 
Appendix A 
Corrected indications for use 
statement in Appendix A, Section 2.1 
Administrative corrections 
H 
Aug 2024 
90702637 
Version AU 
Appendix A 
Modification to definitions (Section 
23.2) for AF, AFL, and AT Burden, 
Detectable AF, AFL, or AT, and 
BeatLogic; modification to the 
primary effectiveness endpoint 
justification, sample size, and 
statistical methods (Section 8.1.2), 
updates, and additions to additional 
effectiveness endpoints (Section 
3.5.2), and added sensitivity analyses 
(Section 8.3.3). 
Answer to Study Design 
Considerations:  G220079/S012, from 
FDA Correspondence 08 Sep 2023, 
G220079/S016 from FDA 
correspondence 09 Feb 2024, and 
G220079/S018, from FDA 
Correspondence 21 Jun 2024. 
H 
Aug 2024 
90702637 
Version AU 
Appendix B 
Addition of Appendix B – LUX-Dx 
long term follow-up sub-study.  
Allow for additional data collection 
up to 3 years post-procedure to 
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Revision 
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Date 
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Section(s) 
Modified 
Summary of Changes 
Justification for Modification 
characterize arrhythmia recurrence 
using LUX-Dx only. 
H 
Aug 2024 
90702637 
Version AU 
Throughout 
Updated to BSC protocol template 
version AU 
Administrative updates 
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Form/Template 90702637_Rev/Ver AU 
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Protocol Synopsis: ADVANTAGE AF Study Phase 1 
A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 1 
STUDY 
OBJECTIVE(S) 
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). 
INDICATION(S) 
FOR USE  
The FARAPULSE™ Pulsed Field Ablation System is indicated for the treatment 
of drug resistant, symptomatic persistent atrial fibrillation. 
The FARAWAVE Catheter is indicated for the isolation of pulmonary veins and 
posterior wall in the ablation of drug resistant, symptomatic persistent atrial 
fibrillation. 
DEVICES UNDER 
STUDY (TEST 
DEVICE) 
The investigational devices comprise the FARAPULSE™ Pulsed Field Ablation 
(PFA) System 
• 
FARAWAVE™ Pulsed Field Ablation (PFA) Catheter  
• 
FARASTAR™ Catheter Connection Cable  
• 
FARASTAR™ Pulsed Field Ablation (PFA) Generator and associated 
cables 
• 
FARASTAR™ Recording System Module and associated cables 
• 
FARADRIVE™ Steerable Sheath 
STUDY DESIGN 
The FARAPULSE ADVANTAGE AF Study is a prospective, single arm, open 
label, multi-center IDE pivotal study utilizing the FARAPULSE PFA System in 
the treatment of patients with PersAF.  
After ablative isolation of the pulmonary veins (PVs), the left atrial posterior wall 
(PW) and if warranted the cavotricuspid isthmus (CTI), subjects will be followed 
at Pre-Discharge, Day 7, Day 30, Day 90, Day 180, and Day 360. The Blanking 
Period will include Days 0 through 90, after which subjects will be monitored 
twice per month plus symptom-driven event monitoring, as well as Day 180 and 
Day 360 24-hour Holter monitoring. 
 
 
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The ADVANTAGE AF Study – Phase 1 
INTERVENTIONS 
DURING INDEX 
PROCEDURE 
Pulmonary Vein Isolation (PVI): PVI will be achieved in target veins using the 
FARAWAVE PFA Catheter. 
Posterior Wall Isolation (PWI): PWI will be achieved in the left atrial 
posterior wall between the PVs using the FARAWAVE PFA Catheter. 
CTI: Ablation of the CTI will be performed using a commercially available 
BSCRF catheter in the following situations: 
• 
Required: For subjects with a history of CTI-mediated (typical) AFL and  
o Who have not had a CTI ablation procedure, or 
o Who have had a CTI ablation procedure but have recurrent CTI 
conduction. 
• 
Required: subjects who manifest CTI-mediated AFL (spontaneous or 
induced) during the Index Procedure, or 
• 
At Investigator discretion: subject welfare indicates that CTI ablation 
should be performed. 
Other Ablation: When the Investigator determines that subject welfare requires 
intervention for either an accessory pathway, AVNRT or spontaneously 
occurring treatment-emergent AFL or AT, ablation for these arrhythmias may be 
performed using any commercially available RF ablation catheter. These 
permitted ablations and the associated data will be documented in the CRF and 
do not constitute Persistent AF Acute Procedural Failure.  
Ablation for an arrhythmia that is provoked only by catheter manipulation or is 
only inducible by pacing or pharmacologic stimulation is not permitted. 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 417 treated subjects will be enrolled in this study (up to  159 
Roll-In Subjects and approximately 258 Treatment Subjects). 
Roll-In Subjects (up to 159): The first subject enrolled by each ablating 
Investigator at each site will be treated with the investigational catheter(s) as part 
of Investigator preparation, up to a maximum of 159 subjects across 53 
investigational sites. Roll-In procedures may be adapted based on prior 
experience, or additional subjects may be required as described in Section 4.3. 
 
Treatment Subjects (258): A planned 258 Treatment Subjects will be enrolled to 
support the proposed primary study outcomes. No site may enroll more than 
~13% of these planned subjects (n= 33 Treatment Subjects maximum). Subject 
enrollment will stop once approximately 258 Treatment Subjects are accrued. 
 
INVESTIGATIONAL 
SITES / COUNTRIES 
Up to 53 clinical sites globally, which may include North America, Europe, and 
Asia.  
At least 50% of study subjects will be enrolled in the United States, and at least 
50% of study sites will be in the United States.  
The number of active ablating Investigators at any site is limited to a maximum 
of three (3). 
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The ADVANTAGE AF Study – Phase 1 
ADDITIONAL 
EFFECTIVENESS 
ENDPOINTS 
• 
Persistent AF Acute Procedural Success 
• 
Persistent AF Chronic Success 
• 
Single Procedure Treatment Success 
• 
Off Drug Treatment Success  
• 
Re-Ablation Rate 
PROCEDURAL 
ASSESSMENTS 
Assessments of procedure durations 
• 
Procedure Time  
• 
LA Dwell Time  
• 
PVI and PWI Ablation Time 
• 
Fluoroscopy Time  
Characterization of lesion sets 
• 
PVI Ablations 
• 
PWI Ablations 
• 
CTI Ablations 
• 
Other Ablations 
QUALITY OF LIFE 
ASSESSMENTS 
Between Baseline and Day 180, and between Baseline and Day 360 
• 
The 3-level EuroQol standardized questionnaire of health states 
(EQ-5D-3L)  
• 
The Atrial Fibrillation Effect on Quality of Life (AFEQT) instrument for 
the measurement of health-related quality of life  
METHOD OF 
ASSIGNING 
PATIENTS TO 
TREATMENT 
The ADVANTAGE AF Study is a single arm study, and any subject that signs 
the Informed Consent Form and meets all study inclusion criteria, and no 
exclusion criteria, will be eligible for treatment either as a Roll-In Subject or a 
Treatment Subject. 
FOLLOW-UP 
SCHEDULE 
• 
Baseline Assessments 
• 
Index Procedure / Rescheduled Index Procedure (Day 0): Cardiac 
ablation 
• 
Pre-Discharge Assessment 
• 
Day 7 Assessment (remote): safety assessment (Window Day 7 to 11) 
• 
Day 30 Assessment (remote): safety assessment (Window Day 30 – 37) 
• 
Day 90 Assessment (in person): clinical assessment, begin twice per 
month and symptomatic event monitoring transmissions (Window Day 90 
± 14) 
• 
Day 180 Assessment (remote): clinical assessment, 24-hour Holter, QoL 
(Window Day 180 ± 30) 
• 
Day 360 Assessment (in person): clinical assessment, 24-hour Holter, 
QoL (Window Day 360 ± 30) 
• 
Re-Ablation Procedure 
• 
Unscheduled Assessments 
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The ADVANTAGE AF Study – Phase 1 
STUDY DURATION 
Enrollment is expected to be completed in approximately 9 months, and subjects 
will be followed for 12 months. There will be an approximate 2-month period of 
site close-out visits, for an estimated first patient in until last patient last 
assessment duration of 23 months. 
SUBJECT 
DURATION 
The study duration for each subject will be approximately 13 ± 1 months to 
allow for screening, pre-procedural diagnostic procedures, treatment, and 12 ± 1 
months of study follow-up. 
INCLUSION 
CRITERIA 
Study subjects are required to meet all the following 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 
 
 
 
 
 
 
 
 
 
 
(CONTINUED NEXT 
PAGE) 
1. Any of the following atrial conditions: 
a. 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) 
b. Any prior atrial endocardial, epicardial or surgical ablation 
procedure for arrhythmia, other than right sided cavotricuspid 
isthmus ablation or for right sided SVT 
c. Current atrial myxoma 
d. Any PV abnormality, stenosis, or stenting (common and middle PVs 
are admissible) 
e. 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 
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The ADVANTAGE AF Study – Phase 1 
EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(CONTINUED NEXT 
PAGE) 
 
 
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 ablation1  
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): 
a. Heart failure associated with NYHA Class III or IV 
b. LVEF < 40% 
c. 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: 
a. Myocardial infarction (MI), unstable angina or coronary intervention 
b. Any cardiac surgery 
c. Heart failure hospitalization 
d. Pericarditis or symptomatic pericardial effusion 
e. Gastrointestinal bleeding 
f. Stroke, TIA, or intracranial bleeding 
g. Any non-neurologic thromboembolic event 
h. 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  
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The ADVANTAGE AF Study – Phase 1 
EXCLUSION 
CRITERIA 
 
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: 
a. Body Mass Index (BMI) > 42.0 
b. Solid organ or hematologic transplant, or currently being evaluated 
for a transplant 
c. Any prior history or current evidence of hemi-diaphragmatic 
paralysis or paresis. 
d. Severe lung disease, pulmonary hypertension, or any lung disease 
involving abnormal blood gases or requiring supplemental oxygen 
e. 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 
f. Active malignancy or history of treated malignancy within 24 
months of enrollment (other than cutaneous basal cell or squamous 
cell carcinoma) 
g. Clinically significant gastrointestinal problems involving the 
esophagus or stomach including severe or erosive esophagitis, 
uncontrolled gastric reflux, gastroparesis, esophageal candidiasis or 
active gastroduodenal ulceration 
h. Active systemic infection 
i. 
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 
STATISTICAL METHODS  
 
1 Subjects may be enrolled with an active implantable loop recorder or insertable cardiac monitor if deactivation 
or removal is planned per standard of care prior to obtaining vascular access for the index ablation procedure.  
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The ADVANTAGE AF Study – Phase 1 
PRIMARY SAFETY 
ENDPOINT: 
HYPOTHESIS AND 
METHOD 
The analysis of the primary safety endpoint (PSE) is a test comparing the 
proportion of Treatment Subjects and Attempt Subjects with one or more CSAEs 
through the Day 360 Assessment (Treatment) or through the Day 30 Assessment 
(Attempt) to a performance goal (PG).  
The null and alternative hypotheses are: 
H0: P ≥ PG versus HA: P < PG 
where P is the proportion of Treatment Subjects and Attempt Subjects with one 
or more CSAEs through the Day 360 Assessment (Treatment) or through the 
Day 30 Assessment (Attempt) and the PG is 12%. 
The proportion of Treatment Subjects and Attempt Subjects with one or more 
CSAEs will be estimated using the Kaplan-Meier method. The 97.5% one-sided 
upper confidence limit of the observed event rate will be compared to the 
performance goal of 12%. If the upper confidence limit is less than the 
performance goal, the null hypothesis will be rejected. The upper confidence 
limit will be calculated as the pointwise confidence limit using the log-log 
methodology.  
Both the PSE and PEE must be met for study success. 
PRIMARY 
EFFECTIVENESS 
ENDPOINT: 
HYPOTHESIS AND 
METHOD 
The analysis of the primary effectiveness endpoint (PEE) is a test comparing the 
proportion of Treatment Subjects with Treatment Success through the Day 360 
Assessment to a PG.  
The null and alternative hypotheses are: 
H0: P ≤ PG versus HA: P > PG 
where P is the proportion of Treatment Subjects with Treatment Success through 
the Day 360 Assessment and the PG is 40%. 
The proportion of Treatment Subjects with Treatment Success through the Day 
360 Assessment will be estimated using the Kaplan-Meier method. The 97.5% 
one-sided lower confidence limit of the observed Treatments Success rate will 
be compared to the performance goal of 40%. If the lower confidence limit is 
greater than the performance goal, the null hypothesis will be rejected. The 
confidence limit will be calculated as the pointwise confidence limit using the 
log-log methodology. 
Both the PSE and PEE must be met for study success. 
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Table of Contents 
PROTOCOL SYNOPSIS: ADVANTAGE AF STUDY PHASE 1 .......................................................1 
TABLE OF CONTENTS ................................................................................................................10 
LIST OF FIGURES .......................................................................................................................15 
LIST OF TABLES ........................................................................................................................16 
1 
INTRODUCTION ..................................................................................................................17 
2 
DEVICE DESCRIPTION ........................................................................................................20 
2.1 
Intended Use....................................................................................................................... 20 
2.2 
Investigational Devices ...................................................................................................... 20 
2.2.1 
FARAPULSE Pulsed Field Ablation System ..................................................... 20 
2.2.2 
FARAWAVE Pulsed Field Ablation Catheter ................................................... 22 
2.2.3 
FARASTAR Catheter Connection Cable ........................................................... 23 
2.2.4 
FARASTAR Pulsed Field Ablation Generator .................................................. 24 
2.2.5 
FARASTAR Recording System Module ........................................................... 24 
2.2.6 
FARADRIVE Steerable Sheath.......................................................................... 25 
3 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................25 
3.1 
Study Objective .................................................................................................................. 25 
3.2 
Primary Safety Endpoint .................................................................................................... 25 
3.2.1 
Composite Serious Adverse Event Definitions .................................................. 26 
3.3 
Primary Effectiveness Endpoint ......................................................................................... 28 
3.3.1 
Persistent AF Acute Procedural Success ............................................................ 28 
3.3.2 
Persistent AF Chronic Success ........................................................................... 29 
3.4 
Additional Endpoints and Assessments ............................................................................. 29 
3.4.1 
Additional Safety Endpoints ............................................................................... 29 
3.4.2 
Additional Effectiveness Endpoints ................................................................... 29 
3.4.3 
Procedural Assessments ..................................................................................... 30 
3.4.4 
Quality of Life Assessments ............................................................................... 30 
3.5 
Summary of Study Endpoints ............................................................................................ 31 
4 
STUDY DESIGN ..................................................................................................................32 
4.1 
Overview of the ADVANTAGE AF Study Design ........................................................... 32 
4.2 
Scale and Duration ............................................................................................................. 33 
4.2.1 
Number of Subjects ............................................................................................ 33 
4.2.2 
Investigational Sites / Countries ......................................................................... 34 
4.2.3 
Study Duration.................................................................................................... 34 
4.2.4 
Subject Duration ................................................................................................. 34 
4.3 
Treatment Assignment ....................................................................................................... 34 
4.4 
Justification for the Study Design ...................................................................................... 34 
5 
SUBJECT SELECTION ..........................................................................................................35 
5.1 
Study Population and Eligibility ........................................................................................ 35 
5.2 
Inclusion Criteria ................................................................................................................ 35 
5.3 
Exclusion Criteria............................................................................................................... 36 
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6 
SUBJECT ENROLLMENT AND ACCOUNTABILITY .................................................................39 
6.1 
Screening ............................................................................................................................ 39 
6.1.1 
Study Candidate Screening ................................................................................. 39 
6.1.2 
Screening and Enrollment Log ........................................................................... 39 
6.1.3 
Informed Consent ............................................................................................... 39 
6.2 
Point of Enrollment ............................................................................................................ 39 
6.3 
Enrollment Controls ........................................................................................................... 40 
6.4 
Withdrawal ......................................................................................................................... 40 
6.5 
Lost to Follow-Up .............................................................................................................. 40 
6.6 
Subject Status and Classification ....................................................................................... 41 
6.6.1 
Consent Ineligible (Screening Failures) ............................................................. 41 
6.6.2 
Roll-In Subjects .................................................................................................. 41 
6.6.3 
Intent Subjects .................................................................................................... 42 
6.6.4 
Attempt Subjects ................................................................................................ 42 
6.6.5 
Treatment Subjects ............................................................................................. 43 
6.7 
End-of-Study Definition ..................................................................................................... 43 
7 
STUDY METHODS ..............................................................................................................43 
7.1 
Overview of Study Interactions.......................................................................................... 43 
7.2 
Data Collection Schedule ................................................................................................... 44 
7.3 
Anticoagulation .................................................................................................................. 45 
7.4 
Antiarrhythmic Drugs ........................................................................................................ 45 
7.5 
Baseline Assessment .......................................................................................................... 46 
7.6 
Index Procedure / Rescheduled Index Procedure ............................................................... 47 
7.6.1 
Index Procedure / Rescheduled Index Procedure Data Collection ..................... 47 
7.6.2 
Index Procedure Workflow ................................................................................ 48 
7.6.3 
Rescheduled Index Procedure ............................................................................ 50 
7.7 
Pre-Discharge Assessment ................................................................................................. 51 
7.8 
Day 7 Safety Assessment ................................................................................................... 52 
7.9 
Day 30 Safety Assessment ................................................................................................. 52 
7.10 Day 90 Assessment ............................................................................................................ 53 
7.11 Day 180 Assessment .......................................................................................................... 54 
7.12 Day 360 Assessment .......................................................................................................... 55 
7.13 Re-Ablation Procedures ..................................................................................................... 55 
7.13.1 
Re-Ablation Procedure within the Blanking Period ........................................... 55 
7.13.2 
Other Re-Ablation Procedures............................................................................ 56 
7.14 Unscheduled Assessments ................................................................................................. 56 
7.15 Unforeseen Circumstances ................................................................................................. 56 
7.16 Study Completion............................................................................................................... 57 
7.17 Source Documents ............................................................................................................. 57 
7.18 Local Laboratory Documentation ...................................................................................... 59 
8 
STATISTICAL CONSIDERATIONS .........................................................................................59 
8.1 
Endpoints ........................................................................................................................... 59 
8.1.1 
Primary Safety Endpoint .................................................................................... 59 
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8.1.2 
Primary Effectiveness Endpoint ......................................................................... 61 
8.1.3 
Other Endpoints and Assessments ...................................................................... 64 
8.2 
General Statistical Methods ............................................................................................... 64 
8.2.1 
Analysis Sets ...................................................................................................... 64 
8.2.2 
Control of Systematic Error / Bias ..................................................................... 65 
8.2.3 
Study Success and Control of Type I Error ........................................................ 65 
8.3 
Data Analyses..................................................................................................................... 65 
8.3.1 
Roll-In Subject Analyses .................................................................................... 65 
8.3.2 
Interim Analyses ................................................................................................. 65 
8.3.3 
Subgroup Analyses ............................................................................................. 65 
8.3.4 
Center Pooling Analysis ..................................................................................... 66 
8.3.5 
Multivariable Analyses ....................................................................................... 66 
8.3.6 
Changes to Planned Analyses ............................................................................. 66 
9 
HEALTH ECONOMICS OUTCOMES ......................................................................................66 
10 DATA MANAGEMENT ........................................................................................................67 
10.1 Data Collection, Processing, and Review .......................................................................... 67 
10.2 Data Retention .................................................................................................................... 67 
10.3 Technical Source Forms ..................................................................................................... 67 
11 CORE LABORATORIES ........................................................................................................68 
11.1 Arrhythmia Core Laboratory .............................................................................................. 68 
11.1.1 
Event Monitors ................................................................................................... 68 
11.1.2 
Holter Monitors .................................................................................................. 69 
11.1.3 
Study ECGs ........................................................................................................ 69 
11.2 Cardiac Imaging Core Laboratory...................................................................................... 69 
12 DEVIATIONS ......................................................................................................................70 
13 DEVICE ACCOUNTABILITY .................................................................................................70 
13.1 Investigationally-Labeled Test Devices ............................................................................. 70 
13.2 Commercially-Labelled Devices Used Investigationally ................................................... 71 
13.3 Non-Medical Devices, Components, and Commercially-Labelled Devices Used Within 
Approved Labeling ............................................................................................................. 72 
14 COMPLIANCE .....................................................................................................................72 
14.1 Statement of Compliance ................................................................................................... 72 
14.2 Investigator Responsibilities .............................................................................................. 73 
14.2.1 
Delegation of Responsibility .............................................................................. 74 
14.3 Institutional Review Board / Ethics Committee / Research Ethics Board ......................... 74 
14.4 Sponsor Responsibilities .................................................................................................... 75 
14.5 Role of BSC Representatives ............................................................................................. 75 
14.6 Insurance ............................................................................................................................ 76 
15 MONITORING .....................................................................................................................76 
16 POTENTIAL RISKS AND BENEFITS ......................................................................................76 
16.1 Anticipated Adverse Events ............................................................................................... 76 
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16.2 Risks Associated with the Study Device(s) ........................................................................ 78 
16.3 Risks associated with Participation in the Clinical Study .................................................. 78 
16.4 Possible Interactions with Concomitant Medical Treatments ............................................ 78 
16.5 Risk Minimization Actions ................................................................................................ 78 
16.6 Anticipated Benefits ........................................................................................................... 78 
16.7 Risk to Benefit Rationale ................................................................................................... 79 
17 SAFETY REPORTING ...........................................................................................................79 
17.1 Reportable Events by Investigator to BSC ......................................................................... 79 
17.2 Classifications for Adverse Event Reporting ..................................................................... 79 
17.3 Relationship Determination for Device Reporting ............................................................. 82 
17.4 Investigator Reporting Requirements................................................................................. 83 
17.5 Device Deficiencies ........................................................................................................... 85 
17.6 Reporting to Regulatory Authorities / IRBs / ECs / REBs / Investigators ......................... 85 
17.7 Subject Death Reporting .................................................................................................... 86 
18 INFORMED CONSENT .........................................................................................................86 
19 COMMITTEES .....................................................................................................................87 
19.1 Safety Monitoring Operations Team .................................................................................. 87 
19.2 Clinical Events Committee ................................................................................................ 88 
19.3 Data Monitoring Committee .............................................................................................. 88 
19.4 Executive Steering Committee ........................................................................................... 88 
20 SUSPENSION OR TERMINATION ..........................................................................................89 
20.1 Premature Termination of the Study .................................................................................. 89 
20.1.1 
Criteria for Premature Termination of the Study ................................................ 89 
20.2 Termination of Study Participation by the Investigator or Withdrawal of IRB / EC / REB 
Approval ............................................................................................................................. 89 
20.3 Requirements for Documentation and Subject Follow-up ................................................. 89 
20.4 Criteria for Suspending or Terminating a Study Site ......................................................... 90 
21 STUDY REGISTRATION AND RESULTS ................................................................................90 
21.1 Study Registration .............................................................................................................. 90 
21.2 Clinical Investigation Report ............................................................................................. 90 
21.3 Publication Policy .............................................................................................................. 90 
21.4 Study Applicability to Medicare Beneficiaries .................................................................. 92 
22 REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .....................................................92 
22.1 Subject Reimbursement ..................................................................................................... 92 
22.2 Subject Incentives .............................................................................................................. 92 
22.3 Compensation for Subject’s Health Injury ......................................................................... 92 
23 ABBREVIATIONS AND DEFINITIONS ...................................................................................92 
23.1 Abbreviations and Acronyms ............................................................................................. 92 
23.2 Definitions .......................................................................................................................... 95 
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24 BIBLIOGRAPHY ..................................................................................................................98 
APPENDIX A: ADVANTAGE AF STUDY PHASE 2 .................................................................103 
APPENDIX B: ADVANTAGE AF STUDY - LUX-DX SUB-STUDY ..........................................104 
 
 
 
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List of Figures 
Figure 2.2-1: Diagram of FARAPULSE Pulsed Field Ablation System  Connections ........................ 21 
Figure 2.2-2: FARAWAVE Pulsed Field Ablation Catheter ............................................................... 22 
Figure 2.2-3: FARAWAVE Pulsed Field Ablation Catheter – Deployed States ................................. 23 
Figure 2.2-4 FARASTAR Catheter Connection Cable ........................................................................ 24 
Figure 2.2-5: FARADRIVE Steerable Sheath ...................................................................................... 25 
Figure 4.1-1: ADVANTAGE AF Study Design .................................................................................. 33 
Figure 7.7-1: Pre-Discharge Stroke Evaluation .................................................................................... 52 
 
 
 
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List of Tables 
Table 2.2-1: Components of the FARAPULSE Pulsed Field Ablation System ................................... 21 
Table 3.2-1: Primary Safety Endpoint Composite Serious Adverse Events ........................................ 26 
Table 3.2-2: Composite Serious Adverse Event Definitions ................................................................ 26 
Table 3.5-1: Primary Endpoint Objectives and Justification ................................................................ 31 
Table 5.2-1: Inclusion Criteria ............................................................................................................. 35 
Table 5.3-1: Exclusion Criteria ............................................................................................................ 36 
Table 7.2-1: Data Collection Schedule ................................................................................................. 44 
Table 7.17-1: Source Documentation Requirements ............................................................................ 57 
Table 8.1-1: Meta-Analysis to Determine Primary Safety Endpoint Parameters ................................. 60 
Table 8.1-2: Assumptions for the Primary Safety Endpoint Sample Size Estimate ............................. 61 
Table 8.1-3: Meta-Analysis to Determine Primary Effectiveness Endpoint Parameters ..................... 63 
Table 8.1-4: Assumptions for the Primary Effectiveness Endpoint Sample Size Estimate ................. 64 
Table 13.1-1 : Device Accountability for the FARAPULSE  PFA System ......................................... 71 
Table 17.2-1: Safety Definitions for Reporting Purposes .................................................................... 80 
Table 17.3-1: Criteria for Assessing Relatedness for Reporting Purposes ........................................... 82 
Table 17.4-1: Investigator Reporting Requirements ............................................................................ 83 
Table 23.1-1: Abbreviations and Acronyms......................................................................................... 92 
Table 23.2-1: Definitions...................................................................................................................... 95 
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1 Introduction 
Atrial Fibrillation 
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting approximately 2.2 
million people in the United States and 4.5 million in the European Union.1,2 The incidence increases 
with advancing age, affecting 6% of the population over age 60 and 10% of the population over 
age 80.3,4 Among Medicare beneficiaries, AF incidence is common and increases as individuals age, 
with incidence rates per 1,000 person-years reported at ages 70-74 of 18.8, increasing to 28.8 for 
persons 75-79 and 38.3 for persons 80-84. Similarly, the overall prevalence among Medicare 
beneficiaries age 70-74 is about 6% increasing to over 13% for individuals 80 years of age and older. 
Age-adjusted population trending projects 16 million people in the United States will have AF by 
2050.5  
Atrial fibrillation remains a significant cause of morbidity and mortality in industrialized societies. 
The annual risk of AF related stroke is 5% per year and one of every six strokes diagnosed occurs in 
the presence of AF.6 Therefore, patients with AF require long-term anticoagulation to prevent 
embolic events. Failure to manage AF may also lead to anatomic and electrical remodeling of the left 
atrium, tachycardia-induced cardiomyopathy, and reduced left ventricular function (heart failure). AF 
remains an extremely costly public health burden, with annual per patient cost of care approaching 
approximately USD 3200 or €3000.7 
The Heart Rhythm Society (HRS) 2017 Consensus Statement on Catheter and Surgical Ablation of 
Atrial Fibrillation8 defines several different stages of AF based on its duration and include: 
• 
Paroxysmal AF (PAF): AF that terminates spontaneously or with intervention within 7 days of 
onset 
• 
Persistent AF (PersAF): continuous AF that is sustained beyond 7 days 
• 
Long-standing PersAF: continuous AF of greater than 12 months’ duration 
Several studies have demonstrated that AF catheter ablation is a safe and superior alternative to anti-
arrhythmic drugs (AADs) for maintenance of sinus rhythm and symptom improvement.9-16 In 
particular, the isolation of the pulmonary veins (PVI), where the majority of arrhythmogenic triggers 
is found, has been shown to be a safe and effective technique to reduce arrhythmia recurrence and 
related symptoms. Over the last 20 years PVI has remained the cornerstone catheter ablation 
technique for AF ablation in subjects with recurrent and symptomatic PAF refractory or intolerant to 
AADs.8,17 More recently, PVI for the treatment of PAF is increasingly being performed as first line 
therapy, and clinical evidence is accruing that this may well become an accepted first line treatment.18 
Persistent Atrial Fibrillation Ablation 
Persistent AF (PersAF) represents approximately 25% of all AF cases.19 In comparison to patients 
with PAF, patients with PersAF are at a significantly greater risk for both cardiac mortality and all-
cause mortality.20 The recent update of the 2020 ESC Guidelines17 for the diagnosis and management 
of atrial fibrillation AF supports catheter ablation for maintaining sinus rhythm in patients with both 
PAF and PersAF, with the eligibility to treat PersAF patients with ablation being weighted by 
additional elements, including risk factors for recurrence (left atrial [LA] size, AF duration, patient 
age, renal dysfunction, and substrate visualization by means of MRI), heart failure with reduced 
ejection fraction, and patient choice. This recommendation is currently reflected in practice as 
approximately one third of all catheter ablation cases are performed on either persistent or long-
standing persistent patients.21 
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There are currently two catheters approved in the US to treat PersAF, supported by data obtained 
from the PRECEPT (Biosense Webster, Thermocool SmartTouch® SF catheter) and STOP Persistent 
AF trials (Medtronic, ArcticFront Advance® Cryoballoon), respectively.22,23 These trials showed that 
safety and effectiveness profile of catheter ablation for PersAF is well-established, with slight 
variations in rates depending upon the patient population and technology utilized. Although the PVs 
have been identified as the main triggers responsible for AF, PVI alone for the treatment of PersAF is 
less effective than for PAF, and PersAF ablation may require additional lesion sets beyond the PVs to 
achieve greater success.24 
PersAF ablation success is challenged by the heterogeneity of the underlying pathophysiologic 
mechanisms, and multiple ablation strategies have evolved in the attempt to improve long-term 
outcomes in this population. These include left atrial lines (roof, mitral isthmus), right atrial lines 
(superior vena cava, cavo-tricuspid isthmus) other techniques aimed at suppressing additional triggers 
outside the PV. To date, limited data from randomized trials exist on the effectiveness of these 
techniques compared to PVI alone.25-28 However, recent studies29-31 have suggested a benefit 
associated with PVI and concomitant isolation of the portion the left atrial posterior wall (LAPW) 
lying between the PVs. The rationale for this ablation technique stands in the common embryological 
origin of this anatomical area in the PVs and the peculiar electrophysiological and structural 
characteristics of this region that give rise to its arrhythmogenic potential.  
Specifically, spontaneous triggers located in the LAPW have been reported in previous studies,32-35 
establishing ablation of this area in addition to PVI being a potential adjuvant strategy in ablation of 
PersAF. Several studies have been recently published adding a dedicated LAPW ablation strategy 
together with PVI, including different available energy sources for ablation.36-41 A recent systematic 
review and meta-analysis29 showed that LAPW isolation can be successfully achieved in a large 
proportion of patients and is associated with a low risk of major-procedure related complications.  
Irreversible Electroporation 
Al-Sakere 200742 described irreversible electroporation (IRE) as a non-thermal tissue ablation 
technique in which intense short duration electrical fields are used to permanently open pores in cell 
membranes, thus producing non-thermal tissue ablation. Their study, using a mouse model, showed 
complete regression in 92% of treated tumors. IRE ablation has a tissue-specific mechanism of 
ablation. The tissue injury from IRE ablation occurs at the cellular level with loss of homeostasis 
leading to necrosis or apoptosis.43-46 IRE ablation typically spares the extracellular matrix, which 
facilitates rapid wound healing.47-51 
With respect to cardiac tissue, multiple studies have been described reporting the effects of IRE in a 
porcine model. Across the studies, no stenosis was observed at 3-weeks and 3-months of follow-up, 
and the lesion depth was further characterized in the proximity of the phrenic nerve and coronary 
arteries, with no damage to the adjacent structures or tissues noted.52-55 These animal studies suggest 
that IRE can safely create deep lesions in heart tissue without harming adjacent tissues. 
FARAPULSE Pulsed Field Ablation System 
Preclinical animal studies investigating the safety and efficacy of the FARAPULSE Pulsed Field 
Ablation (PFA) System have been performed to demonstrate that PFA using the FARAPULSE PFA 
Catheter reliably produces homogeneous, well-demarcated and transmural lesions in porcine atrial 
tissue. Seven- and 30-day studies show mild to moderate inflammatory and healing responses 
consistent with radiofrequency ablation lesions, and importantly demonstrated no tissue injury with 
respect to the esophagus or phrenic nerve as well as no degree of narrowing or flow impairment of the 
pulmonary veins.56-59 
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Paroxysmal Atrial Fibrillation: 
Initial safety and feasibility human clinical studies of the FARAWAVE PFA Catheter were conducted 
in Europe in a PAF population, including the IMPULSE, PEFCAT, and PEFCAT II trials.60-62 All 
studies supported the safety and feasibility of the FARAPULSE PFA System using the FARAWAVE 
PFA Catheter in the treatment of patients with PAF, with a low rate of acute and long-term primary 
safety endpoint events and a high rate (100%) of acute procedural success resulting in CE Mark 
approval for the treatment of PAF in early 2021. 
The randomized ADVENT Trial (A Prospective Randomized Pivotal Trial of the FARAPULSE PFA 
System Compared with Standard of Care Ablation in Patients with Paroxysmal Atrial Fibrillation) is 
being conducted in the United States to establish the safety and effectiveness of the FARAPULSE 
PFA System using the FARAWAVE PFA Catheter in a drug refractory symptomatic PAF patient 
population. Subjects in the study are either randomized to catheter ablation with the FARAPULSE 
PFA system or conventional thermal ablation (radiofrequency or cryoballoon ablation). The data will 
be used to gain initial market approval of the FARAPULSE PFA System using the FARAWAVE 
PFA Catheter in the US for the PAF population.  
Persistent Atrial Fibrillation: 
Initial data on treatment of PersAF with the FARAPULSE PFA System using the FARAWAVE PFA 
Catheter has been collected in the PersAFOne feasibility study (Feasibility Study of the 
FARAPULSE Endocardial Multi Ablation System in the Treatment of Persistent Atrial Fibrillation). 
The objective of the PersAFOne Study is to demonstrate that the endocardial creation of electrically 
isolating lesions in cardiac tissue via PFA using the FARAPULSE PFA System is a feasible and safe 
treatment for PersAF. Patients in the PersAFOne study, after the isolation of the PVs, received an 
additional set of lesions along the posterior wall region between the PVs, performed with the same 
FARAWAVE PFA Catheter used for PVI during the ablation procedure.  
Reliable and safe electrical isolation of the left atrial posterior wall was confirmed via electro-
anatomical mapping. Reddy et al63 reported 100% acute PV isolation, no primary safety events, and 
chronic isolation of the PVs (82 / 85) and LAPW (100% with the pentaspline catheter) after 
remapping at 82 days post-procedure in 25 subjects. The data collected in the study demonstrated that 
the approach proposed in the ADVANTAGE AF Study to ablate the left atrial posterior wall in 
addition to creating PVI using the FARAPULSE PFA System is feasible, leading to an acceptable 
safety and feasibility profile for the study device to date.  
One of the acknowledged challenges to LAPW ablation is the risk of collateral damage to the 
esophagus, given the repeated and additional ablation applications in addition to the PVs that are 
delivered to an anatomical area close to the esophagus.64 Using PFA for LAPW ablation has the 
potential to substantially mitigate this risk, given the marked reduced risk of collateral damage to 
adjacent structures with the energy source noted above.  
Although AF and CTI-dependent atrial flutter (AFL) are different arrhythmias with their own 
mechanisms and electrophysiologic presentation, their interrelationship has long been recognized and 
they coexist in a significant percentage of patients.67 The relationship is reciprocal since patients 
diagnosed with AFL may develop AF after CTI ablation and patients with AF often go on to develop 
AFL.68-70 In particular, the presentation of AFL in the context of AF may be the sign of additional 
atria remodeling or the presence of non-PV triggers.71  
Accordingly, a strategy that includes both PVI and CTI ablation has become an established practice in 
the percutaneous ablative treatment of patients with AF. The current guidelines for the management 
of AF indicate that CTI ablation may be beneficial during procedures of AF ablation, in particular for 
those patients with history of typical AFL and where AFL is induced at the time of AF ablation.8 The 
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present IDE study incorporates the treatment strategy for PersAF ablation utilized in PersAFOne 
using the FARAWAVE PFA Catheter for electrical isolation of the PV and isolation of the LAPW 
region between the PVs; In the PersAFOne II study, LAPW ablation was performed using the 
FARAWAVE Catheter in the fully deployed configuration.  Consistent with the proposed treatment, 
two applications at 2000V at each catheter location was performed, with approximately 50% overlap 
between adjacent catheter positions.  These catheter positions along the posterior wall linked the PVI 
lesion to create a continuous lesion set encompassing the PVs and LAPW, between the superior and 
inferior insertions of the left and right PV pairs.  As of the date of the PersAFOne II interim clinical 
study report, 17 subjects have returned for the invasive remapping procedure.  Sixty-four of sixty-
eight (94.2%) of PVs and sixteen of seventeen (94%) of LAPWs remained durably isolated.  Again, 
two SAEs in two patients, both pericardial effusions, were reported, related to the required remapping 
procedure. 
Expanding the indication of the FARAPULSE PFA System for approval to treat PersAF patients 
would fulfill a clinical need in a growing population of subjects indicated to receive a catheter 
ablation. The present single arm, prospective cohort IDE study has been designed to demonstrate 
safety and effectiveness of the FARAPULSE PFA System in treating symptomatic drug-refractory 
PersAF patients.  
2 Device Description 
2.1 
Intended Use 
The FARAPULSE Pulsed Field Ablation System is indicated for the treatment of drug resistant, 
symptomatic persistent atrial fibrillation. 
The FARAWAVE Catheter is indicated for the isolation of pulmonary veins and posterior wall in the 
ablation of drug resistant, symptomatic persistent atrial fibrillation. 
2.2 
Investigational Devices 
2.2.1 
FARAPULSE Pulsed Field Ablation System 
The FARAPULSE Pulsed Field Ablation (PFA) System is comprised of the following.  The full 
list of components is provided in Table 2.2-1. 
• 
FARAWAVE Pulsed Field Ablation Catheter (FARAWAVE PFA Catheter)  
• 
FARASTAR Catheter Connection Cable  
• 
FARASTAR Pulsed Field Ablation Generator and associated cables 
• 
Recording System Module and associated cables 
• 
FARADRIVE Steerable Sheath 
The FARAPULSE Pulsed Field Ablation System is currently commercialized in Europe and indicated 
for the treatment of Paroxysmal Atrial Fibrillation. The commercial system will be used for the study 
outside of its CE Mark scope. The investigational systems used in North America and in Europe are 
functionally equivalent.  
A copy of the device labeling and DFU/IFU will be provided in local language(s) as required per 
national regulations, as well as the Investigator Brochure. 
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2.2.2 
FARAWAVE Pulsed Field Ablation Catheter 
The FARAWAVE PFA Catheter is a sterile, single use, over-the-wire, non-deflectable device that is 
used with the FARASTAR Catheter Connection Cable and FARASTAR Generator to enable delivery 
of Pulsed Field Ablation energy for irreversible electroporation. 
The FARAWAVE PFA Catheter is offered in 2 different sizes (31 mm and 35 mm fully deployed 
diameters) to accommodate varying PV anatomy. Selection of either catheter will be at the 
Investigator’s discretion.  
The FARAWAVE PFA Catheter is a multi-electrode catheter that connects electrically to the 
FARASTAR PFA Generator (Figure 2.2-2). It consists of a distal section with electrodes arranged on 
splines, a shaft section, and a proximal handle with a manually operated deployment control. 
 
Figure 2.2-2: FARAWAVE Pulsed Field Ablation Catheter 
 
The FARAWAVE PFA Catheter has five (5) variably deployable splines. The five splines are 
undeployed during insertion and removal and during use can deploy continuously from an 
undeployed state through a partially deployed (“basket-shaped”) configuration to a fully deployed 
(“flower-shaped”) configuration with five petals (Figure 2.2-3). 
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Figure 2.2-3: FARAWAVE Pulsed Field Ablation Catheter – Deployed States 
 
Each spline has 1 electrode that is separately wired from the others on that spline to facilitate 
connection to a mapping or recording system via a cable supplied with the system. The handle 
includes a flush port for saline infusion, a deployment control knob with a guidewire lumen hub that 
can be connected to a hemostasis valve and a short cable that terminates in a single connector for 
attachment to the FARASTAR Catheter Connection Cable. The other end of the Connection Cable 
attaches to the front panel of the FARASTAR PFA Generator. The Connection Cable is packaged 
sterile and is single-use only. The PFA energy is delivered from the FARASTAR PFA Generator over 
the set of ablation catheter electrodes.  
In geographies where The FARAWAVE PFA Catheter is commercially available, the device will be 
used for the study under the investigational IFU and will then be handled according to Section 13.2 
Additional important information is provided in the Investigational FARAWAVE PFA Catheter IFU 
regarding precautions, warnings, specific use instructions and procedural steps of the FARAWAVE 
PFA Catheter. 
2.2.3 
FARASTAR Catheter Connection Cable  
The FARASTAR Catheter Connection Cable is a sterile, single-use device that is used to attach the 
FARAWAVE Catheter (31mm or 35mm) to the FARASTAR Generator 
 
 
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Figure 2.2-4 FARASTAR Catheter Connection Cable 
 
It is 3 meters in length and terminated at both ends with auto-coupling connectors which contain 
alignment markers to facilitate connections to the FARASTAR Generator and FARAWAVE 
Catheter. The main cable diameter is approximately 0.318 inches at each end and is fitted with an 
over molded strain relief where the cable meets with the connectors.  
The FARASTAR Catheter Connector Cable comes in two versions, GEN 1 and GEN 2.  
The FARASTAR Connector Cable (GEN1) is investigational in North America. The FARASTAR 
Catheter Connector Cable (GEN1) is commercially available in Europe and approved for use with the 
FARAWAVE PFA Catheter. When used in Europe in conjunction with the FARAWAVE PFA 
Catheter, it will be handled according to Section 13.2. 
 
The FARASTAR Catheter Connector Cable GEN 2 is investigational and will be used in geographies 
where the system is not commercially available.  
Additional important information is provided in the FARASTAR Catheter Connection Cable 
IFU regarding precautions, warnings, specific use instructions and procedural steps.  
2.2.4 
FARASTAR Pulsed Field Ablation Generator 
The FARASTAR PFA Generator is a 12-channel output unit that generates a pulsed voltage 
waveform that can be delivered to the FARAWAVE PFA Catheter.  The user selectable voltage 
options for the FARAWAVE PFA Catheter are 1800V to 2000V in 100V increments. All versions of 
the FARASTAR PFA Generator consist of the components listed above in Table 2.2-1.  
The generator utilized will be dependent upon regulatory approval in a specific geography. In 
geographies where The FARASTAR PFA Generator is commercially available, the commercial 
version of the generator will be used for the study under the investigational IFU and will then be 
handled according to Section 13.2. 
Details regarding the generator are provided in the FARASTAR PFA Generator User Manual. 
2.2.5 
FARASTAR Recording System Module  
The FARASTAR Recording System Module (RSM) is a system component to the FARASTAR 
Generator. The FARASTAR RSM is a filtering and protection unit meant to be placed in between a 
patient in the Electrophysiology Lab and other equipment such as a recording system for surface-lead 
signals (ECGs) and intra-cardiac electrograms (EGMs). The primary function of the FARASTAR 
RSM is to disconnect the inputs of the EP Lab Recording System from their connections to the patient 
during PFA delivery. The inputs include diagnostic catheters and surface ECGs. This action reduces 
the risk of interference to the Recording System inputs during an ablation. The secondary function of 
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the FARASTAR RSM is to provide Stimulation output connectors for Synchronous Mode PFA 
delivery. 
Details regarding the Recording System Module are provided in the FARASTAR Recording System 
Module User Manual. 
2.2.6 
FARADRIVE Steerable Sheath 
The FARAWAVE Catheter will be used with the FARADRIVE Steerable Sheath.  
The FARADRIVE Steerable Sheath consists of two (2) primary components, the Steerable Sheath 
and the Dilator, which are used together. Both components are sterile and single use only. 
The FARADRIVE Steerable Sheath is comprised of a distal steerable section and a shaft section 
which connect to the handle. The handle includes a knob to control the deflection of the distal tip and 
a flush port for infusion of saline or contrast. The Dilator is intended for insertion through the sheath 
lumen and includes a shaped tip for dilation for vascular or chamber access (Figure 2.2-5).  
In geographies where the FARADRIVE Steerable Sheath is commercially available, the device will 
be used for the study under the investigational IFU and will then be handled according to Section 
13.2. 
 
Figure 2.2-5: FARADRIVE Steerable Sheath 
 
Details regarding the sheath are provided in the FARADRIVE Steerable Sheath IFU. 
3 Study Objectives and Endpoints 
3.1 
Study Objective 
The objective of the ADVANTAGE AF Study is to establish the safety and effectiveness of the 
FARAPULSE Pulsed Field Ablation System for treatment of drug resistant, symptomatic persistent 
atrial fibrillation. 
3.2 
Primary Safety Endpoint 
The primary safety endpoint (PSE) is the proportion of Treatment Subjects and Attempt Subjects with 
one or more of the following device or procedure-related Composite Serious Adverse Events 
(CSAEs) following the Index Procedure / Rescheduled Index Procedure or the Re-Ablation Procedure 
within the Blanking Period, with an Onset Date following the procedure as specified in Table 3.2-1: 
 
 
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3.3.2 
Persistent AF Chronic Success 
Persistent AF Chronic Success is defined as freedom from any of the following through the Day 360 
Assessment after the Blanking Period, excluding documented CTI-dependent AFL2: 
a. Arrhythmia: Occurrence of any Detectable AF, AFL or AT  
b. Re-ablation: Any re-ablation for AF, AFL or AT  
c. Cardioversion: Any electrical cardioversion for AF, AFL or AT  
d. AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone 
Within the Blanking Period, recurrent arrhythmias can be managed with AADs, cardioversion or one 
re-ablation procedure with the FARAPULSE PFA System without constituting Persistent AF Chronic 
Failure. Titration of Class I/III antiarrhythmic medications are allowed during the Blanking Period. 
Subjects are allowed to remain on Class I/III antiarrhythmic medications at the historic maximum 
ineffective dose (prior to the ablation procedure) after the 90-day Blanking Period, except 
amiodarone.  Subjects that undergo more than one re-ablation procedure within the Blanking Period 
will be classified as a Persistent AF Chronic Failure.  Complete definitions of the endpoint terms 
(including Blanking Period, Detectable AF, AFL, or AT, Failed AAD and Non-Failed AAD), can be 
found in Section 23.2.  
3.4 
Additional Endpoints and Assessments 
The following additional endpoints and assessments will be analyzed and reported for the 
ADVANTAGE AF Study. 
3.4.1 
Additional Safety Endpoints 
The following endpoints will be descriptively analyzed through the Day 360 Assessment in Treatment 
Subjects and the Day 30 Assessment in Attempt Subjects: 
• 
Composite Non-Serious Adverse Events: 
Defined as the proportion of subjects with one or more composite nonserious AEs otherwise as 
defined in Table 3.2-2: Composite Serious Adverse Event Definitions. 
• 
Related Adverse Events 
Defined as the proportion of subjects with one or more device or procedure-related AEs 
• 
Any Serious Adverse Event 
Defined as the proportion of subjects with one or more SAEs whether or not device or 
procedure-related 
• 
Post-Blanking Arrhythmia Hospitalizations 
Defined as the proportion of Treatment subjects with one or more physician-directed admission 
to an inpatient hospital facility for at least two consecutive calendar days for the primary 
purpose of diagnosing or treating AF, AFL or AT beginning after Day 90 
• 
Post-Blanking Cardioversions 
Defined as the proportion of Treatment subjects with one or more electrical cardioversions for 
AF, AFL or AT after Day 90 
3.4.2 
Additional Effectiveness Endpoints 
The following endpoints will be descriptively analyzed in Treatment Subjects at the indicated time 
points: 
 
2 Post-blanking CTI-dependent AFL or re-ablation or cardioversion for CTI-dependent AFL does not constitute 
Treatment Failure. 
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• 
Persistent AF Acute Procedural Success 
Defined in Section 3.3.1 at the conclusion of the Index Procedure / Rescheduled Index 
Procedure 
• 
Persistent AF Chronic Success 
Defined in Section 3.3.2 through the Day 360 assessment 
• 
Single Procedure Treatment Success  
Treatment Success as defined in Section 3.3.1  but counting subjects with any re-ablation for 
AT, AFL, or AT as Treatment Failures 
• 
Off Drug Treatment Success  
Treatment Success as defined in Section 3.3.1 but counting subjects treated with any Class I / 
III AAD after Day 90 as Treatment Failures 
• 
Re-Ablation Rate  
Defined as the proportion of subjects who receive one or more re-ablations during study follow-
up for AF, AFL, or AT, at any time during follow-up, and subdivided by re-ablation during 
Days 0 – 90 and by Days 91 and thereafter. 
3.4.3 
Procedural Assessments 
The following assessments will be descriptively analyzed at the completion of the Index Procedure / 
Rescheduled Index Procedure: 
Assessments of procedure durations (recorded and rounded to the nearest minute)  
• 
Procedure Time 
Defined as the recorded time of initiation of venous access to the recorded time of venous 
access closure completion 
• 
LA Dwell Time 
Defined as the recorded time between the insertion of the first device into the LA and the 
removal of the last device from the LA 
• 
PVI and PWI Ablation Time 
Defined as the recorded time from the first FARAWAVE PFA Catheter application to the last 
FARAWAVE PFA Catheter application. 
• 
Fluoroscopy Time 
Defined as the recorded total duration of exposure to fluoroscopic imaging 
Characterization of lesion sets 
• 
PVI Ablations 
Defined as the number of applications in each attempted vein 
• 
PWI Ablations 
Defined as the number of applications during ablation of the LA posterior wall 
• 
CTI Ablations 
Defined as the number of applications during CTI ablation  
• 
Other Ablations 
For subjects undergoing welfare-required ablations for an accessory pathway, AVNRT, left-
sided AFL or incessant AT a listing and descriptive summary of ablation lesions delivered. 
3.4.4 
Quality of Life Assessments 
The following assessments will be descriptively analyzed between Baseline and Day 180, and 
between Baseline and Day 360.  
• 
The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L) 
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Figure 4.1-1: ADVANTAGE AF Study Design 
 
 
4.2 
Scale and Duration 
4.2.1 
Number of Subjects 
Approximately 417 treated subjects will be enrolled in this study (up to 159 Roll-In Subjects and 
approximately 258 Treatment Subjects). 
Roll-In Subjects (up to 159): The first subject enrolled by each ablating Investigator at each site will 
be treated with the investigational device(s) as part of Investigator preparation, up to a maximum of 
159 subjects across 53 investigational sites. Roll-In procedures may be adapted based on prior 
experience, or additional subjects may be required as described in Section 4.3. 
Treatment Subjects (258): A planned 258 Treatment Subjects will be enrolled to support the proposed 
primary study outcomes. No site may enroll more than 33 Treatment Subjects(13% of those planned). 
Subject enrollment will stop once approximately 258 Treatment Subjects are accrued. 
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4.2.2 
Investigational Sites / Countries 
Up to 53 clinical sites globally, including North America, Europe, and Asia. 
At least 50% of study subjects will be enrolled in the United States, and at least 50% of study sites 
will be in the United States. 
The number of active ablating Investigators at any site is limited to a maximum of three (3). 
4.2.3 
Study Duration 
Enrollment is expected to be completed in approximately 9 months, and subjects will be followed for 
12 months. There will be an approximate 2-month period of site close-out visits, for an estimated first 
patient in until last patient last assessment duration of 23 months. 
4.2.4 
Subject Duration 
The study duration for each subject will be approximately 13 ± 1 months to allow for screening, pre-
procedural diagnostic procedures, treatment, and 12 ± 1 months of study follow-up. 
4.3 
Treatment Assignment 
The first subject enrolled by each Investigator at each site will be classified as a Roll-In Subject and 
will be treated with the FARAPULSE PFA System as part of Investigator preparation.  Roll-In 
Subjects are further defined in Section 6.6.2.  
The number of Roll-In Subjects for each investigator will be determined by BSC depending on prior 
experience. Sites with more than one (1) active investigator may utilize available Roll-In Subjects 
jointly as required. Each site will be allocated a maximum of 3 Roll-In Subjects total. 
After an individual investigator has completed the Roll-In Subject requirements, BSC will provide the 
investigator with authorization to proceed with the enrollment of Treatment Subjects. 
4.4 
Justification for the Study Design 
BSC believes that a prospective, single arm, open label IDE trial with the FARAPULSE PFA System 
as the treatment device and powered for standard safety and effectiveness performance goals is a 
reasonable method to generate valid scientific evidence regarding the safety and effectiveness of, and 
obtain approval for, the FARAPULSE PFA System for the treatment of persistent atrial fibrillation. 
The rationale for a single arm trial comparing outcomes to performance goals includes the single arm, 
performance goal IDE study “Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat 
AF” (ClinicalTrials.gov Identifier: NCT04198701) utilizing endocardial pulsed field ablation to treat 
PersAF. 
Additionally, the current understanding in the field of catheter ablation of PersAF, ongoing IDE 
investigations, and the presence of additional products approved by the FDA for the ablation of 
PersAF indication from two different manufacturers (Biosense Webster P030031 S100, Medtronic 
P100010 S098) suggests the field is mature enough to consider a single arm design adequate for this 
study.  
Finally, the several clinical trials leading to CE Mark approval, the PersAFOne Trial and the post-
market follow-up FARA-Freedom Trial in the EU using a substantially similar clinical investigation 
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6 Subject Enrollment and Accountability 
6.1 
Screening 
6.1.1 
Study Candidate Screening 
Investigators are responsible for screening all potential subjects and selecting those who are 
appropriate for study inclusion. The subjects selected for participation should be from the 
Investigator’s general patient population. The Investigator is expected to follow standard of care 
testing to diagnose and screen subjects for inclusion in the study. 
6.1.2 
Screening and Enrollment Log 
A Screening and Enrollment Log will be maintained at the investigational site to document select 
information about candidates who sign an Informed Consent Form (ICF) and then fail to meet the 
general and specific selection criteria, including those enrolled in the study and classified either as 
Consent Ineligible, Intent, Attempt or Treatment subjects. 
6.1.3 
Informed Consent 
In order to determine eligibility of a subject, the Investigator or designee needs to implement the 
consent process and verify and document the subject meets the inclusion / exclusion criteria. 
Informed consent is required for all subjects prior to their participation in the study. No study-specific 
procedures can be conducted prior to consent.  
The subject will be given ample time to consider participation and ask questions if necessary. An 
approved ICF shall be personally signed and dated by the subject. The date the subject signs the ICF 
is the Consent Date. The original, signed document is to be kept with the subject’s file and a copy 
must be provided to the subject.  
The Index Procedure must be initiated within 30 days following the Consent Date. If at the Index 
Procedure the subject is found to have inadequate pre-procedural anticoagulation, a current atrial 
thrombus, or other resolvable exclusion criteria as determined by the Investigator, then the 
Rescheduled Index Procedure must be scheduled within 45 days of the Index Procedure. 
If the Index Procedure / Rescheduled Index Procedure has not been performed within these time 
periods, the subject will be classified as an Intent or Consent Ineligible Subject (see Section 6.6.1 and 
Section 6.6.3), depending on the circumstances. An Intent Subject or Consent Ineligible Subject 
cannot be considered for re-enrollment. The site will ensure that originally signed ICFs and 
documentation of the ICF signature process are filed in subject’s file and that the subject’s 
participation into the study is documented per hospital process (e.g.in the medical file). Originally 
signed ICFs and the ICF process will be made available for review at Interim Monitoring Visits 
(IMVs). 
For additional information regarding the informed consent process, refer to Section 18. 
6.2 
Point of Enrollment 
Subjects who have signed and dated the Informed Consent Form are considered enrolled in the study.  
Adverse events will be captured beginning on the Consent Date. Adverse events occurring prior to the 
Index Procedure / Rescheduled Index Procedure will be analyzed and listed separately and will not 
otherwise be part of the outcome analyses specified in this protocol. 
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Screening tests that are part of standard-of-care (SOC) can be used to determine pre-eligibility, but no 
study-related activities, testing, procedures, etc. can take place until the ICF is signed and dated by 
the subject. Study data from exams performed prior to consent / enrollment (e.g., transthoracic 
echocardiography [TTE]) will be collected as medical history data after the subject is consented / 
enrolled in the study.  
6.3 
Enrollment Controls 
Subject study-specific identification (ID) will be generated through the Electronic Data Capture 
(EDC) system used for this study. This database will also be utilized to provide the sites with subject 
classification assignments (including Roll-In Subjects) once a subject has provided written informed 
consent. Enrollment controls will be put in place to ensure no more than 33  (13% of the estimated 
258 Treatment Subjects) will occur at a single site. In addition, BSC will communicate the process 
that will be followed for enrolling subjects as the enrollment ceiling of 258 Treatment Subjects is 
approached.  
6.4 
Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study) shall be 
accounted for and documented. If a subject withdraws from the clinical investigation, the reason(s) 
shall be reported. If such withdrawal is due to problems related to investigational device safety or 
performance, the Investigator shall ask for the subject’s documented permission to follow his / her 
status / condition outside of the clinical study. 
Reasons for withdrawal may include physician discretion, subject choice to withdraw, lost to follow-
up, or death. While study withdrawal is discouraged, subjects may withdraw from the study at any 
time, with or without reason, and without prejudice to further treatment. In the event a subject does 
decide to withdraw from the study, every effort should be made to obtain full information on any on-
going reportable adverse events up to the point of withdrawal. Additional data may no longer be 
collected after the point at which a subject has been withdrawn from the study or withdraws his / her 
consent, for whatever reason. Data collected up to the point of subject withdrawal may be used, 
unless any local regulations apply which require removal of the data. 
If the withdrawal is due to the Investigator’s discretion, the Investigator is obligated to follow all open 
reportable adverse events until they can be considered as resolved or not resolved. 
The outcome of all open reportable adverse events should be documented. If the withdrawal is due to 
problems related to device safety or performance, the Investigator shall ask for the subject’s 
documented permission to follow his / her status / condition. 
Withdrawn subjects will not be replaced. 
All applicable electronic case report forms (eCRFs) up to the point of subject withdrawal / lost to 
follow up and an “End of Study” eCRF must be completed. 
6.5 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return after documented attempts to 
attend a scheduled assessment and is unable to be contacted by the study site staff.  
The following actions must be taken if a subject fails to participate in a required study assessment: 
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• 
The site will attempt to contact the subject to reschedule the missed assessment and counsel 
the subject on the importance of maintaining the assigned assessment schedule and ascertain 
if the subject wishes to and / or should continue in the study. 
• 
Before a subject is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the subject (at minimum 3 telephone calls and a certified letter to 
the subject’s last known mailing address or local equivalent methods). These contact attempts 
must be documented in the subject’s medical record or study file.  
• 
Should the subject continue to be unreachable, he or she will be considered lost to follow-up 
from the study. 
All applicable eCRFs up to the point of subject withdrawal / lost to follow up and an “End of Study” 
eCRF must be completed.  
6.6 
Subject Status and Classification 
As subjects are evaluated, enrolled, and treated in the study, they will be grouped into one of the 
following categories. Categorization will determine follow-up, data, and analysis requirements. 
Investigational sites will list all Consent Ineligible (screening failure), Intent, Attempt and Treatment 
subjects in the Screening and Enrollment Log. 
6.6.1 
Consent Ineligible (Screening Failures) 
A subject who has signed informed consent but is found ultimately not to meet eligibility criteria will 
be classified as “Consent Ineligible”.6 There are no follow-up reporting requirements for consent 
ineligible subjects. Subjects determined to be Consent Ineligible do not count towards the enrollment 
ceiling and will not be used for analysis of the endpoints. The original signed Informed Consent must 
be maintained in the center’s patient file. A subject ID will be assigned in the EDC system.  
For consent ineligible subjects the following forms must be completed: 
• 
Enrollment and End of Study eCRF must be completed  
• 
Adverse Event CRFs for any reportable event, as defined in Section 17 for any adverse event 
that occurs after signing the Informed Consent, up to the point of subject withdrawal 
6.6.2 
Roll-In Subjects 
The first subject enrolled by each Investigator at each site will be treated with the FARAPULSE 
Pulsed Ablation System as part of Investigator preparation (Section 4.2.1) and be enrolled into the 
study as a Roll-In Subject.   
Roll-In Subjects will: 
• 
Be consented using the approved ICF 
• 
Count against the Roll-In Subject enrollment ceiling  
• 
Follow the Index Procedures as specified in Section 7.6 
• 
Have all study data gathered as specified in Section 7 
• 
Be followed for 12 months post-ablation, completing Day 7, Day 30, Day 90, Day 180, and 
Day 360 Assessments identically with Treatment / Attempt Subjects 
• 
Be analyzed and reported separately from the Treatment / Attempt Subjects. 
 
6 See Section 5.3 regarding the acceptability of exclusion criteria that can be remediated and thus do not 
constitute an ultimate failure of eligibility criteria. 
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6.6.3 
Intent Subjects 
Intent Subjects include the following types of subjects: 
• 
Any subject who signs informed consent, meets eligibility criteria, but does not have any 
study investigational devices inserted into the body.  
• 
Any subject that is enrolled in the study but does not undergo the Index Procedure within 30 
days from the Consent Date or a Rescheduled Index Procedure within 45 days of the Index 
Procedure. These subjects will be withdrawn from the study as of the end of the above 
disqualifying interval.  
Intent Subjects: 
• 
Do not count towards the Treatment Subject enrollment ceiling  
• 
Have no follow-up requirements once classified as an Intent Subject 
• 
Will not be used for analysis of any study endpoints 
• 
Will not be allowed to re-enroll in the study 
For Intent Subjects, at a minimum the following forms must be completed:  
• 
Enrollment and baseline CRFs such as, but not limited to, informed consent, enrollment 
information and other related CRFs 
• 
End of Study CRF 
• 
Adverse Event CRFs for any reportable event as defined in Section 17.1 for any adverse 
event that occurs after signing the Informed Consent, up to the point of subject withdrawal 
The original signed Informed Consent must be maintained in the investigation site’s patient file. A 
subject ID will be assigned in the EDC system. 
6.6.4 
Attempt Subjects 
An Attempt Subject is a subject who signs informed consent, meets eligibility criteria, and has any 
investigational device inserted into the body but does not receive any pulsed field ablation 
application.  
Attempt Subjects: 
• 
Do not count towards the Treatment Subject enrollment ceiling.  
• 
Will be followed up to the Day 30 assessment with all applicable CRFs completed 
• 
Will be used for analysis of the study safety outcomes  
• 
Will not be used for analysis of the study effectiveness outcomes including subgroup, 
multivariable, and center pooling analyses. 
• 
Will not be allowed to re-enroll in the study. 
For Attempt Subjects, at a minimum the following forms must be completed:  
• 
Enrollment and baseline CRFs such as, but not limited to, informed consent, enrollment 
information and other related CRFs 
• 
End of Study CRF 
• 
Adverse Event CRFs for any reportable event as defined in Section 17.1 for any adverse 
event that occurs after signing the Informed Consent, up to the point of subject withdrawal 
The original signed Informed Consent for each Attempt Subject must be maintained in the 
investigational site’s patient file. A subject ID will be assigned in the EDC system.  
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6.6.5 
Treatment Subjects 
Any subject that signs the Consent Form, meets eligibility criteria, has an investigational device 
inserted into the body and receives at least one pulsed field ablation application will be classified as a 
Treatment Subject.  
Treatment Subjects: 
• 
Count towards the Treatment Subject enrollment ceiling. 
• 
Will be followed up to the 360 Day Assessment with all applicable CRFs completed 
• 
Will be included in all study analyses.  
The original signed Informed Consent and any relevant documentation must be maintained in the 
investigational site’s patient file. A subject ID will be assigned in the EDC system.  
6.7 
End-of-Study Definition  
A clinical trial is considered completed when subjects are no longer being examined or the last 
subject’s last study assessment has occurred. The end of the study is defined as completion of the last 
assessment or procedure shown in the Data Collection Schedule in the trial globally.  
7 Study Methods 
7.1 
Overview of Study Interactions 
Each Treatment subject will undergo the following formal study interactions: 
• 
Baseline Assessment 
• 
Index Procedure / Rescheduled Index Procedure (Day 0) 
• 
Pre-Discharge Assessment (immediately prior to discharge after the Index Procedure) 
• 
Day 7 Safety Assessment (window Day 7 – 11, remote) 
• 
Day 30 Safety Assessment (window Day 30-37, remote) 
• 
Day 90 Assessment (window 90 ± 14 days, in-person) 
• 
Day 180 Assessment (window 180 ± 30 days, remote) 
• 
Day 360 Assessment (window 360 ± 30 days, in-person) 
In addition, the following events may also occur for some study subjects: 
• 
Re-ablation Procedure: Re-ablations for AF, AFL and AT will be captured in the EDC 
database using the Re-Ablation Procedure CRF 
• 
Unscheduled Assessments: Any unscheduled cardiovascular assessments will be captured in 
the EDC database using the Unscheduled Assessment CRF 
 
The data collection schedule for these various interactions is shown in Table 7.2-1. 
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7.3 
Anticoagulation 
Anticoagulation will be guided by the 2017 Heart Rhythm Society Expert Consensus Statement8 and 
the 2019 American Heart Association / American College of Cardiology / Heart Rhythm Society 
Focused Update72 relating to this issue.  
With the exception of substantial compliance with 4 weeks of anticoagulation prior to the Index / 
Rescheduled Index Procedure (Section 7.6.2.1), adjustments in anticoagulation therapy for subject 
welfare may be made by Investigators based on clinical judgment and do not constitute protocol 
deviations. 
Throughout the study: 
• 
Subjects with a CHA2DS2-VASc score ≥ 2 (men) or ≥ 3 (women) should receive oral 
anticoagulants throughout the study.  
• 
DOACs are recommended over warfarin for eligible subjects.  
• 
Subjects on warfarin should have at least monthly INR assessment. 
Peri-procedural: 
• 
Non-anticoagulated subjects will be placed on therapeutic anticoagulation for 4 weeks prior to 
an ablation procedure regardless of baseline CHA2DS2-VASc score. 
• 
Subjects taking warfarin should continue warfarin through the procedure. 
• 
Subjects taking a DOAC should have either uninterrupted treatment (if receiving rivaroxaban) 
or a single dose interruption in DOAC with a restart shortly after the procedure, at Investigator 
discretion. 
• 
A heparin bolus will be delivered prior to or immediately following transseptal puncture 
according to institutional standard of care. Procedural activated clotting times (ACTs) will be 
sampled regularly throughout the procedure according to institutional standard of care and 
maintained at a minimum of 300 seconds at least until all devices are withdrawn from the left 
atrium. 
Post-ablation: 
• 
If the subject is not otherwise indicated for anticoagulation, suitable anticoagulation will be 
maintained for a minimum of 2 months following any ablation procedure. 
• 
Thereafter, decisions regarding anticoagulation should be based on the guidelines referenced 
in this section. 
7.4 
Antiarrhythmic Drugs 
Use of Class I / III AADs during the ADVANTAGE AF Study must be managed carefully. 
The terms “Antiarrhythmic Drugs, Class I and III”, “Blanking Period”, “Failed AAD” and “Non-
Failed AAD” are defined specifically in Section 23.2. 
Failed AADs 
At the Baseline Assessment, Section 7.5, all Class I and III AADs previously used by the subject 
must be defined as Failed AADs or Non-Failed AADs in the CRF, including for any Failed AADs the 
maximum failed dose (see Section 23.2). 
Amiodarone 
• 
May not be used after the Blanking Period or the subject becomes a Treatment Failure. 
• 
If subjects are prescribed Amiodarone, treatment should be stopped within 30 days following 
the Index Procedure.  
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Managing AADs During the Blanking Period 
During the Blanking Period the subject should be assessed for AAD continuation. Titration of Class 
I / III AADs is allowed during the Blanking Period.  
To account for the hard cutoff of the Blanking Period at 90 days and given the permitted visit window 
for the Day 90 Assessment (90 ± 14 days), AADs that are taken during the Blanking Period but are 
stopped at the time of a within-window Day 90 visit (up to and including Day 104) will not be 
counted as potential Treatment Failures to allow the necessary physician evaluation. 
Managing AADs After the Blanking Period 
If indicated, subjects may remain on Class I / III AADs following the Blanking Period, preferably 
those established as Failed AADs (see Section 23.2) at or below the maximum failed dose so as not to 
create a post-Blanking Period Treatment Failure.  
Use of a Non-Failed AAD after the Day 90 Assessment constitutes a Treatment Failure for the 
primary effectiveness endpoint. 
AAD Monitoring 
At all subsequent follow-up assessments, subject compliance with, and changes in drugs and daily 
doses for any Class I / III AAD, will be elicited and recorded.  
7.5 
Baseline Assessment 
Type of Assessment: In-person at investigational site 
The completion of the Baseline Assessment requires an in-person assessment. Such 
assessments must be deferred if this is not possible. 
The below baseline data will be generated in the window beginning 30 days prior to the Consent Date 
and ending on the date of the Index Procedure, unless otherwise specified.  
This data will include but is not limited to: 
• 
Demographics including gender, height, and weight, race and ethnicity, in accordance with 
local requirements7 
• 
Pertinent medical and cardiovascular history 
• 
AAD history to establish Failed AAD and Non-Failed AAD status 
• 
Anticoagulation medication history 
• 
Cardiac physical examination 
• 
Pregnancy test (all women of child-bearing potential) 
• 
Hematocrit, hemoglobin, electrolytes, blood urea nitrogen (BUN), creatinine 
• 
COVID-19 testing according to investigation site requirements. The following information is 
not required if it is not a site requirement, but if available the data should be recorded: 
o A negative PCR for SARS-CoV-2 virus or equivalent testing, or  
o Confirmation of vaccination with a commercially available vaccine 
 
7 With a goal of achieving an unbiased estimate of treatment effect in the general population, Boston Scientific 
seeks to enroll a diverse population including representative proportions of relevant age, racial, and ethnic 
subgroups, which are consistent with the intended use population of the device. Case Report Forms will collect 
data on age, race and ethnicity in order to achieve this goal, in accordance with local regulations. 
 
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• 
12-lead ECG 
• 
Imaging (within the window beginning 180 days prior to the Consent Date and ending on the 
date of the Index Procedure) 
o TTE or Cardiac CT/ MRI for LA dimensions  
o TTE for LVEF 
o Cardiac CT or MRI establishing cardiac anatomy for mapping and PV dimensions 
• 
NYHA Classification 
• 
National Institutes of Health Stroke Scale (NIHSS) score by NIHSS-certified site personnel 
• 
CHA2DS2-VASc score 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L)  
o The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
Introduction to the Rhythm Monitoring: At the Baseline Assessment, the subject will receive an 
introduction to event and Holter monitoring (rhythm monitoring) and how this will be performed 
during the follow-up period. The importance of compliance with these critical assessments will be 
stressed.  
7.6 
 Index Procedure / Rescheduled Index Procedure 
7.6.1 
Index Procedure / Rescheduled Index Procedure Data Collection 
Type of Assessment: In-person at investigational site 
The performance of the Index Procedure / Rescheduled Index Procedure and the Pre-
Discharge Assessment both require an in-person assessment. The Index Procedure / 
Rescheduled Index Procedure must be deferred if this is not possible. 
Procedural data will be collected including but not limited to: 
• 
The results of transesophageal echocardiography (TEE) or volumetric CT within 48 hours 
prior to procedure, or intracardiac echocardiography (ICE) prior to transseptal puncture, 
utilized for exclusion of LA thrombus. 
• 
Pregnancy test (all women of childbearing potential if the baseline pregnancy test was 
obtained more than 30 days prior to the Index Procedure / Rescheduled Index Procedure) 
• 
Documentation of PVI for each attempted vein, of PWI, and if performed, of CTI BDB 
• 
Post-ablation electroanatomical maps, if performed with Rhythmia 
• 
The functional status of both phrenic nerves will be assessed radiographically pre and post 
ablation. 
• 
Method of sedation or anesthesia 
• 
Whether adenosine was used to confirm PVI and / or PWI 
• 
Whether a post-procedure cardioversion was performed 
• 
Adverse events 
• 
For the 3D mapping system: Manufacturer and model, when applicable 
• 
Procedural times  
• 
Ablation data  
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• 
Procedural anticoagulation data: 
o For subjects on a DOAC whether DOAC therapy was interrupted for procedure 
o For subjects on warfarin, a pre-ablation international normalized ratio (INR) value 
o Procedural heparin administration and timing 
• 
Device deficiencies and malfunctions  
7.6.2 
Index Procedure Workflow 
This section contains important information regarding the procedures for cardiac ablations specified 
in the ADVANTAGE AF Study. Investigators and staff should refer to training materials and the IFU 
documents as applicable per device and study region. 
Ablation under this protocol will generally follow the order below. However, the Investigator may 
alter the ablation sequence if necessary for subject welfare. 
Unless otherwise directed by Sponsor, at the conclusion of the procedure, all single-use components 
of the FARAPULSE PFA System should be returned to the Sponsor. 
7.6.2.1 
Preparation 
Subjects must be screened for substantial compliance with 4 weeks of systemic anticoagulation prior 
to the Index Procedure and, if in the opinion of the Investigator, this condition has not been met, the 
subject will be rescheduled as defined in Section 7.6.3. 
 
TEE or volumetric CT within 48 hours of the procedure or ICE during the procedure will be utilized 
prior to transseptal puncture for exclusion of LA thrombus. If the study reveals atrial thrombus, the 
investigational procedure will not begin or will be terminated, no ablation will be performed, and the 
subject will be rescheduled as defined in Section 7.6.3. 
Phrenic nerve function will be assessed prior to ablation per Investigator standard of care, preferably 
by a pre-sedation fluoroscopic sniff test. Subjects will undergo sedation / anesthesia according to 
institutional protocol. They will then be prepared in conventional sterile fashion for a cardiac 
catheterization procedure.  
Femoral vein access will be obtained aseptically under ultrasound guidance.  
Commercially available diagnostic catheters may be placed before or after transseptal access at the 
Investigator’s discretion. Transseptal access to the LA will be obtained using commercially available 
devices, establishing guidewire access to the LA. 
A heparin bolus will be delivered prior to or immediately after transseptal puncture. Procedural ACTs 
will be monitored according to the investigational site’s standard of care and maintained at a 
minimum of 300 seconds at least until all devices are withdrawn from the left atrium. 
7.6.2.2 
Pulmonary Vein Isolation 
Ablation of the PVs will be performed according to the IFU and institutional practice. 
Ablation will be attempted in every clinically relevant PV, including any vein with an electrically 
active muscular sleeve. Small anomalous PVs that are electrically silent need not be attempted. 
 
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The use of ICE is recommended but not required for Pulsed Field Ablation procedures. 
 
All catheter exchanges should be carefully performed to avoid introducing air bubbles into the 
FARADRIVE Steerable Sheath. 
 
Esophageal temperature monitoring, esophageal cooling and esophageal deviation are unnecessary 
during PVI and PWI ablation with the FARAWAVE PFA Catheter and should not be utilized. 
7.6.2.3 
Posterior Wall Isolation 
Following PVI ablation, LAPW ablation will be performed according to the IFU and institutional 
practice.  
LAPW ablation will be performed in the area below the superior aspect of the superior PVs, above 
the inferior aspect of the inferior veins, and between the insertions of the left sided and right sided 
PVs. In the event the PW is found to be electrically isolated following PVI, LAPW ablation will still 
be performed using the same anatomically guided approach until there is sufficient overlap between 
PFA application sites. No ablation in other locations, including the left atrial appendage, is permitted. 
LAPW ablation should be guided by electroanatomical mapping, ICE and / or fluoroscopy to ensure 
the entire area of LAPW is ablated with the appropriate amount of overlap between PFA application 
sites.  
 
All catheter exchanges should be carefully performed to avoid introducing air bubbles into the 
FARADRIVE Steerable Sheath. 
 
Esophageal temperature monitoring, esophageal cooling and esophageal deviation are unnecessary 
during PVI and LAPW ablation with the FARAWAVE PFA Catheter and should not be utilized. 
7.6.2.4 
Assessment of Isolation and Phrenic Nerve Function 
Assessment of Isolation 
After the completion of the planned PV and LAPW ablations, isolation will be assessed as: 
• 
The isolation of all attempted PVs at least 20 minutes following the last PFA application in 
each respective vein by entrance block performed with or without adenosine testing, AND 
• 
The isolation of the LAPW at the end of the LAPW ablation, performed with or without 
adenosine testing, via interrogation by multipolar diagnostic catheter or 3D electroanatomical 
mapping. If electroanatomical mapping is used, electrograms demonstrating PWI are required 
per Section 7.17. At the Investigator’s discretion, exit block pacing of the PW may be 
performed to detect any epicardial exit pathways. 
Additional PV and LAPW ablation as described above may be performed as needed at any time to 
achieve complete PVI and PWI. Alternative dosing or fewer applications may be performed as 
needed for subject welfare, technical difficulties, or anatomical challenges and will not constitute a 
Treatment Failure if electrical isolation is still confirmed as required. In the event that touch-ups are 
performed after the initial isolation assessment, further waiting periods are not required.  
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Assessment of Phrenic Nerve Function 
Once all PV and LAPW ablation is completed and isolation is confirmed, the functional status of both 
phrenic nerves will be assessed per Investigator standard of care (e.g. radiographically either by 
pacing, fluoroscopy, or a sniff test.8) 
7.6.2.5 
CTI Ablation 
The following subjects will undergo CTI ablation: 
• 
Required: For subjects with a history of CTI-mediated (typical) AFL and  
o Who have not had a CTI ablation procedure, or 
o Who have had a CTI ablation procedure but have recurrent CTI conduction. 
• 
Required: Subjects who manifest CTI-mediated AFL (spontaneous or induced) during the Index 
Procedure 
• 
At Investigator discretion: Subject welfare indicates that CTI ablation should be performed. 
Ablation of the CTI will be performed using, a commercially available BSC RF catheter.  If 
performed, CTI ablation should occur following PV and LAPW ablation.  FARAWAVE usage is not 
allowed to complete any CTI lesion. 
After CTI ablation is completed in these subjects, BDB will be assessed, and if necessary, additional 
applications may be performed until BDB is confirmed. The CTI ablation data will be documented in 
the CRF and does not constitute a Persistent AF Acute Procedural Failure. 
7.6.2.6 
Other Ablation 
When the Investigator determines that subject welfare requires intervention for either an accessory 
pathway, AVNRT or spontaneously occurring treatment-emergent AFL or AT, ablation for these 
arrhythmias may be performed using any commercially available RF ablation catheter. Such ablations 
should be performed after all ablation with the FARAPULSE PFA System is complete.  These 
permitted ablations and the associated data will be documented in the CRF and do not constitute 
Persistent AF Acute Procedural Failure. FARAWAVE usage is not allowed to complete any lesion 
outside of the PVs and LAPW, as described in the IFU.  
Ablation for an arrhythmia that is provoked only by catheter manipulation or is only inducible 
by pacing or pharmacologic stimulation is not permitted. 
7.6.3 
Rescheduled Index Procedure 
If, at the Index Procedure, the subject is found to have inadequate pre-procedural anticoagulation, a 
current atrial thrombus, COVID-19, or other temporarily disqualifying condition, the subject may 
have their Index Procedure rescheduled not later than 45 days later. The Rescheduled Index 
Procedure will otherwise follow the data and procedural requirements of Section 7.6.1.  
The Rescheduled Index Procedure must be scheduled within 45 days of the Index Procedure, and only 
one Rescheduled Index Procedure may be allowed; otherwise, the subject will be exited from the 
study as an Intent Subject. 
This rescheduling is permissible and does not create an Acute Procedural Failure. The subject remains 
a potential Treatment Subject.  
 
8 If anesthesia necessitates, a pre-discharge fluoroscopic sniff test or inspiration / expiration CXR may be 
acceptable. See Section 7.7. 
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References to “Index Procedure” in this protocol should be assumed when appropriate to include 
“Rescheduled Index Procedure” as well if not otherwise specified. 
7.7 
Pre-Discharge Assessment 
Subjects should be prescribed a form of systemic anticoagulation treatment for at least two months 
following the ablation procedure. See Section 7.3 regarding post-ablation anticoagulation 
requirements.  
Type of Assessment: In-person at investigational site 
Prior to hospital discharge, study data will be collected including but not limited to: 
• 
Adverse events 
• 
Hematocrit, hemoglobin, electrolytes, BUN, creatinine 
• 
12-lead ECG to document the subject’s rhythm and if any new conduction disturbances are 
observed.   
o A 12-lead ECG collected at the end of the Index Procedure / Rescheduled Index 
Procedure after all ablation was complete is also acceptable.  
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs. 
• 
Occurrence, date, indication and outcome of any post-procedure cardioversion(s) 
• 
Phrenic nerve assessment, as only applicable: 
o If the function of both phrenic nerves could not be confirmed at the end of the Index 
Procedure / Rescheduled Index Procedure, a radiologic examination of the diaphragm 
(fluoroscopic sniff test or inspiration / expiration CXR) 
o If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated 
diminished phrenic nerve response and resolution has not been previously demonstrated, 
a radiologic examination of the diaphragm 
 
Pre-Discharge Stroke Evaluation: 
• 
NIHSS score by NIHSS-certified site personnel after the effects of anesthesia have fully 
resolved. 
• 
If either of the following occurs: 
o The post-procedure NIHSS score has increased by 1 or more points over the pre-procedure 
NIHSS score OR 
o There is a clinical suspicion of stroke or TIA 
Then a consulting neurologist will perform a stroke assessment and include the results of a concurrent 
brain DW-MRI scan. This assessment will be sufficient to determine with reasonable certainty 
whether a stroke, TIA or neither have occurred, using the definitions in Table 3.2-2. Please refer to 
Figure 7.7-1. 
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Figure 7.7-1: Pre-Discharge Stroke Evaluation 
 
 
7.8 
Day 7 Safety Assessment 
Type of Assessment: Remote 
Window: Days 7 – 11 
The Day 7 Assessment is essential to establish the primary safety endpoint and every effort 
must be made to complete this assessment between Day 7 and Day 11.  
If the assessment is delayed, the onset date of an AE must be elicited as carefully as possible to 
establish whether it occurred within the interval between the ablation procedure and Day 7, 
or thereafter. 
Subjects will be assessed remotely between Day 7 and 11 post-Index Procedure / Rescheduled Index 
Procedure. Any subject who continues to be hospitalized at the time of the assessment will have their 
Day 7 assessment performed in-hospital. 
Study data will be collected by interview, including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs. 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since discharge 
• 
The date and communication method(s) used to collect the data remotely 
 
7.9 
Day 30 Safety Assessment 
Type of Assessment: Remote 
Window: Days 30 – Day 37 
The Day 30 Assessment is essential to establish the primary safety endpoint and every effort 
must be made to complete this assessment between Day 30 and Day 37.  
If the assessment is delayed, the onset date of an AE must be elicited as carefully as possible to 
establish whether it occurred within the interval between the ablation procedure and Day 30, 
or thereafter. 
AAD Treatment: Between the Day 30 Assessment and the Day 90 Assessment – the subject 
should be assessed for AAD continuation. See Section 7.10. 
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Discharged subjects will be assessed remotely between Day 30 and Day 37 post-Index 
Procedure / Rescheduled Index Procedure. Any subject who is hospitalized at the time of the 
assessment will have their Day 30 assessment performed in-hospital.  
Study data will be collected by interview including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs. 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since 7-day telephonic 
assessment 
• 
The date and communication method(s) used to collect the data remotely 
7.10 Day 90 Assessment 
Type of Assessment: In-person at investigational site required; remote only for documented 
COVID-19 related disruption. 
Window: 90 ± 14 Days 
If a COVID-19-related disruption prevents an in-person assessment within window:  
• 
As much data as possible may be collected remotely.  
• 
The absence of a 12-lead ECG during a remote assessment is not a protocol deviation but the 
subject should make an EM transmission at the time of the assessment.  
• 
If a radiologic examination is required due to prior diminished phrenic nerve response, an 
inspiration / expiration chest X-ray (CXR) performed in-person or at another healthcare site 
may be substituted. 
 
Event Monitoring: Prior to or at the scheduled Day 90 Assessment, the subject will receive event 
monitor (EM) hardware and training regarding its use and the importance of event monitoring. The 
subject will be instructed to begin using the twice per month EM recordings starting at the time of the 
Day 90 Assessment and also for any symptomatic episodes experienced at any time throughout the 
remainder of study follow-up. 
The subject will be reminded of the critical importance of full compliance with rhythm monitoring 
both for successful treatment of their arrhythmia and for the success of the study. 
 
AAD Treatment: During the Blanking Period the subject should be assessed for AAD continuation. 
At Investigator discretion, Class I / III AADs may be stopped to allow assessment of the subject’s 
potential for off-drug freedom from recurrent AF, AFL, or AT.  
Subjects who require continued AAD treatment may be continued; preferably with a Failed AAD. 
Using a Non-Failed AAD or amiodarone would create an unnecessary Treatment Failure. See Section 
7.4. 
Subjects will be assessed at Day 90 ± 14 days following the Index Procedure / Rescheduled Index 
Procedure. Study data will be collected at the Day 90 Assessment including but not limited to: 
• 
Adverse events 
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• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment 
• 
Cardiac rhythm as determined by a 12-lead ECG at the time of the assessment (in-person 
assessment only). All 12-lead ECGs will be provided to the Arrhythmia Core Laboratory 
(ACL).   
• 
If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated diminished 
phrenic nerve response and resolution has not been previously demonstrated, a radiologic 
examination of the diaphragm 
• 
If there is a clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as the 
baseline scan to assess the dimensions of the PVs. 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the 
data remotely. 
7.11 Day 180 Assessment 
Type of Assessment: Remote; In-person allowed 
Window: 180 ± 30 Days 
If a COVID-19-related disruption interferes with the performance of this assessment, as much 
data as possible may be collected remotely, in or out of window.  
Subjects will be assessed remotely at Day 180 ± 30 days following the Index Procedure / 
Rescheduled Index Procedure. Any subject who is hospitalized or seen in the office as standard of 
care at the time of the assessment may have their Day 180 assessment performed in-person. 
Rhythm Monitoring 
• 
Holter Monitor: Within the 180 ± 30-day window for this assessment, the subject will be 
contacted, receive remote training regarding the use of the Holter and complete a 24-hour 
monitoring session. 
• 
EM Review: During this assessment, EM compliance will be reviewed for twice per month 
and ad hoc symptomatic monitoring, and retraining of the subject provided as needed. 
Study data will be collected at the Day 180 Assessment including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L) The 
Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
• 
The date, time and communication method(s) used to collect the data remotely 
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7.12 Day 360 Assessment 
Type of Assessment: In-person at investigational site required; remote only for documented 
COVID-19 related disruption. 
Window: 360 ± 30 Days 
If a COVID-19-related disruption interferes with the performance of this assessment:  
• 
As much data as possible may be collected remotely, in or out of window. 
• 
The absence of a 12-lead ECG during a remote assessment is not a protocol deviation but the 
subject should make an EM transmission at the time of the assessment.  
• 
If a radiologic examination is required due to prior diminished phrenic nerve response, an 
inspiration / expiration chest X-ray (CXR) performed in-person or at another healthcare site 
may be substituted. 
Subjects will be assessed at 360 days ± 30 days following the Index Procedure / Rescheduled Index 
Procedure. 
Rhythm Monitoring: Within the 360 ± 30-day window for this assessment the subject will be 
contacted, receive remote training regarding the use of the Holter, complete a 24-hour monitoring 
session and return both the Holter and EM as instructed. 
Study data will be collected at the Day 360 Assessment including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment  
• 
If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated diminished 
phrenic nerve response and resolution has not been previously demonstrated, a radiologic 
examination of the diaphragm 
• 
If there is a new clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as 
the baseline scan to assess the dimensions of the PVs. 
• 
Cardiac rhythm as determined by a 12-lead ECG at the time of the assessment (in-person 
assessment only). All 12-lead ECGs will be provided to the ACL. 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L)  
o The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the 
data remotely 
At the completion of all components of the Day 360 Assessment a Study Exit CRF will be 
completed. 
7.13 Re-Ablation Procedures 
7.13.1 Re-Ablation Procedure within the Blanking Period 
For subjects undergoing a first re-ablation procedure within the Blanking Period for Detectable AF, 
AFL or AT, the procedure will be performed by the investigator under the procedures and data 
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requirements of Section 7.6, modified to assess and treat only those locations required, and including 
the pre- and post-procedure NIHSS.  
Such re-ablation using the methods and devices described in Section 7.6 does not constitute a 
Treatment Failure.  
7.13.2 Other Re-Ablation Procedures 
For a second re-ablation during the Blanking Period and for any re-ablation after the Blanking Period, 
any commercially available ablation catheter may be used for re-ablation.  
The FARAPULSE Pulsed Field Ablation System is not permitted to be used for these 
procedures. 
Such re-ablations constitute Treatment Failures, and therefore during such procedures other sites may 
be ablated at Investigator discretion.  
The following data will be collected for these procedures: 
• 
Adverse events 
• 
During re-ablation procedures, a mapping procedure will be performed to characterize the 
reconnection status for each originally treated PV and the PW (if a left-sided re-ablation), and 
the CTI, to characterize lesion durability. 
• 
Limited ablation data 
7.14 Unscheduled Assessments 
Type of Assessment: Either remote or in-person at investigational site. 
Any unscheduled follow-up assessments for cardiovascular events that occur throughout study 
follow-up will be documented. Study data will be collected including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment  
• 
EM compliance will be reviewed for twice per month and ad hoc symptomatic monitoring and 
retraining of the subject provided as needed. 
• 
Cardiac rhythm 
o At the investigational site: 12-lead ECGs will be collected and provided to the ACL. 
o At another health care site: a record of any ECG should be obtained if available. 
o Remote, not at a health care site: An EM submission should be requested. 
• 
If there is a new clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as 
the baseline scan to assess the dimensions of the PVs. 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the 
data remotely 
7.15 Unforeseen Circumstances 
There may be unforeseen circumstances that occur during the course of the study, such as a natural 
disaster or a global pandemic (e.g., COVID-19) that prevents a subject from participating in study 
assessments during the required follow-up window. While every attempt should be made to avoid 
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7.18 Local Laboratory Documentation 
Normal values for the required blood tests for each participating laboratory will be collected for each 
study site. Appropriate certifications and documentation records are required to be maintained at the 
site for participating laboratories.  
8 Statistical Considerations 
8.1 
Endpoints 
The ADVANTAGE AF Study has primary endpoints designed to assess the safety and effectiveness 
of the FARAPULSE PFA System for the treatment of symptomatic, drug-refractory persistent atrial 
fibrillation. The ADVANTAGE AF Study will be considered successful if both the primary safety 
and effectiveness endpoints are passed. 
8.1.1 
Primary Safety Endpoint 
The primary safety endpoint (PSE) is defined in Section 3.2. 
The expected safety event rate for the PSE has been estimated by performing a meta-analysis on 
recently completed studies (see Table 8.1-1).  
The selection of the studies eligible for the meta-analysis for safety was based on the following 
criteria: 
• 
Prospective studies either single cohort or randomized trials with only large sample size 
(N>100), high quality, multi-center. 
• 
Patients with PersAF: Studies with PAF or long-standing PersAF were excluded from the 
analysis. Also, studies with mixed population (i.e., including both PersAF and other forms of 
AF) were excluded if the safety results were not presented for PersAF subset only. 
• 
Patients undergoing transcatheter ablation of AF, with approved energy source (e.g., 
radiofrequency, cryoballoon, laser). Studies that included any other concomitant treatment, 
surgical or trans-catheter (e.g., LAA closure, surgical ablation) were excluded.  
• 
Collection of procedure-related serious adverse events had to be identified as an endpoint in 
the study (indicated as primary, secondary, or additional in the methods section of the paper, 
into SSED or supplementary material) and adequately reporting all the components of the 
safety endpoint were included in the ADVANTAGE-AF protocol (i.e.: 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, Cardiac tamponade / perforation, pericarditis, PV 
stenosis and  Atrio-esophageal fistula). Timeframe of reporting had to be at least 7 days post-
procedure (i.e., peri-procedural events). 
The analysis included 6 studies: event rates and their 95% confidence intervals were estimated from 
SSED, primary publications or results disclosed on clinicaltrials.gov and calculated based on the 
occurrence of the events that constitute the PSE defined in this protocol. 
 
 
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• 
Patients undergoing transcatheter ablation of AF, with any energy source (e.g., 
radiofrequency, Cryoballoon, laser). Studies that included any other concomitant treatment, 
surgical or trans-catheter (e.g., LAA closure, surgical ablation) were excluded.  
• 
Effectiveness outcome / endpoint identified in the study according to HRS Consensus 
Statement for AF ablation and including at minimum: 
o Presence of a 3-month blanking period, inclusive of a follow up at three months. 
During the blanking period treatment with AADs could be applied per standard of 
care, and any arrhythmia occurring during this period was not counted as an 
effectiveness failure. 
o Endpoint was identified at least as freedom from recurrence of arrhythmias inclusive 
of AF, AFL and AT between 3 and 12 months of follow up.  
o Presence of periodic follow ups at 3, 6 and 12 months,  
o Monitoring of arrhythmia recurrence performed with ECG during the assessments, 
Holter monitoring (at least 12 month) and arrhythmia monitoring via remote event 
monitor in the timeframe between 3 and 12 months.  
The table below shows the meta-analysis results, with expected rate 67.23% [62.87%, 71.46%] from 
the random effect model. There are differences in methods when comparing these trials: these include 
different AAD management after blanking period (patients off AAD or under stable dose of previous 
AAD) or different methods for monitoring of recurrences (Holter monitoring frequency and duration, 
frequency of reporting from EMs). A selection of studies with a strictly uniform set of methods would 
lead to too few data to analyze in the meta-analysis. Accordingly, a conservative approach has been 
applied and a value of 55% has been selected for the expected rate of the PEE, to acknowledge the 
methods differences and multiple variance sources. This is justified by the following aspects: (1) 
Acute Procedural Success is considered both as successful isolation of the PV and the LAPW and all 
studies analyzed do not consider LAPW isolation success as part of the endpoint (2) the 
FARAPULSE PFA System is different from those of listed studies in which either Cryoballoon 
ablation or RF ablation or other ablation systems were utilized.  
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Table 8.1-3: Meta-Analysis to Determine Primary Effectiveness Endpoint Parameters 
 
 
A PEE performance goal of 40% has been chosen based on the minimum chronic acceptable success 
rate for PersAF at 12-month follow-up defined in the 2017 HRS / EHRA / ECAS Expert Consensus 
document.8 The recommendation for evaluating the effectiveness of a treatment for PersAF described 
as:  
“If minimum chronic success rate is selected as an objective effectiveness endpoint for a 
clinical trial, we recommend that the minimum chronic acceptable success rate for PersAF at 
12-month follow-up is 40%.” 
8.1.2.1 
Hypotheses 
Let P be the proportion of Treatment Subjects with Treatment Success through the Day 360 
Assessment and PG be the performance goal, the following hypothesis will be tested in a one-sided 
test at 0.025 significance level.  
• 
H0: P ≤ PG 
• 
HA: P > PG  
Where PG = 40%. 
8.1.2.2 
Sample Size  
The sample size estimate was obtained using the binomial exact method. The following assumptions 
were used in the sample size calculation: 
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8.2.2 
Control of Systematic Error / Bias 
Control and reduction of potential bias associated with a single-arm study design have been addressed 
by a series of measures including but not limited to: 
• 
Patients meeting the eligibility criteria and signing the ICF will be eligible for sequential 
enrollment in the study. 
• 
ECG, Holter monitoring, and event monitoring data will be evaluated by a third-party 
Arrhythmia Core Laboratory according to standardized protocols. 
• 
Cardiac MRI / CT images utilized for assessing potential PV stenosis will be evaluated by a 
third-party Cardiac Imaging Core Laboratory according to standardized protocols. 
• 
The use of a comprehensive set of study procedures as defined in the protocol which ensure 
consistent patient management. 
• 
Comprehensive site and data monitoring to ensure accurate and complete recording of study 
data. 
• 
The use of an independent Clinical Events Committee (Section 19.2) will review and 
adjudicate all potential SAEs and primary safety outcomes. 
• 
Creation of a complete Clinical Study Report and full dataset to allow scientific and clinical 
reviewers to independently assess potential error and bias. 
To avoid any center effect and bias, no center will be authorized to enroll more than 33 Treatment 
Subjects (13% of the total planned enrollment of  258 Treatment Subjects). 
8.2.3 
Study Success and Control of Type I Error 
Both the primary endpoints must pass in order to achieve study success. Each primary endpoint will 
be tested at a significance level of 2.5% while still maintaining the overall Type I error level at no 
greater than 2.5%. This follows the methodology of the Intersection-Union Test (IUT).  
8.3 
Data Analyses 
8.3.1 
Roll-In Subject Analyses 
The stipulated analyses for Roll-In Subjects will be summarized with descriptive statistics. Endpoint 
data for Roll-In Subjects will be summarized but no hypothesis testing will be performed.  
8.3.2 
Interim Analyses  
No formal interim analyses are planned for the purpose of stopping the study early for declaring 
success or futility. Analysis of each endpoint will be performed for regulatory submission when all 
applicable data for that endpoint has been collected,9 dependent on specific geographic requirements 
where applicable.  The ADVANTAGE AF Study may be used to satisfy the requirements of multiple 
regulatory bodies. Details on these analyses will be included in the ADVANTAGE AF SAP when 
available. 
8.3.3 
Subgroup Analyses 
An analysis will be performed to evaluate whether any significantly different effects exist in the 
primary endpoints within subgroups of subjects. The list of covariates (with applicable subgroups in 
parentheses) will include at least the following: 
 
9 Additional data analysis and reporting may be performed after a sub-set of subjects have completed their 
Assessment for regulatory submission outside of the United States.  
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• 
Subject demographics (e.g., age [e.g. age >=65 vs. <65, Medicare eligible], gender) 
• 
Subject baseline characteristics (e.g., LVEF, cardioversion history, BMI, and LA diameter) 
• 
Index Procedure lesion sets 
o PV + LAPW ablation alone versus PV + LAPW plus additional ablations 
o CTI ablation versus no CTI ablation 
• 
Geography  
• 
FARAPULSE PFA System used (Investigational vs. Commercial) 
Each subgroup covariate will be included as a single independent variable in a logistic regression 
model with the primary endpoint outcome as the dependent variable and a test for significance at the 
15% level will be performed.  
In addition to subgroup analyses, descriptive statistics of subject demographic and baseline 
characteristics will be presented for each subgroup listed in this section. 
8.3.4 
Center Pooling Analysis 
Center-to-center heterogeneity will be assessed for the primary endpoints by performing a Chi-square 
test, treating site as a fixed effect. Descriptive statistics for each site will be presented. Small sites 
(sites enrolling less than five subjects) will be combined to form “supercenters”. Small centers will be 
combined until the newly created supercenter has five enrollments and then a new super center will 
be created. If sites are not deemed poolable in the initial Chi-square analysis, the poolability analysis 
will be reperformed by treating site as a random effect. A significance level of 15% will be used for 
each test. 
8.3.5 
Multivariable Analyses 
For each primary endpoint, univariable analyses of the following covariates will be performed, and 
any found to be significantly associated with the outcome at the 0.15 alpha level will be included as 
covariates in a multivariable regression model. Backward selection with 0.15 alpha level stay 
criterion will be used to determine the final multivariable model.  
The list of baseline covariates includes, but is not necessarily limited to: 
• 
Subject demographics (e.g., age, gender) 
• 
Subject baseline characteristics (e.g., LVEF, cardioversion history, BMI, and LA diameter) 
• 
Index Procedure lesion sets 
o PVI + LAPW ablation alone versus PVI + LAPW plus additional ablations 
o CTI ablation versus no CTI ablation 
• 
Geography 
• 
FARAPULSE PFA System used (Investigational vs. Commercial) 
8.3.6 
Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended Statistical Analysis Plan approved prior to performing the analyses. 
Changes from the planned statistical methods after performing the analyses will be documented in the 
clinical study report along with a reason for the deviation. 
9 Health Economics Outcomes 
A formal health economics analysis may be completed as part of this trial study, given meaningful 
clinical results are obtained. This will take into consideration complication rates, quality of life, and 
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resource utilization. The EQ-5D-3L, a generic quality of life measure, will be used to assess health 
utilities. Costs associated with the health care utilization measures may be estimated at all sites. These 
inputs may be used in health economics analysis performed. 
10 Data Management 
10.1 Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system. The 
clinical database will reside on a production server hosted by Medidata EDC System. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review by the 
Sponsor or its representative(s). The associated Rave software and database have been designed to 
meet regulatory compliance for deployment as part of a validated system compliant with laws and 
regulations applicable to the conduct of clinical studies pertaining to the use of electronic records and 
signatures. Database backups are performed regularly. 
The Investigator provides his / her electronic signature on the appropriate electronic case report forms 
(eCRFs) in compliance with local regulations. A written signature on printouts of the eCRFs must 
also be provided if required by local regulation. Changes to data previously submitted to the Sponsor 
require a new electronic signature by the Investigator acknowledging and approving the changes. 
Visual and / or electronic data review will be performed to identify possible data discrepancies. 
Manual and / or automatic queries will be created in the EDC system and will be issued to the site for 
appropriate response. Site staff will be responsible for resolving all queries in the database. Data 
transfers from other systems including the ACL, the CICL, CEC records and electronic questionnaires 
will be coordinated by BSC. CRF Completion Guidelines will be created by BSC and provided to all 
sites.  
10.2 Data Retention 
The Principal Investigator or his / her designee or Investigational site will maintain all essential study 
documents and source documentation that support the data collected on the study subjects in 
compliance with applicable regulatory requirements.  
The Principal Investigator or his / her designee will take measures to prevent accidental or premature 
destruction of these documents. If for any reason the Principal Investigator or his / her designee 
withdraws responsibility for maintaining these essential documents, custody must be transferred to an 
individual who will assume responsibility and BSC must receive written notification of this custodial 
change. Sites are required to inform BSC in writing where paper or electronic files are maintained in 
case files are stored off site and are not readily available. 
10.3 Technical Source Forms 
The Technical Source Form (TSF) is the Sponsor-approved document to capture protocol-required 
data elements that are not duplicated in any other source documents. This form when completed 
requires review and approval by the Investigator and may be used as a source document. 
Collection and completion of all information on the TSF is the responsibility of the appropriately 
delegated site personnel. If available, the protocol trained BSC representative will provide the 
delegated site personnel with the study related data collected during the case directly from the 
console. 
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Data collected on any site created worksheets must not be attributable to the Boston Scientific 
representative. The Boston Scientific representative providing technical support is not part of the 
site study team.  
General TSF documentation considerations for the protocol trained Boston Scientific representative 
are as follows:  
• 
Data that is collected as part of a clinical study must be attributable to the individual 
collecting/providing the data, and must include the individual’s name, signature, and date of 
signature.  
• 
Boston Scientific Representative involvement with data collection/providing source 
documentation should be minimized.  
• 
Any source data collected to capture protocol required data elements by a Boston Scientific 
representative must be provided to a member of the study team at the conclusion of the visit 
and retained at the site.  
• 
The Boston Scientific representative and Research Coordinator must make arrangements in 
advance as to how the clinical trial data will be transferred from the Boston Scientific 
representative to a member of the study team. 
• 
 The Boston Scientific representative completes the sections of the TSF that are appropriate 
to his/her role only (e.g., technical sections.)  
• 
The Boston Scientific representative signs and dates completed sections of the TSF 
applicable to the Boston Scientific representative role.  
• 
The Boston Scientific representative may assist in obtaining the signature and date of the 
Investigator or clinical research site staff delegated by the Investigator to oversee the study 
activity.  
 
At the conclusion of the procedure, the completed TSF should be signed (and initialed as needed) by 
the following people: 
• 
Delegated Site Personnel completing the TSFs 
• 
Delegated Investigator conducting and / or supervising the case 
• 
Protocol trained BSC representative supporting the case 
 
11 Core Laboratories 
11.1   Arrhythmia Core Laboratory 
Specified arrhythmic events will be analyzed by an ACL to determine if the episodes are associated 
with Detectable AF.  
During the ADVANTAGE AF Study, more than one ACL may be utilized for either EM or Holter 
studies to optimize equipment availability, vendor capacity or other factors as determined by BSC. 
Each vendor utilized will be described in the final study report. 
11.1.1 Event Monitors 
The ACL will provide the investigational site and / or subject as applicable all necessary instructions 
and materials related to the use of the EM.  
All Roll-In Subjects and Treatment Subjects: 
• 
Will be introduced to the use and importance of EMs at the Baseline Assessment 
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• 
Will receive a device and be fully instructed by either the ACL or the study site on the use of 
an EM prior to or at the scheduled Day 90 Assessment 
• 
Will be reminded that beginning on Day 90, they are to: 
o Record and transmit all symptomatic episodes potentially associated with cardiac 
arrhythmias (e.g., palpitations, lightheadedness, syncope, dyspnea) for detection and / 
or treatment of recurrences.  
o At a minimum, transmit at least two recordings (symptomatic or asymptomatic) every  
month. 
Careful monitoring and subject follow-up will be implemented to ensure compliance with the 
required twice per month and ad hoc symptomatic utilization and transmission of the EMs.  
Individual missed monthly transmissions will not be counted as protocol deviations, but a subject that 
misses > 20% of their total monthly required EM transmissions will be considered a protocol 
deviation. 
All EMs must be returned to the ACL or investigational site upon completion of a subject’s 12-month 
follow-up or withdrawal from the study.  
ECG data from the EM will be analyzed by the ACL.  
11.1.2 Holter Monitors 
The ACL will provide the investigational site and / or subject as applicable all necessary instructions 
and materials related to the use of the Holter monitor.  
Each subject: 
• 
Will be introduced to the use and importance of the Holter monitoring at the Baseline 
assessment. 
• 
Will receive a device and be fully instructed on the use of a 24-hour continuous ECG (Holter) 
monitor prior to the Day 180 and Day 360 Holter monitoring.  
Careful monitoring and subject follow-up will be implemented to ensure that the device will be 
utilized by the subject for the nominal 24-hour period for both the Day 180 and Day 360 
Assessments. The ACL will work with the investigational site to ensure compliance. 
All Holter monitors must be returned to the ACL or investigational site upon completion of a 
subject’s Day 360 Assessment or withdrawal from the study.  
ECG data from the Holter monitor will be analyzed by the ACL.  
11.1.3 Study ECGs 
To ensure objective assessment of rhythm monitoring data, the following 12-lead ECG tracings will 
be reviewed by the ACL and/or CEC and included as study data: 
• 
ECGs obtained during the following assessments: Day 90 and Day 360 
• 
ECGs submitted during monitoring and adjudication of adverse events 
• 
ECGs submitted during the evaluation of potential arrhythmias during the effectiveness 
evaluation period 
11.2 Cardiac Imaging Core Laboratory 
A qualified CICL will be established to receive, review, and assess any cardiac MRIs and CTs 
obtained for the evaluation of potential PV stenosis.  
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Baseline cardiac MRIs and CTs will only be read by the CICL if subsequent events result in follow-
up imaging for the assessment of potential PV stenosis. 
Pulmonary Vein Dimensions 
Treated veins to be assessed will have the baseline and post-ablation assessments of standardized 
diameters (See definition of PV Diameter in Section 23.2). 
Cardiac Imaging Data Review and Transmission 
The CICL will analyze PV dimensions, calculate changes in dimensions, make available the primary 
data for review and transmit the PV dimensional analyses of each imaging study to the Sponsor for 
inclusion in the study dataset. 
12 Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect the life 
and physical well-being of a subject in an emergency. An Investigator shall notify the Sponsor, the 
reviewing IRB / EC / REB, and the regulatory authority if applicable of any deviation from the 
investigational plan to protect the life or physical well-being of a subject in an emergency, and those 
deviations which affect the scientific integrity of the clinical investigation. Such notice shall be given 
as soon as possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the Sponsor using the eCRF. Sites may also be 
required to report deviations to the IRB / EC / REB, and the regulatory authority, per local guidelines 
and national / government regulations.  
When unforeseen circumstances (See Section 7.15) result in a deviation from the requirements of the 
protocol, the deviations will be distinguished from routine protocol deviations and reported 
separately. 
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including IRB / EC / REB and any regulatory authority 
notification, site re-training, or site discontinuation / termination) will be put into place by the 
Sponsor. 
The Sponsor will not approve any waivers to the requirements of this protocol or its supporting 
documentation that would affect the rights, safety or welfare of study subjects or the scientific 
validity of the study results.  
 
13 Device Accountability  
13.1 Investigationally-Labeled Test Devices 
Table 13.1-1below shows a list of FARAPULSE PFA System components for which device 
accountability is required by the investigational site.  
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• 
Maintain accurate and timely Device Accountability Records in a form specified by the 
Sponsor and provide copies of the record and any supporting documentation to the Sponsor 
upon request. Such records shall include the following content at a minimum: 
o Date or dates items were used investigationally for this study 
o Subject identification 
o Return or disposal date, identity, and quantity, as directed by Sponsor 
• 
Return or dispose of devices used investigationally for this study, as directed by Sponsor  
o Complaint / deficiency related items should be returned whenever possible 
o Used non-complaint / non-deficiency related items should be returned or disposed as 
directed by Sponsor 
o Unopened items – not applicable, as the devices are not investigational until they are 
opened / used for the study 
 
13.3 Non-Medical Devices, Components, and Commercially-Labelled Devices Used 
Within Approved Labeling 
Investigational Device Accountability does not apply to components of the FARASTAR Generator, 
RSM (See Table 2.2-1) nor to commercially-labelled items that are used within their currently 
approved labeling. Unless otherwise directed by this protocol or other study-related materials, the 
tracking or special labeling of such items (if any) will be for logistical purposes only to facilitate 
study operations.   
 
14 Compliance 
14.1 Statement of Compliance 
This clinical investigation is financed by the Sponsor. Before the investigational site can be 
“Authorized to Enroll,” the investigational site must enter into a Clinical Study Agreement with the 
Sponsor that details the financing of the study as well as the rights and obligations of the 
investigational site and the Investigator. 
This study will be conducted in accordance with 21 CFR 812, 814.20, Part 50, Part 54, and Part 56; 
European Medical Device Regulation; EN ISO 14155 Clinical Investigation of Medical Devices for 
Human Subjects - Good Clinical Practice; ethical principles that have their origins in the Declaration 
of Helsinki; and applicable individual country laws and regulations.  
The study shall not begin until  
• 
The required approval / favorable opinion from the IRB / EC / REB and regulatory authority 
has been obtained, if appropriate.  
• 
The issuance of the site Authorization to Enroll, as provided by the Sponsor.  
Any additional requirements imposed by the IRB / EC / REB or regulatory authority shall be 
followed.  
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14.2 Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the study is 
conducted in accordance with the Clinical Study Agreement, the clinical investigation plan, ISO 
14155 Clinical Investigation of Medical Devices for Human Subjects - Good Clinical Practice, any 
conditions of approval imposed by the reviewing IRB / EC / REB, and prevailing local and / or 
country laws and / or regulations, whichever affords the greater protection to the subject.  
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• 
Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.  
• 
Prior to beginning the study, sign the Investigator Brochure Signature Page (if applicable) 
and the Protocol Signature page documenting his / her agreement to conduct the study in 
accordance with the protocol. 
• 
Provide his / her qualifications and experience to assume responsibility for the proper conduct 
of the study and that of key members of the site team through up-to-date curriculum vitae or 
other relevant documentation and disclose potential conflicts of interest, including financial, 
that may interfere with the conduct of the clinical study or interpretation of results. 
• 
Make no changes in or deviate from this protocol, except to protect the life and physical well-
being of a subject in an emergency; document and explain any deviation from the approved 
protocol that occurred during the course of the clinical investigation. 
• 
Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• 
Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
Sponsor in the CRFs and in all required reports. 
• 
Record, report, and assess (seriousness and relationship to the device / procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 
• 
Report to Sponsor, per the protocol requirements, all reportable events. 
• 
Report to the IRB / EC / REB and regulatory authorities any SAEs and device deficiencies 
that could have led to a SADE and potential / USADE or UADE, if required by applicable 
laws or regulations or this protocol or by the IRB / EC / REB, and supply BSC with any 
additional requested information related to the safety reporting of a particular event. 
• 
Maintain the Device Accountability Records and control of the device, ensuring that the 
investigational device is used only by authorized / designated users and in accordance with 
this protocol and instructions for use. 
• 
Allow the Sponsor to perform monitoring and auditing activities and be accessible to the 
clinical research monitor or auditor and respond to questions during monitoring visits or 
audit(s). 
• 
Allow and support regulatory authorities and the IRB / EC / REB when performing auditing 
activities. 
• 
Ensure that informed consent is obtained in accordance with applicable laws, this protocol 
and local IRB / EC / REB requirements. 
• 
Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form (ICF). 
• 
Inform the subject of the nature and possible cause of any adverse events experienced. 
• 
As applicable, provide the subject with necessary instructions on proper use, handling, 
storage, and return of study-related devices and equipment when they are used / operated by 
the subject. 
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• 
Inform the subject of any new significant findings occurring during the clinical investigation, 
including the need for additional medical care that may be required. 
• 
Provide the subject with well-defined procedures for possible emergency situations related to 
the clinical study and make the necessary arrangements for emergency treatment. 
• 
Ensure that clinical medical records are clearly marked to indicate that the subject is enrolled 
in this clinical study. 
• 
Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided with 
some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• 
Inform, with the subject’s approval or when required by national regulations, the subject’s 
personal physician about the subject’s participation in the clinical investigation. 
• 
Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal 
from clinical investigation while fully respecting the subject’s rights. 
• 
Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
All Investigators will provide their qualifications and experience to assume responsibility for their 
delegated tasks through up-to-date curriculum vitae or other relevant documentation and disclose 
potential conflicts of interest, including financial, that may interfere with the conduct of the clinical 
study or interpretation of results. 
14.2.1 Delegation of Responsibility 
When specific tasks are delegated by an Investigator, including but not limited to conducting the 
informed consent process, the Principal Investigator is responsible for providing appropriate training 
to site staff, ensuring that staff are competent to perform the tasks they have been delegated and 
supervising those to whom tasks are delegated. Where there is a sub-Investigator at a site, the sub-
Investigator should not be delegated the primary supervisory responsibility for the site. The 
Investigator is accountable for regulatory violations resulting from failure to adequately supervise the 
conduct of the clinical study.  
14.3 Institutional Review Board / Ethics Committee / Research Ethics Board 
The investigational site will obtain the written and dated approval / favorable opinion of the IRB / EC 
/ REB for the clinical investigation before recruiting subjects and implementing all subsequent 
amendments, if required. 
A copy of the written IRB / EC / REB and / or competent authority (CA) approval of the protocol (or 
permission to conduct the study) and ICF, must be received by the Sponsor before recruitment of 
subjects into the study and shipment of investigational product / equipment. Prior approval must also 
be obtained for other materials related to subject recruitment or which will be provided to the subject. 
Any amendment to the protocol will require review and approval by the IRB / EC / REB before the 
changes are implemented to the study. All changes to the ICF will be IRB / EC / REB approved; a 
determination will be made regarding whether a new ICF needs to be obtained from subjects who 
provided consent, using a previously approved ICF. Annual IRB / EC / REB approval and renewals 
will be obtained throughout the duration of the study as required by applicable local / country laws or 
regulations or IRB / EC / REB requirements. Copies of the study reports and the IRB / EC / REB 
continuance of approval must be provided to the Sponsor.  
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14.4 Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study will be 
considered confidential by BSC and will be kept confidential in accordance with all applicable laws 
and regulations. Only authorized BSC personnel and / or a BSC representative including, but not 
limited to Contract Research Organization (CRO), will have access to this information. Authorized 
regulatory personnel have the right to inspect and copy all records pertinent to this study. Study data 
collected during this study may be used by BSC for the purposes of this study, publication, and to 
support future research and / or other business purposes, such as overseeing and improving the 
performance of its device, new medical research, and proposals for developing new medical products 
and procedures. All data used in the analysis and reporting of this study or shared with a third-party 
researcher will be without identifiable reference to specific subjects. 
Information received during the study will not be used to market to subjects; subject names will not 
be placed on any mailing lists or sold to anyone for marketing purposes.  
14.5 Role of BSC Representatives 
BSC personnel can provide technical support to the Investigator and other health care personnel 
(collectively HCP) as needed during ablation procedures, testing required by the protocol, and follow-
ups. Support may include HCP training, addressing HCP questions, or providing clarifications to 
HCPs concerning the operation of BSC equipment / devices (including generators, connection cables 
and boxes, and other support equipment). 
At the request of the Investigator and while under Investigator supervision, BSC personnel may, 
where permitted by law and hospital procedures, operate equipment during ablation procedures, assist 
with the conduct of testing specified in the protocol, and interact with the subject to accomplish 
requested activities.  
Typical tasks may include the following: 
• 
Providing instructions for the safe return of investigational products. For potentially 
hazardous items, provide specialized instructions and materials, as applicable. 
• 
Clarifying device behavior, operation or diagnostic output as requested by the Investigator or 
other health care personnel 
• 
Entering technical data on technical source form as long as the responsible Investigator 
verifies and signs the completed form  
• 
Providing technical expertise / support to subjects during office assessments and / or during 
teleconference calls / electronic communications with the Investigator or their delegated site 
staff and the subject.  
In addition, BSC personnel may perform certain activities to ensure study quality. These activities 
may include the following. 
• 
Observing testing or medical procedures to provide information relevant to protocol 
compliance 
• 
Reviewing collected data and study documentation for completeness and accuracy 
BSC personnel will not do the following.  
• 
Practice medicine 
• 
Provide medical diagnosis or treatment to subjects 
• 
Discuss a subject’s condition or treatment with a subject  
• 
Independently collect critical study data (defined as primary or secondary endpoint data) 
• 
Enter data in electronic data capture systems or on paper case report forms 
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If the situation necessitates, Boston Scientific personnel may use remote case support technology (e.g. 
video conferencing software) to establish a tele-mentoring communication stream/live stream to 
perform the applicable support tasks described above. The streaming will be in a secure and 
encrypted high-definition format and will not be recorded. The BSC personnel on the live stream will 
not have any direct contact with the subject. 
14.6 Insurance  
Where required by local / country regulation, proof and type of insurance coverage, by BSC for 
subjects in the study will be obtained. 
15 Monitoring 
Monitoring will be performed during the study to assess continued compliance with the protocol and 
applicable regulations. In addition, clinical research monitors will verify that study records are 
adequately maintained, that data are reported in a satisfactory manner with respect to timeliness, 
adequacy, and accuracy, and that the Principal Investigator continues to have sufficient staff and 
facilities to conduct the study safely and effectively. The Principal Investigator and his or her 
institution guarantee direct access to original source documents by BSC personnel, their designees, 
and appropriate regulatory authorities. 
The Sponsor will put a plan in place to document the specific monitoring requirements.  
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator and 
relevant study personnel are available during on-site monitoring visits or audits and that sufficient 
time as determined by the Sponsor is devoted to the process. 
16 Potential Risks and Benefits 
16.1 Anticipated Adverse Events  
Subjects participating in this study are subject to the same risks shared by all patients undergoing an 
ablation procedure for the treatment of PersAF. Since the characteristics of the FARAPULSE PFA 
System are similar to those of other commercially available devices for AF ablation, it is anticipated 
that the rate of complications in this study will be similar to those reported from ablations performed 
with other commercially available catheter ablation systems. The protocol-required testing for this 
study uses standard techniques that are routinely used for the treatment and management of subjects 
with drug refractory PersAF. 
Based upon the current literature and prior reports on adverse events with an ablation catheter, the list 
below includes an alphabetical list of the possible anticipated adverse events and possible adverse 
device effects associated with ablation with the FARAPULSE PFA System for the treatment of 
PersAF. Occurrence of any of the listed events could lead to harm, the need for intervention, or 
prolonged hospitalization for the subject.  
These anticipated events may be caused by or associated with the proposed use of the investigational 
devices and other devices, the failure, misuse or malfunction of the investigational devices or other 
devices, or the related procedures stipulated by this protocol or associated with this clinical study.  
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• 
Access site complications (e.g., hematoma, fistula, pseudo-aneurysm, laceration, bleeding) 
potentially requiring surgical intervention 
• 
Allergic reaction or fever resulting from contact with catheters or drugs 
• 
Anemia 
• 
Arrhythmia, potentially requiring cardioversion, defibrillation, or rhythm management device 
• 
Arteriovenous fistula 
• 
Back pain 
• 
Bed sores 
• 
Bleeding, hematoma, hemorrhage, or aneurysm at vascular access sites 
• 
Blood pressure changes including hypotension or hypertension 
• 
Cardiac tamponade or perforation 
• 
Cardiac arrest or cardiac failure  
• 
Cardiogenic shock 
• 
Catheter entrapment/impingement potentially requiring endovascular or surgical intervention 
• 
Conduction system injury, either transient or permanent, potentially requiring pacemaker 
insertion 
• 
Coronary artery or vein injury 
• 
Damage to cardiac structure 
• 
Death 
• 
Esophageal injury, ulcer, or fistula 
• 
Gastric motility / pyloric spasm disorders 
• 
Harmful large muscular contraction 
• 
Heart failure 
• 
Hemodynamic compromise 
• 
Hemopericardium 
• 
Hemoperitoneum 
• 
Hemothorax 
• 
Local infection, systemic infection and / or sepsis 
• 
Muscle contractions due to electric stimulation 
• 
Myocardial infarction / ischemia 
• 
Nerve damage 
• 
Organ failure 
• 
Pain 
• 
Perforation (e.g., of diaphragm, liver, and lung). 
• 
Pericardial effusion 
• 
Pericarditis 
• 
Peritonitis 
• 
Phrenic nerve injury with potential paralysis of the diaphragm and breathing impairment 
• 
Pneumomediastinum 
• 
Pneumopericardium 
• 
Pneumoperitoneum 
• 
Pneumothorax 
• 
Procedural delay 
• 
PV injury, perforation, or stenosis 
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• 
Risk of cancer or birth defect / harm to fetus from x-ray exposure 
• 
Skin burns / irritation from X-ray exposure  
• 
Stroke / TIA 
• 
Surgical procedure to correct any anticipated AE 
• 
Thrombosis 
• 
Vessel damage, dissection, or occlusion. 
• 
Vessel obstruction due to thrombus, debris, introduction of gas, or vascular spasm 
16.2 Risks Associated with the Study Device(s)  
Benchtop studies, pre-clinical research and CE Mark clinical studies have demonstrated that the 
FARAPULSE PFA System is safe for human use. Potential risks have been evaluated and mitigation 
strategies have been implemented to reduce potential risks to acceptable levels. 
16.3 Risks associated with Participation in the Clinical Study 
There are no specific tests or procedures outside those recommended as standard practice for catheter 
ablation of PersAF required by this clinical study protocol. Therefore, there is no foreseen increased 
risk to subjects for participating in the ADVANTAGE AF Study. 
16.4 Possible Interactions with Concomitant Medical Treatments 
Anti-arrhythmic and anticoagulant medications included in ADVANTAGE AF procedures are all 
approved for their indicated uses in the relevant geography. Therefore, there is no foreseen increased 
risk to subjects for participating in the ADVANTAGE AF Study. 
16.5 Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject selection 
criteria, close monitoring of the subject's physiologic status during research procedures and / or 
follow-ups and by promptly supplying BSC with all pertinent information required by this protocol. 
16.6 Anticipated Benefits 
Subjects may or may not receive any benefit from participating in the ADVANTAGE AF Study as 
compared to the current standard of care received for treatment of PersAF. Potential benefits of the 
FARAPULSE PFA System for the subject may include the following: 
• 
Complete or partial reduction in symptoms related to PersAF 
• 
Complete or partial reduction in the number of cardioversions, medications a subject is taking, 
and in the number of hospitalizations related to PersAF 
• 
Treatment using an investigational device which has demonstrated the ability to isolate PVs 
and the PW endocardially, to reduce the subsequent occurrence of symptomatic AF in treated 
subjects and potentially to reduce the risk for severe ablation complications associated with 
thermal ablation such as phrenic nerve palsy or atrio-esophageal fistula. 
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16.7 Risk to Benefit Rationale 
Risk management activities, including Hazard Analyses (HA) and Failure Mode Effects Analyses 
(FMEA), have been performed on the FARAPULSE PFA System and its components to identify and 
analyze known and foreseeable hazards (in both normal and fault conditions) and reasonably 
foreseeable sequences or combinations of events that could result from using this product and the 
risks associated with each hazard. Mitigations have been implemented in the design, processes, and / 
or labeling and directions for use of the product to reduce the residual risk of each hazard as 
necessary and practicable. The HA has been reviewed and approved and the remaining risks are 
acceptable when weighed against the anticipated benefits to the subject. 
17 Safety Reporting 
17.1 Reportable Events by Investigator to BSC 
It is the responsibility of the Investigator to assess and report to BSC any event which occurs in any 
of following categories: 
• 
All Serious Adverse Events 
• 
All thromboembolic adverse events 
• 
All study procedure-related adverse events  
• 
All investigational device-related adverse events 
• 
All study-related device deficiencies  
• 
Unanticipated Adverse Device Effects / Unanticipated Serious Adverse Device Effects if not 
previously defined in the IFU or ICF 
• 
The occurrence of any ventricular tachycardia or ventricular fibrillation (VT/VF) during 
ablation with the FARAPULSE PFA System. 
• 
New findings / updates in relation to already reported events. 
When possible, the medical diagnosis should be reported as the Event Term instead of individual 
symptoms. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot be 
isolated from the device or procedure, it should be submitted as an adverse event and / or device 
deficiency. 
Any reportable event, experienced by the study subject after informed consent and once considered 
enrolled in the study (as defined in study subject classification section), whether prior to, during or 
subsequent to the study procedure, must be recorded in the eCRF. 
Underlying diseases and chronic conditions are not reported as AEs unless there is an increase in 
severity or frequency during the course of the investigation. Death should not be recorded as an AE 
but should only be reflected as an outcome of one (1) specific SAE (see Table 17.2-1 for AE 
definitions).  
Refer to Section 16.1 for a listing of anticipated adverse events and Section 16.2 for the known risks 
associated with the study device(s). 
17.2 Classifications for Adverse Event Reporting 
Adverse event definitions for the purpose of investigator assessment and reporting to BSC and 
subsequent regulatory reporting are provided in Table 17.2-1 and Table 17.3-1. Administrative edits 
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17.7 Subject Death Reporting 
A subject death during the study should be reported to BSC as soon as possible and, in any event, 
within three (3) calendar days of site notification. The site’s IRB / EC / REB must be notified of any 
deaths in accordance with that site’s IRB / EC / REB policies and procedures.  
Notification of death must include a detailed narrative (death letter) that provides detailed information 
describing the circumstances surrounding the death. A death narrative in the local language is 
acceptable, if accompanied by a translation in English. The details listed below should be addressed 
in the death narrative, in order for BSC to understand the circumstance surrounding the death:  
• 
Date and time of death  
• 
Place death occurred  
• 
Immediate cause of death  
• 
Rhythm at the time of death, if known (include any available documentation)  
• 
Whether the death was related to the catheter, clinical investigation, procedure, or patient 
condition  
• 
Whether or not the death was witnessed  
• 
Whether the patient had worsening heart failure  
• 
Any other circumstances surrounding the death  
• 
Approximate time interval from the initiating event to death (temporal course) -items to 
consider include, but are not limited to information regarding last time subject was seen by 
Investigator, last office visit, etc. 
• 
Investigator or sub-Investigator signature and date  
Also submit the following documentation:  
• 
If the patient expired in the hospital: 
o A copy of the medical records for that admission (e.g., H & P, consults, test results, 
operative reports, and / or progress notes from the hospital chart)  
o Death certificate (if available)  
o Autopsy report (if applicable)  
• 
If the patient expired outside of the hospital (e.g., home):  
o A copy of the most recent clinic visit or study assessment (if not already submitted to 
BSC) 
o Death certificate (if available)  
18 Informed Consent 
Subject participation in this clinical study is voluntary. Informed Consent is required from each 
subject or his / her legally authorized representative. The Investigator is responsible for ensuring that 
Informed Consent is obtained prior to the use of any investigational devices, study-required 
procedures and testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the principles of 
the Declaration of Helsinki, ISO 14155, any applicable national regulations, and local Ethics 
Committee and / or Regulatory authority, as applicable. The ICF must be accepted by BSC or its 
delegate (e.g., CRO), and approved by the site’s IRB / EC / REB, or central IRB, if applicable. 
BSC will provide a study-specific template of the ICF to Investigators participating in this study. The 
ICF template may be modified to meet the requirements of the investigative site’s IRB / EC / REB. 
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Any modification requires acceptance from BSC prior to use of the ICF. The ICF must be in a 
language understandable to the subject and if needed, BSC will assist the site in obtaining a written 
consent translation. Translated ICFs must also have IRB / EC / REB approval prior to their use. 
Privacy language shall be included in the body of the ICF or as a separate ICF as applicable.  
The process of obtaining Informed Consent shall at a minimum include the following steps, as well as 
any other steps required by applicable laws, rules, regulations, and guidelines: 
• 
be conducted by the Principal Investigator or designee authorized to conduct the process,  
• 
include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• 
avoid any coercion of or undue influence of subjects to participate, 
• 
not waive or appear to waive subject’s legal rights, 
• 
use native language that is non-technical and understandable to the subject or his / her legal 
representative, 
• 
provide ample time for the subject to consider participation and ask questions if necessary, 
• 
ensure important new information is provided to new and existing subjects throughout the 
clinical study.  
The ICF shall always be signed and personally dated by the subject or legal representative competent 
to sign the ICF under the applicable laws, rules, regulations, and guidelines and by the Investigator 
and / or an authorized designee responsible for conducting the informed consent process. If a legal 
representative signs, the subject shall be asked to provide informed consent for continued 
participation as soon as his / her medical condition allows. The original signed ICF will be retained 
by the site and a copy of the signed and dated ICF and any other written information must be given to 
the person signing the ICF.  
Failure to obtain informed consent will be reported by BSC to the applicable regulatory authority 
according to their requirements (e.g., FDA requirement is within 5 working days of learning of such 
an event). Any violations of the informed consent process must be reported as deviations to the 
Sponsor and local regulatory authorities (e.g., IRB / EC / REB), as appropriate. 
If new information becomes available that can significantly affect a subject's future health and 
medical care, that information shall be provided to the affected subject(s) in written form via a revised 
ICF or, in some situations, enrolled subjects may be requested to sign and date an addendum to the 
ICF. In addition to new significant information during the course of a study, other situations may 
necessitate revision of the ICF, such as if there are amendments to the applicable laws, protocol, a 
change in Principal Investigator, administrative changes, or following annual review by the IRB / EC 
/ REB. The new version of the ICF must be approved by the IRB / EC / REB. Acceptance by BSC is 
required if changes to the revised ICF are requested by the site’s IRB / EC / REB. The IRB / EC / 
REB will determine the subject population to be re-consented. 
19 Committees  
19.1 Safety Monitoring Operations Team 
The BSC personnel from the Medical Safety and Safety Trial Operation Teams review safety data as 
it is reported by the sites throughout the duration of the study. During scheduled monitoring activities, 
clinical research monitors further support this review through their review of source documents and 
other data information. The BSC Medical Safety and Safety Trial Operations team include health care 
providers with expertise in electrophysiology and endocardial ablation of cardiac arrhythmias and 
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with the necessary therapeutic and subject matter expertise to evaluate and classify the events into the 
categories outlined above. 
19.2 Clinical Events Committee 
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent expertise 
that will adjudicate events reported by study Investigators and their relationship toward potential 
primary endpoints. 
• 
All deaths 
• 
All Serious Adverse Events 
• 
All adverse events included in the composite primary safety endpoint per Section 3.2 of this 
protocol 
• 
All adverse events that are potentially related to the procedure or any of the devices included 
in the FARAPULSE PFA System 
• 
All unanticipated device effects. 
• 
Other events at the discretion of BSC 
Committee members will include practitioners of Electrophysiology (EP), and / or Cardiology, as 
well as other experts with the necessary therapeutic and subject matter expertise to adjudicate the 
event categories outlined above. A complete description of CEC responsibilities, qualifications, 
membership, and committee procedures will be outlined in the CEC charter.  
The CEC will review a safety event dossier, prepared by BSC, which may include copies of subject 
source documents provided by study sites, core lab results and independent reviewer information as 
available for the above listed events. For purposes of determining inclusion into the primary safety 
endpoint, the CEC will adjudicate all the above listed events as to their level of seriousness and 
relation to the ablation procedure and / or catheter. All supporting source documentation provided by 
the center will be sent to the CEC for adjudication as defined in the CEC charter. The CEC’s 
adjudication of study adverse event data is final. 
19.3 Data Monitoring Committee 
A Data Monitoring Committee (DMC) is responsible for the oversight review of all AEs. The DMC 
will include leading experts in Electrophysiology and Biostatistics who are not participating in the 
study and who have no affiliation with BSC. During the course of the study, the DMC will review 
accumulating safety data to monitor the incidence of AEs sent to the CEC and other trends that would 
warrant modification or termination of the study. Responsibilities, qualifications, membership, and 
DMC procedures will be included in the DMC Charter.  
Any DMC recommendation for study modification or termination due to concerns over subject safety 
or issues relating to data monitoring or quality control will be submitted in writing to BSC and the 
study Principal Investigator for consideration and final decision. If the DMC at any time determines 
that a potentially serious risk exists to subjects in this study, the DMC chairman will immediately 
notify both BSC and the Principal Investigator. 
19.4 Executive Steering Committee 
A Steering Committee composed of the Sponsor’s Clinical Management, the study Principal 
Investigator and other prominent Electrophysiologists from around the globe has been convened for 
this study. Responsibilities for the Committee include oversight of the overall conduct of the study 
with regards to protocol development, study progress, subject safety, overall data quality and 
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integrity, and first line review and final decision making of independent medical reviewer 
recommendations, as well as disseminating any study results through appropriate scientific sessions 
and publications. Steering Committee members may participate in the review and approval of all 
requests for data analysis, abstract and manuscript preparation, and submission.  
20 Suspension or Termination 
20.1 Premature Termination of the Study 
BSC reserves the right to terminate the study at any stage but intends to exercise this right only for 
valid scientific or business reasons and reasons related to protection of subjects. Investigators, 
associated IRBs / ECs / REBs, and regulatory authorities, as applicable, will be notified in writing in 
the event of study termination.  
20.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
• 
Suspicion of an unacceptable risk, including serious health threat. In this case, the Sponsor 
shall suspend the clinical investigation while the risk is assessed. The Sponsor shall terminate 
the clinical investigation if an unacceptable risk which cannot be controlled is confirmed. 
• 
Instructions by the IRB / EC / REB or regulatory authorities to suspend or terminate the 
clinical investigation. 
• 
An enrollment rate far below expectation that prejudices the conclusion of the study.  
• 
A decision on the part of BSC to suspend or discontinue development of the device. 
20.2 Termination of Study Participation by the Investigator or Withdrawal of IRB / EC / 
REB Approval 
Any Investigator, or associated IRB / EC / REB or regulatory authority may discontinue participation 
in the study or withdraw approval of the study, respectively, with suitable written notice to BSC. 
Investigators, associated IRBs / ECs / REBs, and regulatory authorities, as applicable, will be notified 
in writing in the event of these occurrences. 
20.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination, a written statement as to why the premature termination 
has occurred will be provided to all participating sites by BSC. The IRB / EC / REB and regulatory 
authorities, as applicable, will be notified. Detailed information on how enrolled subjects will be 
managed thereafter will be provided.  
In the event an IRB / EC / REB terminates participation in the study, participating Investigators, 
associated IRBs / ECs / REBs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided by BSC. 
In the event a Principal Investigator terminates participation in the study, study responsibility will be 
transferred to another Investigator, if possible. In the event there are no opportunities to transfer 
Principal Investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by BSC. 
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The Principal Investigator or his / her designee must return all investigational product to BSC and, 
unless such action would jeopardize the rights, safety, or welfare of the subjects, must return all 
study-related documents. 
20.4 Criteria for Suspending or Terminating a Study Site 
BSC reserves the right to suspend or terminate the inclusion of subjects at a study site at any time for 
slow enrollment, or if the site has multiple or severe protocol violations / noncompliance without 
justification and / or fails to follow remedial actions. 
In the event of termination of site participation, the site must return all investigational product and 
testing equipment to BSC and, unless such action would jeopardize the rights, safety, or welfare of 
the subjects, must return all study-related documents. The site must continue to allow BSC full access 
to study data and documents as stipulated in this protocol and any contract documents.  
The IRB / EC / REB and regulatory authorities, as applicable, will be notified. Study subjects will be 
contacted, as applicable, and be informed of changes to study assessment schedule. 
 
21 Study Registration and Results 
21.1 Study Registration 
This research-study will be registered on http://www.ClinicalTrials.gov, as required by U.S. Law and 
other jurisdictions, prior to the first enrollment.  
21.2 Clinical Investigation Report 
Study results will be made available in accordance with the legal requirements and the recognized 
ethical principles, in accordance with the BSC Policy. A Clinical Investigation Report will be made 
available to all Investigators, IRB / EC / REB, and regulatory authorities, as applicable in accordance 
with the BSC Policy and local requirements. As applicable an abbreviated Clinical Investigation 
Report will be made available on a publicly accessible database. 
21.3 Publication Policy 
BSC requires disclosure of its involvement as a Sponsor or financial supporter in any publication or 
presentation relating to a BSC study or its results. BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. BSC adheres to 
the Contributorship Criteria set forth in the Uniform Requirements of the International Committee of 
Medical Journal Editors (ICMJE; http://www.icmje.org). In order to ensure the public disclosure of 
study results in a timely manner, while maintaining an unbiased presentation of study outcomes, BSC 
personnel may assist authors and Investigators in publication preparation provided the following 
guidelines are followed:  
• 
All authorship and contributorship requirements as described above must be followed. 
• 
BSC involvement in the publication preparation and the BSC Publication Policy should be 
discussed with the Coordinating Principal Investigator(s) and / or Executive / Steering 
Committee at the onset of the project. 
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• 
The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
The data, analytic methods, and study materials for this clinical trial may be made available to other 
researchers in accordance with the BSC Data Sharing Policy (https://www.bostonscientific.com/).  
 
 
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21.4 Study Applicability to Medicare Beneficiaries 
The study results are directly applicable to Medicare beneficiaries as enrollment is anticipated to 
comprise a significant portion of Medicare-eligible patients that are age 65 or older. The primary 
target patient population for this clinical trial includes patients indicated for a cardiac ablation.  
Utilizing the HCUP National Inpatient Sample11, approximately 62% of patients receiving heart 
conduction procedures (including cardiac ablation) in 2018 were Medicare beneficiaries.  In addition, 
other published clinical studies indicate that the average age of cardiac ablation patients is above 65, 
making most of these patients Medicare eligible.12  
 
Based on the Subject Selection for this clinical trial (Section 5), it is anticipated that the percentage of 
patients enrolled in the trial that are Medicare-eligible (i.e. age 65 or older) will be consistent with 
real-world experience, and as such, the trial results will be generalizable to the Medicare patient 
population. 
  
 
22 Reimbursement and Compensation for Subjects 
22.1 Subject Reimbursement 
Reasonable travel and other expenses incurred by subjects as a result of participation in the study will 
be reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.  
22.2 Subject Incentives 
Modest incentive payments to study subjects to encourage compliance with key study procedures 
such as transmitting electrocardiographic information may be offered in accordance with pertinent 
country laws and regulations and per the study site’s regulations.  
22.3 Compensation for Subject’s Health Injury 
BSC will purchase an insurance policy to cover the cost of potential health injury for study subjects, 
if required by applicable law.  
23 Abbreviations and Definitions  
23.1 Abbreviations and Acronyms 
Table 23.1-1: Abbreviations and Acronyms 
3D 
Three dimensional 
AAD 
Antiarrhythmic drug 
ACL 
Arrhythmia Core Laboratory 
 
11 https://hcupnet.ahrq.gov/#setup, accessed October 8, 2020; Analysis 2017 hospital inpatient procedures utilizing ICD-10-PCS code for 
Destruction of conduction mechanism, percutaneous approach (02583ZZ) 
12 Bunch TJ, et al; Cardiovasc Electrophysiol. 2016 Feb;27(2):141-6. doi:10.1111/jce.12849. Epub 2015 Nov 20 
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ACT 
Activated clotting time 
ADE 
Adverse Device Effect 
AE 
Adverse event 
AF 
Atrial fibrillation 
AFEQT 
Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire 
AFL 
Atrial flutter 
AT 
Atrial tachycardia 
AVNRT 
Atrioventricular nodal reentrant tachycardia 
BDB 
Bidirectional block 
BMI 
Body Mass Index 
BSC 
Boston Scientific Corporation (Sponsor) 
BUN 
Blood urea nitrogen 
CBA 
Cryoballoon ablation 
CEC 
Clinical Events Committee 
CHA2DS2-VASc  
A clinical prediction rule for stroke 
CHF 
Congestive heart failure 
CICL 
Cardiac Imaging Core Laboratory 
CIP 
Clinical Investigation Plan (synonymous with study protocol) 
COVID-19 
COrona VIrus Disease 2019: an illness caused by SARS-CoV-2 
CPS 
Chronic Procedural Success 
CRF 
Includes CRF (case report form) and eCRF (electronic CRF) 
CT 
Computed tomography 
CTI 
Cavo-tricuspid isthmus 
CXR 
Chest X-ray 
DOAC 
Direct oral anticoagulant 
DW, DWI 
Diffusion weighted, Diffusion weighted image 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EM 
Event monitor (any of several hardware modalities) 
EQ-5D-3L 
The 3-level EuroQol standardized questionnaire of health states 
FDA 
Food and Drug Administration 
HCP 
Health care personnel 
HCT 
Hematocrit 
HGB 
Hemoglobin 
Holter 
Holter monitor 
ICE 
Intracardiac echocardiography 
ICF 
Informed consent form 
INR 
International normalized ratio 
IRB / EC / REB 
Institutional Review Board / Ethics Committee / Research Ethics Board 
IRE 
Irreversible electroporation 
ITT 
Intent(ion)-to-Treat 
IVC 
Inferior vena cava 
LA 
Left atrium or left atrial 
LAPW 
Left atrial posterior wall 
LBBB 
Left bundle branch block 
LTFU 
Lost-to-follow-up 
MITT 
Modified Intent(ion)-to-Treat 
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MRI 
Magnetic resonance imaging 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association 
PAF 
Paroxysmal atrial fibrillation 
PersAF 
Persistent atrial fibrillation 
PFA 
Pulsed field ablation 
PP 
Per Protocol 
PV 
Pulmonary vein 
PVI  
Pulmonary vein isolation 
PW 
Posterior wall 
PWI 
Posterior wall isolation 
RFA 
Radiofrequency ablation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious adverse event  
SOC 
Standard of care 
TEE 
Transesophageal echocardiography 
TIA 
Transient ischemic attack 
TSF 
Technical Source Form (see Section 10.3) 
TTE 
Transthoracic echocardiography 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
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23.2 Definitions 
Protocol terms not otherwise defined in the protocol are defined in Table 23.2-1:  
Table 23.2-1: Definitions 
Term 
Definition 
Acute Procedural 
Success 
• 
Persistent AF Acute Procedural Success is defined in Section 3.3.1. 
• 
CTI-Mediated Flutter Acute Procedural Success is defined in 
Section 3.4.2 
Antiarrhythmic Drugs, 
Class I and III 
Class I / III AADs are those pharmaceutical agents approved or used in 
the relevant jurisdiction for the treatment of cardiac arrhythmia. For the 
ADVANTAGE AF Study, Class I and III AADs include but are not 
limited to: 
• 
Class I, sodium channel blockers: disopyramide, flecainide, 
procainamide, propafenone, quinidine. 
• 
Class III, potassium channel blockers: amiodarone, dofetilide, 
dronedarone, sotalol. 
Should other Class I or III AADs become approved or used in the 
relevant jurisdiction for the treatment of cardiac arrhythmia during the 
ADVANTAGE AF Study, they will be considered as Class I / III AADs 
for this protocol. 
Attempt Subjects 
Attempt Subjects are defined in Section 6.6.4. 
Blanking Period 
An interval in which recurrent AF, AFL or AT, cardioversion or a first 
re-ablation do not constitute Treatment Failure beginning on Day 0 and 
running for 90 days thereafter. 
• 
The Blanking Period has no impact on the assessment of AEs. 
• 
For subjects with only an Index Procedure, the Blanking Period 
will be Day 0 to Day 90 inclusive. 
• 
For subjects who require a Rescheduled Index Procedure, the 
Blanking Period will be the Study Day of the Rescheduled Index 
Procedure (Day 0) plus 90 days inclusive 
• 
For subjects treated with a Non-Failed AAD during the Blanking 
Period, a Treatment Failure due to the use of that drug only occurs 
if there is continued use of that drug following the earlier of either 
the Day 90 visit or Day 104.  
Chronic Success 
• 
Persistent AF Chronic Success is defined in Section 3.3.2. 
• 
CTI-Mediated Flutter Chronic Success is defined in Section 3.4.2 
Composite Serious 
Adverse Events 
Composite Serious Adverse Events are defined in Section 3.2. 
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Term 
Definition 
COVID-19 Related 
Disruptions 
A disruption to any study procedure resulting directly or indirectly from 
the COVID 19 pandemic, including but not limited to subject illness, 
study site restrictions and limitations, shipping / manufacturing 
interruptions, significant changes in regulatory guidance and / or 
governmental restrictions on travel, association, and the prioritization of 
healthcare resources. 
Dates 
• 
Consent Date: The date a subject signs the ICF. 
• 
Exit Date: The date on which a subject’s study participation ends. 
• 
Onset Date: The date on which a condition or AE begins. 
• 
Start Date: Day 0, the date of the Index Procedure or Rescheduled 
Index Procedure 
Day (or Study Day) 
A Day is an enumerated day of follow-up that begins on an Enrolled 
Subject’s Start Date (Day 0). 
Detectable AF, AFL, or 
AT 
Detectable AF, AFL or AT is an episode of AF, AFL or AT which: 
• 
Is permanently recorded for review on a study-specific ECG, EM 
or Holter monitor 
o Excludes arrhythmias recorded on other devices including 
implantable monitors and consumer wearables not specified 
in the ADVANTAGE AF Study procedures. 
• 
Contains at least 30 seconds of continuous interpretable signal 
o Exception: Continuous AF, AFL or AT for the entirety of a 
12 lead ECG constitutes Detectable AF, AFL or AT if the 
continuous interpretable signal is 10 seconds or longer 
• 
Includes symptomatic and asymptomatic episodes.  
• 
Excludes CTI isthmus-dependent AFL 
Failed AAD 
Failed AADs include any and all Class I / III AAD determined at the 
time of enrollment to have been failed for effectiveness or intolerance.  
Failed AADs do not include Class I / III AADs determined at the time of 
enrollment solely to be contraindicated. 
Failed AADs must be established as part of the Baseline Assessment for 
agent, type of failure (arrhythmia recurrence or AAD intolerance) and 
the maximum failed dose (the total daily dose at which such failure 
occurred).  
Intent Subjects 
Intent Subjects are defined in Section 6.6.3. 
Non-Failed AAD 
A Non-Failed AAD is: 
• 
Any Class I / III AAD not established at the Baseline Assessment 
as a Failed AAD 
• 
Any Failed AAD used after Day 90 at a daily dose exceeding the 
maximum failed dose established at the Baseline Assessment 
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Term 
Definition 
Persistent atrial 
fibrillation 
PersAF is defined as continuous AF that is sustained beyond 7 days, but 
not greater than 12 months duration. 
Pulmonary vein 
dimensions 
For the purpose of assessing potential PV stenosis: 
• 
PV dimensions will be measured in two roughly orthogonal 
diameters approximating the longest and shortest diameters at the 
plane of measurement.  
• 
The measured PV diameter is defined as the geometric mean of 
these 2 measurements.  
• 
The PV cross-sectional area is computed using the formula for 
area of an ellipse, where the longest and shortest axis 
measurements of the PV diameter serve as the major and minor 
axes of the ellipse, using half of each axis diameter as the radii for 
calculation. 
Roll-In Subjects 
Roll-In Subjects are defined in Section 4.2.1, Section 4.3 and Section 
6.6.2.  
Severe COVID-19 
Subjects 
Any study subject who contracts COVID-19 infection during study 
participation that: 
• 
Requires supplemental oxygen, positive pressure ventilation, and / 
or intubation OR  
• 
Is associated with any medically serious sequelae of COVID 19, 
including but not limited to new onset cardiac arrhythmia, heart 
failure, myocarditis, neurologic dysfunction or other organ 
dysfunction, or thromboembolic disease. 
Such subjects will be initially defined by the Investigator and confirmed 
by the CEC. The Onset Date will be the date of symptom onset in a 
subsequently clinically confirmed case of COVID-19 infection. 
Source data 
Ref: ISO 14155 
All information in original records, certified copies of original records of 
clinical findings, observations, or other activities in a clinical 
investigation, necessary for the reconstruction and evaluation of the 
clinical investigation This includes source data initially recorded in an 
electronic format. 
Source document 
Ref: ISO 14155 
Original or certified copy of printed, optical, or electronic document 
containing source data, including TSFs. 
Treatment Failure 
Treatment Failure is the absence of Treatment Success due to one or 
more protocol-stipulated reasons. 
Treatment Subjects 
Treatment Subjects are defined in Section 6.6.5. 
Treatment Success 
Treatment Success is defined in Section 3.3. 
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Term 
Definition 
Vulnerable Subject 
Ref: ISO 14155 
 
Individuals who are unable to fully understand all aspects of the 
investigation that are relevant to the decision to participate, or who 
could be manipulated or unduly influenced as a result of a compromised 
position, expectation of benefits or fear of retaliatory response 
 
 
 
24 Bibliography 
 
 
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57. 
BSC. PCR0901 Rev A FARAWAVE 31mm and 35mm GLP Safety and 
Effectiveness Study in a 30-Day Chronic Porcine Model. 2020. 
58. 
BSC. PCR1222 Rev B FARAWAVE Plus Safety and Effectiveness in 7 Day Porcine 
Report. 2021. 
59. 
Koruth JS, Kuroki K, Kawamura I, et al. Pulsed Field Ablation Versus 
Radiofrequency Ablation: Esophageal Injury in a Novel Porcine Model. Circ 
Arrhythm Electrophysiol. 2020;13(3):e008303. 
60. 
BSC. Final Clinical Study Report, Document Number CS1009, Rev A. The 
IMPULSE Study: A Safety and Feasibility Study of the FARAPULSE™ Endocardial 
Ablation System in the Treatment of Paroxysmal Atrial Fibrillation. 2020. 
61. 
BSC. Interim Clinical Study Report, Document Number CS1010, Rev A. PEFCAT: 
A Safety and Feasibility Study of the FARAPULSE™ Endocardial Ablation System 
to Treat Paroxysmal Atrial Fibrillation. 2020. 
62. 
BSC. Interim Clinical Study Report, Document Number CS1011, Rev A. PEFCAT II: 
Expanded Safety and Feasibility Study of the FARAPULSE™ Endocardial Multi 
Ablation System to Treat Paroxysmal Atrial Fibrillation. 2020. 
63. 
Reddy VY, Anic A, Koruth J, et al. Pulsed Field Ablation in Patients With Persistent 
Atrial Fibrillation. J Am Coll Cardiol. 2020;76(9):1068-1080. 
64. 
Martinek M, Meyer C, Hassanein S, et al. Identification of a high-risk population for 
esophageal injury during radiofrequency catheter ablation of atrial fibrillation: 
procedural and anatomical considerations. Heart Rhythm. 2010;7(9):1224-1230. 
 
66. 
 
67. 
Waldo AL, Feld GK. Inter-relationships of atrial fibrillation and atrial flutter 
mechanisms and clinical implications. J Am Coll Cardiol. 2008;51(8):779-786. 
68. 
Celikyurt U, Knecht S, Kuehne M, et al. Incidence of new-onset atrial fibrillation 
after cavotricuspid isthmus ablation for atrial flutter. Europace. 2017;19(11):1776-
1780. 
69. 
Brembilla-Perrot B, Girerd N, Sellal JM, et al. Risk of atrial fibrillation after atrial 
flutter ablation: impact of AF history, gender, and antiarrhythmic drug medication. J 
Cardiovasc Electrophysiol. 2014;25(8):813-820. 
70. 
Candeias R, Adragcao P, Cavaco D, et al. Atrial fibrillation ablation: importance of 
cavotricuspid isthmus block. Rev Port Cardiol. 2009;28(10):1031-1040. 
71. 
Moreira W, Timmermans C, Wellens HJ, et al. Can common-type atrial flutter be a 
sign of an arrhythmogenic substrate in paroxysmal atrial fibrillation? Clinical and 
ablative consequences in patients with coexistent paroxysmal atrial fibrillation/atrial 
flutter. Circulation. 2007;116(24):2786-2792. 
. 
72. 
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 
2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial 
Fibrillation: A Report of the American College of Cardiology/American Heart 
Association Task Force on Clinical Practice Guidelines and the Heart Rhythm 
Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 
2019;140(2):e125-e151. 
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 Appendix A: ADVANTAGE AF Study Phase 2 
ADVANTAGE AF Study Phase 2 protocol will be provided to sites within the United States 
who are eligible for participation in ADVANTAGE AF Study Phase 2. 
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Appendix A:  ADVANTAGE AF - Phase 2 
 
 
 
 
 
A Prospective Single Arm Open Label Study of the  
FARAPULSE Pulsed Field Ablation System in  
Subjects with Persistent Atrial Fibrillation 
 
The ADVANTAGE AF Study: Phase 2 
92836802 
   PF106 
CLINICAL INVESTIGATION PLAN 
 
G220079 
NCT 05443594 
 
Sponsored By 
Boston Scientific Corporation 
 
Sponsored By 
Boston Scientific Corporation 
4100 Hamline Ave N. 
St. Paul, MN 55112 
 
and 
 
Boston Scientific International S.A.  
Le Val Saint-Quentin 
2 rue René Caudron 
78960 Voisins le Bretonneux, France 
 
 
This protocol contains confidential information for use by the Investigators and their designated 
representatives participating in this clinical investigation. The protocol should be held confidential 
and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
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Protocol Synopsis 
A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
STUDY 
OBJECTIVE(S) 
The objective of the ADVANTAGE AF Study is to establish the safety and 
effectiveness of the FARAPULSE Pulsed Field Ablation System for treatment 
of drug resistant, symptomatic persistent atrial fibrillation (PersAF). 
ADVANTAGE AF Phase 2 incorporates the use of the FARAPOINT PFA 
Catheter as an adjunctive device to the FARAPULSE PFA System. 
INDICATION(S) FOR 
USE  
The FARAPULSE™ Pulsed Field Ablation System is indicated for the 
treatment of drug resistant, symptomatic persistent atrial fibrillation. 
The FARAWAVE™ Pulsed Field Ablation Catheter is indicated for the 
isolation of pulmonary veins and posterior wall in the ablation of drug 
resistant, symptomatic persistent atrial fibrillation. 
The FARAPOINT™ Pulsed Field Ablation Catheter is indicated for use as an 
adjunctive device in the endocardial treatment of drug resistant, symptomatic 
persistent atrial fibrillation in conjunction with the FARAWAVE Catheter for 
the creation of an ablation line between the inferior vena cava and the tricuspid 
valve. 
DEVICES UNDER 
STUDY (TEST 
DEVICE) 
The investigational devices comprise the FARAPULSE™ Pulsed Field 
Ablation (PFA) System 
• 
FARAWAVE™ Pulsed Field Ablation (PFA) Catheter  
• 
FARAPOINT™ Pulsed Field Ablation (PFA) Catheter 
• 
FARASTAR™ Catheter Connection Cable  
• 
FARASTAR™ Pulsed Field Ablation (PFA) Generator and associated 
cables 
• 
FARASTAR™ Recording System Module and associated cables 
• 
FARASTAR™ Mapping System Module and associated cables 
(optional) 
• 
FARADRIVE™ Steerable Sheath 
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
STUDY DESIGN 
Phase 2 of the ADVANTAGE AF Study is a prospective, single arm, open 
label, multi-center IDE pivotal study utilizing the FARAPULSE PFA System 
for treatment of drug resistant, symptomatic PersAF, including the adjunctive 
use of the PFA Catheter as an adjunctive device to the FARAPULSE PFA 
System.  
Subjects requiring ablative intervention for PersAF meeting study entry 
criteria will undergo percutaneous ablative pulmonary vein isolation (PVI) and 
left atrial posterior wall isolation (PWI) using the FARAWAVE PFA 
Catheter. Subjects meeting protocol criteria will undergo ablative intervention 
of a line between the inferior vena cava and the tricuspid valve with the 
FARAPOINT PFA Catheter. 
All subjects will have a commercially available LUX-Dx insertable cardiac 
monitor (ICM) inserted within seven (7) days after the Index Procedure (if not 
previously inserted) to detect the recurrence of cardiac arrhythmias. Subjects 
will be followed at Pre-Discharge, Day 7, Day 30, Day 90, Day 180, and Day 
360. The Blanking Period will include Days 0 through 90. 
INTERVENTIONS 
DURING INDEX 
PROCEDURE 
Pulmonary Vein Isolation (PVI): PVI will be achieved in target veins using 
the FARAWAVE PFA Catheter. 
Posterior Wall Isolation (PWI): PWI will be achieved in the left atrial 
posterior wall between the PVs using the FARAWAVE PFA Catheter. 
CTI: Ablation of the CTI will be performed using the FARAPOINT PFA 
Catheter in the following situations: 
• 
Required: For subjects with a history of CTI-mediated (typical) AFL 
and  
o Who have not had a CTI ablation procedure, or 
o Who have had a CTI ablation procedure but have recurrent CTI 
conduction. 
• 
Required: subjects who manifest CTI-mediated AFL (spontaneous or 
induced) during the Index Procedure, or 
• 
At Investigator discretion: subject welfare indicates that CTI ablation 
should be performed. 
Other Ablation: When the Investigator determines that subject welfare 
requires intervention for either an accessory pathway, AVNRT or 
spontaneously occurring treatment-emergent AFL or AT, ablation for these 
arrhythmias may be performed using any commercially available RF ablation 
catheter. These permitted ablations and the associated data will be documented 
in the CRF and do not constitute Persistent AF Acute Procedural Failure.  
Ablation for an arrhythmia that is provoked only by catheter manipulation or is 
only inducible by pacing or pharmacologic stimulation is not permitted. 
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 338 subjects will be enrolled in Phase 2 of the ADVANTAGE 
AF study (up to 80 Roll-In Subjects and approximately 258 Treatment 
Subjects) after enrollments in Phase 1 are complete. 
Roll-In Subjects (up to 80): The first subject enrolled and treated by each 
ablating Investigator at each site will be treated with the investigational 
devices as part of Investigator preparation, up to a maximum of 80 subjects 
across 40 investigational sites. Roll-In Subjects will be pre-screened prior to 
enrollment to ensure the criteria for CTI ablation will be met and the 
FARAPOINT PFA Catheter is utilized. Roll-In procedures may be adapted 
based on prior experience, used jointly by investigators, or additional subjects 
may be required as described in Section 4.2. 
 
Treatment Subjects (258): A planned 258 Treatment Subjects will be enrolled 
to support the proposed primary safety endpoint. No site may enroll more than 
~13% of these planned subjects (n= 33 Treatment Subjects maximum). 
Subject enrollment will stop once approximately 258 Treatment Subjects are 
accrued and may be controlled to ensure an estimated 80 subjects are treated 
with the FARAPOINT PFA Catheter. 
INVESTIGATIONAL 
SITES / COUNTRIES 
Up to 40 clinical sites in the United States that participated in Phase 1 will 
contribute enrollments in Phase 2 of the ADVANTAGE AF Study.   
The number of active ablating Investigators at any site is limited to a 
maximum of three (3). 
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
PRIMARY 
EFFECTIVENESS 
ENDPOINT 
The primary effectiveness endpoint (PEE) is the proportion of LUX-Dx 
monitored Treatment Subjects with Treatment Success through the Day 360 
Assessment.  
Treatment Success is defined as: 
1. Persistent AF Acute Procedural Success AND 
2. Persistent AF Chronic Success, defined as freedom from the following 
after the Blanking Period (excluding documented CTI-dependent flutter if 
subject was not treated with the FARAPOINT PFA Catheter): 
i. 
Arrhythmia: Occurrence of any Detectable AF, AFL or AT  
ii. 
Re-ablation: Any re-ablation for AF, AFL or AT  
iii. 
Cardioversion: Any electrical cardioversion for AF, AFL or 
AT  
iv. 
AAD Use: Use of a Non-Failed Class I / III AAD or 
amiodarone. 
ADDITIONAL 
EFFECTIVENESS 
ENDPOINTS 
• 
CTI-Mediated AFL Treatment Success 
• 
Re-Ablation Rate for CTI-Mediated AFL 
• 
Persistent AF Acute Procedural Success 
• 
Persistent AF Chronic Success 
• 
Freedom from Detectable AF, AFL, AT 
• 
Freedom from Symptomatic Recurrence and Intervention to Treat AF, 
AFL, or AT 
• 
Single Procedure Treatment Success 
• 
Off Drug Treatment Success  
• 
Re-Ablation Rate 
• 
AF, AFL, and AT Burden 
• 
Healthcare Utilization by AF, AFL, and AT Burden 
• 
Healthcare Utilization by AF, AFL, or AT Recurrence Duration 
PROCEDURAL 
ASSESSMENTS 
Assessments of procedure durations  
• 
Procedure Time  
• 
LA Dwell Time  
• 
PVI and PWI Ablation Time 
• 
CTI Ablation Time 
• 
Fluoroscopy Time  
Characterization of lesion sets 
• 
PVI Ablations 
• 
PWI Ablations 
• 
CTI Ablations 
• 
Other Ablations 
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
QUALITY OF LIFE 
ASSESSMENTS 
Between Baseline and Day 180, and between Baseline and Day 360 
• 
The 3-level EuroQol standardized questionnaire of health states 
(EQ-5D-3L)  
• 
The Atrial Fibrillation Effect on Quality of Life (AFEQT) instrument 
for the measurement of health related quality of life  
METHOD OF 
ASSIGNING 
PATIENTS TO 
TREATMENT 
Phase 2 of the ADVANTAGE AF Study is a single arm study, and any subject 
that signs the Informed Consent Form and meets all study inclusion criteria, 
and no exclusion criteria, will be eligible for treatment either as a Roll-In 
Subject or a Treatment Subject. 
FOLLOW-UP 
SCHEDULE 
• 
Baseline Assessments 
• 
LUX-Dx Insertion (from enrollment up to 7 days after Index 
Procedure) 
• 
Index Procedure / Rescheduled Index Procedure (Day 0): Cardiac 
ablation 
• 
Pre-Discharge Assessment 
• 
Day 7 Assessment (remote): safety assessment (Window Day 7 to 11) 
• 
Day 30 Assessment (remote): safety assessment (Window Day 30 – 
37) 
• 
Day 90 Assessment (in person): clinical assessment (Window Day 90 
± 14) 
• 
Day 180 Assessment (remote): clinical assessment, QoL 
(Window Day 180 ± 30) 
• 
Day 360 Assessment (in person): clinical assessment, QoL (Window 
Day 360 ± 30) 
• 
Re-Ablation Procedure 
• 
Unscheduled Assessments 
STUDY DURATION 
Enrollment is expected to be completed in approximately 6 months, and 
subjects will be followed for 12 months. There will be an approximate 2-
month period of site close-out visits, for an estimated first patient in until last 
patient last assessment duration of 20 months. 
SUBJECT DURATION The study duration for each subject will be approximately 13 ± 1 months to 
allow for screening, pre-procedural diagnostic procedures, treatment, and 12 ± 
1 months of study follow-up. 
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EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(CONTINUED NEXT 
PAGE) 
l. 
Stents 
Pre-existing right coronary artery stent 
 
3. Any of the following conditions at baseline (Section 7.5): 
a. 
Heart failure 
NYHA 
Heart failure associated with NYHA Class III or IV 
b. 
Ejection fraction 
LVEF < 40% 
c. 
Uncontrolled 
hypertension 
Uncontrolled hypertension (SBP > 160 mmHg or DBP 
> 95 mmHg on two (2) BP measurements at baseline 
assessment 
d. 
Ventricular 
dysfunction 
Right ventricular dysfunction 
4. Any of the following events within 90 Days of the Consent Date: 
a. 
Coronary disease 
Myocardial infarction (MI), unstable or Prinzmetal 
angina or coronary intervention 
b. 
Cardiac surgery 
Any cardiac surgery 
c. 
Heart failure 
hospitalization 
Heart failure hospitalization 
d. 
Pericardium 
Pericarditis or symptomatic pericardial effusion 
e. 
GI bleeding 
Gastrointestinal bleeding 
f. 
Neurovascular 
event 
Stroke, TIA, or intracranial bleeding 
g. 
Thromboembolis
m 
Any non-neurologic thromboembolic event 
h. 
Carotid 
intervention 
Carotid stenting or endarterectomy 
5. Bleeding diathesis 
Thrombocytosis, thrombocytopenia, disorder of blood 
clotting or bleeding diathesis 
6. Contraindication to 
anticoagulation 
Contraindication to, or unwillingness to use, systemic 
anticoagulation 
7. Pre-ablation 
anticoagulation 
Patients who have not been on anticoagulation therapy 
for at least 4 weeks prior to the ablation procedure 
8. Pregnancy 
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: 
a. 
Obesity 
Body Mass Index (BMI) > 42.0 
b. 
Transplantation 
Solid organ or hematologic transplant, or currently being 
evaluated for a transplant 
c. 
Diaphragmatic 
abnormality 
Any prior history or current evidence of hemi-
diaphragmatic paralysis or paresis 
d. 
Pulmonary 
• 
Severe pulmonary hypertension (at Baseline 
Assessment) 
• 
Severe lung disease 
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EXCLUSION 
CRITERIA 
 
• 
Any lung disease involving abnormal blood 
gases or requiring supplemental oxygen 
e. 
Renal 
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 
f. 
Malignancy 
Active malignancy or history of treated malignancy 
within 24 months of enrollment (other than cutaneous 
basal cell or squamous cell carcinoma) 
g. 
Gastrointestinal 
Clinically significant gastrointestinal problems involving 
the esophagus or stomach including severe or erosive 
esophagitis, uncontrolled gastric reflux, gastroparesis, 
esophageal candidiasis or active gastroduodenal 
ulceration 
h. 
Infections 
Active systemic infection 
i. 
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 
Date2 
j. 
Diabetes 
Uncontrolled diabetes mellitus or a recorded HgbA1c > 
8.0% in the 90 days prior to the Consent Date 
k. 
Sleep apnea 
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  
10. Life expectancy 
Predicted life expectancy less than one (1) year 
11. Participation in 
another trial 
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 
12. Any of the following congenital conditions: 
a. 
Congenital heart 
disease 
Congenital heart disease with any clinically significant 
residual anatomic or conduction abnormality 
b. 
Methemoglobine
mia 
History of known congenital methemoglobinemia 
c. 
G6PD deficiency 
History of known G6PD deficiency 
13. Contraindication to 
ICM insertion 
Patients who cannot tolerate a subcutaneous, chronically-
inserted LUX-Dx device  
14. LUX-Dx longevity 
Patients with a LUX-Dx device inserted > 6 months prior 
to enrollment or an estimated longevity of less than 1 
year 
 
1Excluding hypotension which is a known physiological response 
2Clinical resolution of COVID-19 disease is to be determined by the investigator, based on signs and 
symptoms of current active viral infection, not long-term sequelae of the disease such as anosmia or chronic 
fatigue. 
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A Prospective Single Arm Open Label Study of the FARAPULSE Pulsed Field Ablation System in 
Subjects with Persistent Atrial Fibrillation 
The ADVANTAGE AF Study – Phase 2 
STATISTICAL METHODS  
PRIMARY SAFETY 
ENDPOINT: 
HYPOTHESIS AND 
METHOD 
The analysis of the primary safety endpoint (PSE) is a test comparing the 
proportion of Treatment Subjects and Attempt Subjects with one or more 
CSAEs through the Day 90 Assessment to a performance goal (PG).  
The null and alternative hypotheses are: 
H0: P ≥ PG versus HA: P < PG 
where P is the proportion of Treatment Subjects and Attempt Subjects with 
one or more CSAEs through the Day 90 Assessment and the PG is 12%. 
The proportion of Treatment Subjects and Attempt Subjects with one or more 
CSAEs will be estimated using the Kaplan-Meier method. The 97.5% one-
sided upper confidence limit of the observed event rate will be compared to 
the performance goal of 12%. If the upper confidence limit is less than the 
performance goal, the null hypothesis will be rejected. The upper confidence 
limit will be calculated as the pointwise confidence limit using the log-log 
methodology.  
Both the PSE and PEE must be met for study success. 
PRIMARY 
EFFECTIVENESS 
ENDPOINT: 
HYPOTHESIS AND 
METHOD 
The analysis of the primary effectiveness endpoint (PEE) is a test comparing 
the proportion of LUX-Dx monitored Treatment Subjects with Treatment 
Success through the Day 360 Assessment to a PG.  
The null and alternative hypotheses are: 
H0: P ≤ PG versus HA: P > PG 
where P is the proportion of LUX-Dx monitored Treatment Subjects with 
Treatment Success through the Day 360 Assessment and the PG is 40%. 
The proportion of subjects with Treatment Success through the Day 360 
Assessment will be estimated using the Kaplan-Meier method. The 97.5% 
one-sided lower confidence limit of the observed Treatments Success rate will 
be compared to the performance goal of 40%. If the lower confidence limit is 
greater than the performance goal, the null hypothesis will be rejected. The 
confidence limit will be calculated as the pointwise confidence limit using the 
log-log methodology. 
 
Both the PSE and PEE must be met for study success. 
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Table of Contents 
APPENDIX A:  ADVANTAGE AF - PHASE 2 ..............................................................................1 
PROTOCOL SYNOPSIS ..................................................................................................................2 
TABLE OF CONTENTS ................................................................................................................14 
LIST OF FIGURES .......................................................................................................................17 
LIST OF TABLES ........................................................................................................................18 
1 
INTRODUCTION ..................................................................................................................19 
1.1 
Cavo-Tricuspid Isthmus (CTI) Mediated Atrial Flutter ..................................................... 19 
1.2 
FARAPOINT Pulsed Field Ablation Catheter ................................................................... 20 
1.3 
Arrhythmia Detection via Implantable Cardiac Monitor (ICM) ........................................ 20 
1.4 
Summary ............................................................................................................................ 21 
2 
DEVICE DESCRIPTION ........................................................................................................21 
2.1 
Intended Use....................................................................................................................... 21 
2.2 
Investigational Devices ...................................................................................................... 22 
2.2.1 
FARAPULSE Pulsed Field Ablation System ..................................................... 22 
2.2.2 
FARAPOINT Pulsed Field Ablation Catheter ................................................... 24 
2.2.3 
FARASTAR Mapping System Module (optional) ............................................. 25 
2.3 
Non-Investigational Devices .............................................................................................. 25 
2.3.1 
LUX-Dx Insertable Cardiac Monitor ................................................................. 25 
2.3.2 
Mobile Applications ........................................................................................... 26 
3 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................26 
3.1 
Study Rationale .................................................................................................................. 26 
3.2 
Study Objective .................................................................................................................. 27 
3.3 
Primary Safety Endpoint .................................................................................................... 27 
3.3.1 
Composite Serious Adverse Event Definitions .................................................. 28 
3.4 
Primary Effectiveness Endpoint ......................................................................................... 30 
3.4.1 
Persistent AF Acute Procedural Success ............................................................ 30 
3.4.2 
Persistent AF Chronic Success ........................................................................... 30 
3.5 
Additional Endpoints and Assessments ............................................................................. 31 
3.5.1 
Additional Safety Endpoints ............................................................................... 31 
3.5.2 
Additional Effectiveness Endpoints ................................................................... 31 
3.5.3 
Procedural Assessments ..................................................................................... 33 
3.5.4 
Quality of Life Assessments ............................................................................... 34 
4 
ADVANTAGE AF PHASE 2 STUDY DESIGN ....................................................................34 
4.1 
Scale and Duration ............................................................................................................. 35 
4.1.1 
Phase 1 of ADVANTAGE AF ........................................................................... 35 
4.1.2 
Number of ADVANTAGE Phase 2 Subjects ..................................................... 35 
4.1.3 
Investigational Sites / Countries ......................................................................... 36 
4.1.4 
Study Duration.................................................................................................... 36 
4.1.5 
Participant Duration ............................................................................................ 36 
4.2 
Treatment Assignment (Roll-In vs Treatment) .................................................................. 36 
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4.3 
Justification for the Study Design ...................................................................................... 36 
5 
SUBJECT SELECTION ..........................................................................................................37 
5.1 
Study Population and Eligibility ........................................................................................ 37 
5.2 
Inclusion Criteria ................................................................................................................ 37 
5.3 
Exclusion Criteria............................................................................................................... 38 
6 
SUBJECT ENROLLMENT AND ACCOUNTABILITY .................................................................41 
7 
STUDY METHODS ..............................................................................................................42 
7.1 
Overview of Study Interactions.......................................................................................... 42 
7.2 
Data Collection Schedule ................................................................................................... 43 
7.3 
Anticoagulation .................................................................................................................. 44 
7.4 
Antiarrhythmic Drugs ........................................................................................................ 44 
7.5 
Baseline Assessment .......................................................................................................... 45 
7.6 
LUX-Dx Insertion .............................................................................................................. 46 
7.7 
Index Procedure / Rescheduled Index Procedure ............................................................... 47 
7.7.1 
Index Procedure / Rescheduled Index Procedure Data Collection ..................... 47 
7.7.2 
Index Procedure Workflow ................................................................................ 48 
7.7.3 
Rescheduled Index Procedure ............................................................................ 52 
7.8 
Pre-Discharge Assessment ................................................................................................. 52 
7.9 
Day 7 Safety Assessment ................................................................................................... 53 
7.10 Day 30 Safety Assessment ................................................................................................. 54 
7.11 Day 90 Assessment ............................................................................................................ 55 
7.12 Day 180 Assessment .......................................................................................................... 56 
7.13 Day 360 Assessment .......................................................................................................... 56 
7.14 Re-Ablation Procedures ..................................................................................................... 57 
7.14.1 
Re-Ablation Procedure within the Blanking Period ........................................... 57 
7.14.2 
Other Re-Ablation Procedures............................................................................ 58 
7.15 Unscheduled Assessments ................................................................................................. 58 
7.16 Unforeseen Circumstances ................................................................................................. 59 
7.17 Study Completion............................................................................................................... 59 
7.18 Source Documents ............................................................................................................. 59 
7.19 Local Laboratory Documentation ...................................................................................... 61 
8 
STATISTICAL CONSIDERATIONS .........................................................................................61 
8.1 
Endpoints ........................................................................................................................... 61 
8.1.1 
Primary Safety Endpoint .................................................................................... 61 
8.1.2 
Primary Effectiveness Endpoint ......................................................................... 64 
8.1.3 
Other Endpoints and Assessments ...................................................................... 66 
8.2 
General Statistical Methods ............................................................................................... 66 
8.2.1 
Analysis Sets ...................................................................................................... 66 
8.2.2 
Control of Systematic Error / Bias ..................................................................... 67 
8.2.3 
Study Success and Control of Type I Error ........................................................ 67 
8.3 
Data Analyses..................................................................................................................... 67 
8.3.1 
Roll-In Subject Analyses .................................................................................... 67 
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8.3.2 
Interim Analyses ................................................................................................. 67 
8.3.3 
Sensitivity Analyses ........................................................................................... 68 
8.3.4 
Subgroup Analyses ............................................................................................. 69 
8.3.5 
Center Pooling Analysis ..................................................................................... 69 
8.3.6 
Treatment Success Rate by Arrhythmia Detection Method ............................... 69 
8.3.7 
Multivariable Analyses ....................................................................................... 70 
8.3.8 
Changes to Planned Analyses ............................................................................. 70 
9 
HEALTH ECONOMICS OUTCOMES ......................................................................................70 
10 DATA MANAGEMENT ........................................................................................................70 
11 CORE LABORATORIES AND INDEPENDENT ASSESSMENT ...................................................71 
11.1 Arrhythmia Core Laboratory .............................................................................................. 71 
11.1.1 
Study ECGs ........................................................................................................ 71 
11.2 LUX-Dx Recordings .......................................................................................................... 71 
11.3 Cardiac Imaging Core Laboratory...................................................................................... 71 
12 DEVIATIONS ......................................................................................................................72 
13 DEVICE ACCOUNTABILITY .................................................................................................72 
13.1 Investigationally Labeled Test Devices ............................................................................. 72 
14 COMPLIANCE .....................................................................................................................72 
14.1 Institutional Review Board/ Ethics Committee .................................................................. 72 
15 MONITORING .....................................................................................................................73 
16 POTENTIAL RISKS AND BENEFITS ......................................................................................73 
16.1 Anticipated Adverse Events ............................................................................................... 73 
16.2 Anticipated Adverse Events – LUX-Dx ICM .................................................................... 75 
16.3 Risks Associated with the Study Device(s) ........................................................................ 75 
16.4 Risks associated with Participation in the Clinical Study .................................................. 75 
16.5 Possible Interactions with Concomitant Medical Treatments ............................................ 75 
16.6 Risk Minimization Actions ................................................................................................ 75 
16.7 Anticipated Benefits ........................................................................................................... 75 
16.8 Risk to Benefit Rationale ................................................................................................... 76 
17 SAFETY REPORTING ...........................................................................................................76 
17.1 Reportable Events by Investigator to BSC ......................................................................... 76 
17.2 Investigator Reporting Requirements................................................................................. 76 
17.3 Reporting to Regulatory Authorities / IRBs / ECs / REBs / Investigators ......................... 77 
18 INFORMED CONSENT .........................................................................................................77 
19 COMMITTEES .....................................................................................................................77 
20 SUSPENSION OR TERMINATION ..........................................................................................77 
21 STUDY REGISTRATION AND RESULTS ................................................................................78 
22 REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .....................................................78 
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23 ABBREVIATIONS AND DEFINITIONS ...................................................................................78 
23.1 Abbreviations and Acronyms ............................................................................................. 78 
23.2 Definitions .......................................................................................................................... 80 
24 BIBLIOGRAPHY – ADVANTAGE AF PHASE 2 .................................................................84 
 
List of Figures 
Figure 2-1: Diagram of FARAPULSE Pulsed Field Ablation System  Connections with FARAPOINT 
and Mapping System Module .......................................................................................... 23 
Figure 2-2: Diagram of FARAPULSE Pulsed Field Ablation System................................................. 24 
Figure 2-3: FARAPOINT Pulsed Field Ablation Catheter .................................................................. 24 
Figure 2-4: FARAPOINT Pulsed Field Ablation Catheter – Distal Section ........................................ 25 
Figure 2-5: LUX-Dx ICM Device and Mobile App ............................................................................. 26 
Figure 4-1: ADVANTAGE AF Phase 2 Study Design ........................................................................ 35 
Figure 7-1: Pre-Discharge Stroke Evaluation ....................................................................................... 53 
 
 
 
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List of Tables 
Table 2.2-1: Components of the FARAPULSE Pulsed Field Ablation System ................................... 22 
Table 2.2-2: FARAPOINT Feature List ............................................................................................... 25 
Table 3.3-1: Primary Safety Endpoint Composite Serious Adverse Events ........................................ 27 
Table 3.3-2: Composite Serious Adverse Event Definitions ................................................................ 28 
Table 5.2-1: Inclusion Criteria ............................................................................................................. 37 
Table 5.3-1: Exclusion Criteria ............................................................................................................ 38 
Table 7.2-1: Data Collection Schedule ................................................................................................. 43 
Table 7.6-1: LUX-Dx Initial Parameter Settings .................................................................................. 47 
Table 7.18-1: Source Documentation Requirements ............................................................................ 60 
Table 8.1-1: Meta-Analysis to Determine Primary Safety Endpoint Parameters ................................. 62 
Table 8.1-2: Assumptions for the Primary Safety Endpoint Sample Size Estimate ............................. 63 
Table 8.1-3: Assumptions for the Primary Effectiveness Endpoint Sample Size Estimate ................. 65 
Table 13.1-1 : Device Accountability for the FARAPULSE  PFA System ......................................... 72 
Table 17.2-17.2-1: Investigator Reporting Requirements .................................................................... 77 
Table 23.1-1: Abbreviations and Acronyms......................................................................................... 78 
Table 23.2-1: Definitions...................................................................................................................... 80 
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1 Introduction 
The primary study introduction content remains unchanged and is included within Phase 1 of the 
ADVANTAGE AF clinical investigational plan. New background specific to Phase 2 of the 
ADVANTAGE AF study is provided below.  
1.1 
Cavo-Tricuspid Isthmus (CTI) Mediated Atrial Flutter 
Atrial flutter (AFL) is a supraventricular arrhythmia caused by a macro-reentrant loop in either the 
right or left atrium. The macro-reentrant circuits of AFL are well defined with the critical zone of 
slowing the reentrant rhythm, defined as the isthmus between the tricuspid valve and the inferior vena 
cava (IVC). Other names for right atrial flutter have included “common”, “type 1”, “typical” and 
“cavotricuspid isthmus (CTI)-dependent atrial flutter.1 Cosio et al2 describes the two more common 
circuits of AFL that are best denoted as typical counter-clockwise (CCW) cavotricuspid isthmus CTI-
dependent AFL and reverse typical clockwise (CW) cavotricuspid isthmus CTI-dependent AFL. 
While the CCW and CW forms of CTI-dependent AFL are easily diagnosed and distinguished from 
other atypical types of AFL or atrial tachycardia during invasive electrophysiology study, these types, 
in general, can also be diagnosed using routine surface 12-lead electrocardiograms (ECG).  
Historically, treatment options for patients that suffer from this arrhythmia have been life-long drug 
therapy, ablation of the atrio-ventricular junction (AVJ) or His bundle area creating permanent 
complete heart block (CHB) and leaving the patient dependent on pacemaker therapy. However, RF 
cardiac ablation using conventional small and large tip electrode catheters has evolved into a mature 
technology also using open-irrigation catheters and cryoablation.3 Nonetheless, cardiac ablation is the 
first line therapy for AFL with highly predictable results. For successful ablation of any reentrant 
circuit involving a protected isthmus of slow conduction, a lesion (or lesions) must be placed such 
that the isthmus is severed completely. Current literature on RF ablation for CTI AFL with bi-
directional block (BDB) report procedural long-term success rates are between 80-100%, depending 
on the definition of success and the catheter used.4,5 
Although AF and CTI-dependent atrial flutter (AFL) are different arrhythmias with their own 
mechanisms and electrophysiologic presentation, their interrelationship has long been recognized and 
they coexist in a significant percentage of patients.6 The relationship is reciprocal since patients 
diagnosed with AFL may develop AF after CTI ablation and patients with AF often go on to develop 
AFL.7-9 In particular, the presentation of AFL in the context of AF may be the sign of additional atria 
remodeling or the presence of non-PV triggers.10  
Accordingly, a strategy that includes both Pulmonary Vein Isolation (PVI) and CTI ablation has 
become an established practice in the percutaneous ablative treatment of patients with AF. The 
current guidelines for the management of AF indicate that CTI ablation may be beneficial during 
procedures of AF ablation, in particular for those patients with history of typical AFL and where AFL 
is induced at the time of AF ablation.11 Adjunctive prophylactic CTI isolation is emerging as a 
potential strategy during AF ablation as a means to reduce rates of AFL. Previous studies reported 
that prophylactic CTI ablation may lead to recurrence rates of AFL lower than or equal to those for 
AF ablation only.12-15 Additionally, adjunctive CTI ablation may mitigate the effect of adjunctive non-
PV triggers on AF recurrences in patients with Persistent AF (PersAF).16  
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1.2 
FARAPOINT Pulsed Field Ablation Catheter 
An additional catheter included in the ADVANTAGE AF Phase 2 Study is the FARAPOINT PFA 
Catheter, which is designed for ablation of the cavotricuspid isthmus (CTI).  
Initial data on the safety and feasibility of the FARAPOINT Catheter has been collected in twenty 
subjects in the PersAFOne II Study.  In this study subjects undergoing ablation for PersAF using the 
FARAWAVE Catheter for PVI and Left Atrium Posterior Wall (LAPW) ablation also received 
ablation of the CTI using the FARAPOINT Catheter delivering two applications per site at 2000V.  
Study follow-up included an invasive electrophysiological remapping procedure to assess index 
treatment durability at 60 days post-index procedure.   
No primary safety events were reported in any subjects. Two SAEs (pericardial effusion) have been 
reported in two subjects during study follow-up during required remapping procedures.  Neither was 
deemed related to the FARAPULSE PFA devices or ablation procedure.  All subjects had successful 
acute CTI ablation as determined by electrophysiological assessment of bidirectional block across the 
cavotricuspid isthmus.  As reported in the interim progress report, dated 02-Feb-2022, 17 subjects had 
undergone the protocol-specified re-mapping procedures.  Among these, bidirectional isthmus block 
remained in 14 of the 17 subjects (82.4%).17    
It has been reported that CTI ablation may cause subclinical spasm of the coronary arteries18. Less 
often, patients may develop spasm that manifests in a clinically relevant manner such as ECG 
changes, hemodynamic changes or an arrhythmia requiring additional intervention. In the PersAFOne 
II feasibility study there were no events related to clinical signs of coronary spasm such as ECG 
changes or wall motion abnormalities on echocardiogram at the time of the procedure or post-
procedure. PersAFOne III is an additional European prospective, multi-center safety and feasibility 
study in subjects with PersAF. Subjects undergo percutaneous PFA for PVI as well as CTI 
interruption and other left atrial ablations at the Investigator's discretion. The most recent revision of 
the PersAFOne III Clinical Investigation Plan (CIP) allows coronary assessments, including 
angiography and fractional flow reserve (FFR), to assess potential response to PFA application at the 
discretion of the Investigator in addition to prophylactic administration of nitroglycerin at the 
Investigator’s discretion to mitigate the likelihood of coronary spasm. Accordingly, the 
ADVANTAGE AF Phase 2 Study incorporates a workflow during CTI ablation including 
administration of nitroglycerin to prevent the occurrence of coronary spasm. 
1.3 
Arrhythmia Detection via Implantable Cardiac Monitor (ICM) 
Post-ablation assessment of arrhythmia recurrence over time is an important aspect to determine the 
chronic success of ablation therapy and has been extensively introduced in the definition of the 
effectiveness endpoints into ablation trials. Traditionally, recurrence has been assessed by means of  
short-duration monitoring strategies such as Holter and trans-thoracic monitors (TTM), which have 
been extensively used in clinical trials. The standard assessment recommended for arrhythmia 
monitoring from the 2017 expert consensus statement20 requires both a 24 hours Holter monitoring at 
standard follow up timeframes (3, 6, and 12 months post procedure) and the use of a TTM to transmit 
periodically (at least twice a month) recordings of the heart rhythm. However, these methods have 
limited sensitivity in detecting AF and tend to underestimate the true AF recurrence rates, achieving a 
sensitivity of arrhythmia detection far inferior to the rates that could be captured by a continuous 
source of rhythm monitoring.19  
 
The capability to use a source of continuous monitoring for heart rhythm has been recently introduced 
with the use of implantable loop recorders or implantable cardiac monitors (ICM). A ICM is a device 
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able to monitor the heart rhythm over an extended period and it is implanted subcutaneously with a 
minor surgery. This kind of device, available since the 1990s, has been improved and miniaturized 
over the past few years and has become an important tool to detect and diagnose heart arrhythmias. 
The implantation of an ICM in the subcutaneous tissue is currently a safe procedure with very rare 
complications, generally limited to mild pain or small hematoma at the implant site. 
 
Compared to a TTM, the ICM has the advantage of allowing the continuous recording of patient 
rhythm and to transmit automatically arrhythmia episodes whenever they occur. This also implies the 
capability to capture all arrhythmias independently from patient symptoms and the possibility to 
simplify the device management compared to TTMs, that requires adequate patient compliance to 
ensure periodic transmission.  An ICM also allows the calculation of the AF burden, which is the 
proportion of time an individual spends in AF over a certain period,expressed as a percentage. This 
metric is gaining importance in the management of AF and is increasingly considered a crucial 
factor.11 
 
Thus, the utilization of ICM in this setting could potentially identify a new and more efficient 
approach for detecting arrhythmia and quantifying AF burden. As such, it has the potential to become 
the gold standard for arrhythmia detection in clinical trials in the near future. Since this is a novel 
method of assessment in the context of AF ablation trials (in particular persistent AF), the standards 
for the determination of a successful treatment in terms of arrhythmia rates and distribution (time to 
first recurrence, minimal duration, and AF burden) still need to be established in clinical trials. 
1.4 
Summary 
The present IDE study incorporates the treatment strategy for PersAF ablation utilized in the 
PersAFOne studies using the FARAWAVE PFA Catheter for electrical isolation of the PV and 
isolation of the LAPW region between the PVs, coupled with selective CTI isolation using the 
FARAPOINT PFA Catheter. In addition to further characterizing PVI, PWI, and CTI ablation, this 
study will also give the opportunity to explore the effectiveness of ablation therapy assessed through a 
continuous source of recording (ICM) and evaluate recurrence rates and AF burden which may help 
to define a standard in the PersAF population useful for the design of future studies. 
2 Device Description 
2.1 
Intended Use 
The FARAPULSE Pulsed Field Ablation System is indicated for the treatment of drug resistant, 
symptomatic persistent atrial fibrillation. 
The FARAWAVE Catheter is indicated for the isolation of pulmonary veins and posterior wall in the 
ablation of drug resistant, symptomatic persistent atrial fibrillation. 
 
The FARAPOINT Catheter is indicated for use as an adjunctive device in the endocardial treatment 
of drug resistant, symptomatic persistent atrial fibrillation in conjunction with the FARAWAVE 
Catheter for the creation of an ablation line between the inferior vena cava and the tricuspid valve. 
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Diagrams of the FARAPULSE Pulsed Field Ablation System set-up with and without the optional 
FARASTAR Mapping System Module (MSM) are provided in  
Figure 2-1 and Figure Figure 2-2,  respectively.   
 
Figure 2-1: Diagram of FARAPULSE Pulsed Field Ablation System  
Connections with FARAPOINT and Mapping System Module 
 
 
 
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Figure 2-2: Diagram of FARAPULSE Pulsed Field Ablation System  
Connections 
 
 
2.2.2 
FARAPOINT Pulsed Field Ablation Catheter 
The FARAPOINT PFA Catheter is a multi-electrode bidirectional, deflectable percutaneous catheter 
that connects to the FARASTAR PFA Generator via the FARASTAR Connection Cable (GEN2) and 
is designed to deliver Pulsed Electric Field (PEF) energy for cardiac tissue ablation. The 
FARAPOINT PFA Catheter is an adjunctive catheter designed to create focal-type lesions for the 
creation of an ablation line between the inferior vena cava and the tricuspid valve. 
The catheter consists of the following major sections: 1) a deflectable distal section with electrodes, 
2) an 8F catheter shaft, and 3) a proximal handle with a manually operated deflection control and a 
connector for attachment to the FARASTAR Pulsed Field Ablation Generator. 
 
Figure 2-3: FARAPOINT Pulsed Field Ablation Catheter 
 
 
The FARAPOINT Catheter is an 8F device with a bi-directional deflectable section length of 9.5cm 
and a usable length of 110cm measured from the catheter strain relief to the catheter tip when in the 
undeflected state. Two pairs of 2mm and 1.5mm length electrodes enable bipolar delivery of PFA 
energy. These electrodes attach to the FARASTAR PFA Generator through one FARASTAR 
Connection Cable. The FARAPOINT Catheter can be used with the FARADRIVE Steerable Sheath 
or any commercially available sheath at least 8.5Fr. The FARAPOINT PFA Catheter also includes a 
magnetic sensor to facilitate navigation with the Rhythmia mapping system. 
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Figure 2-5: LUX-Dx ICM Device and Mobile App  
 
 
 
2.3.2 
Mobile Applications 
There are two mobile applications used to interrogate the LUX-Dx ICM and transmit data from the 
device to the LATITUDE ClarityTM: a patient-specific app called myLUX, and a clinic specific- app 
called LUX-Dx Clinic Assistant. The patient app also allows patients to record and send S-ECGs of 
symptomatic events to the LATITUDE server. Both apps communicate with the device using Bluetooth 
Low Energy (BLE) technology, and with the LATITUDE server using a Wi-Fi or cellular connection. 
Refer to Figure 2-5 for a diagram of the LUX-Dx ICM System. 
3 Study Objectives and Endpoints 
3.1 
Study Rationale 
Phase 2 of the ADVANTAGE AF study is an appendix to Phase 1 of the ADVANTAGE AF protocol 
and contains relevant sections detailing requirements that differ from the original protocol. If protocol 
requirements remain unchanged from Phase 1 of the ADVANTAGE AF study, it will be noted as 
such within the Phase 2 appendix, and full details will be contained with and followed within the 
Phase 1 protocol.  
ADVANTAGE AF Phase 2 is a prospective, non-randomized, multi-center, investigation being 
conducted to establish the safety and effectiveness of Boston Scientific’s FARAPULSE PFA System, 
including the FARAPOINT PFA Catheter, for treatment of drug resistant, symptomatic persistent 
atrial fibrillation (PersAF). The aim of the trial is to collect data with the FARAPULSE PFA System 
and ensure a sufficient number of subjects are treated with the FARAPOINT PFA Catheter. This 
study seeks to obtain approval for the FARAPULSE PFA System with the FARAPOINT PFA 
Catheter for adjunctive use in the endocardial treatment of drug resistant, symptomatic persistent 
atrial fibrillation in conjunction with the FARAWAVE Catheter for the creation of ablation line 
between the inferior vena cava and the tricuspid valve.. Data from up to 338 additional subjects who 
will undergo treatment with the FARAPULSE PFA System will be evaluated in this second phase of 
the ADVANTAGE AF study.   
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• 
AEs will be deemed serious according to the criteria and notes in Section 17 of the Phase 1 
ADVANTAGE AF protocol. 
3.4 
Primary Effectiveness Endpoint 
The primary effectiveness endpoint (PEE) is the proportion of LUX-Dx monitored Treatment 
Subjects with Treatment Success through the Day 360 Assessment. Treatment Success is defined as 
Persistent AF Acute Procedural Success AND Persistent AF Chronic Success. 
3.4.1 
Persistent AF Acute Procedural Success 
Persistent AF Acute Procedural Success is defined as: 
• 
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. 
Both PWI and PVI must be achieved using only the FARAWAVE Catheter to be classified as a 
Persistent AF Acute Procedural Success. If the Investigator determined that subject welfare required 
intervention for an accessory pathway, AVNRT or spontaneously occurring treatment-emergent AFL 
or AT, ablation for these arrhythmias may be performed using any commercially available RF 
ablation catheter, and these permitted ablations do not constitute Persistent AF Acute Procedural 
Failure.  
3.4.2 
Persistent AF Chronic Success 
Persistent AF Chronic Success is defined as freedom from any of the following through the Day 360 
Assessment after the Blanking Period, excluding documented CTI-dependent AFL1: 
a. Arrhythmia: Occurrence of any Detectable AF, AFL or AT  
b. Re-ablation: Any re-ablation for AF, AFL or AT  
c. Cardioversion: Any electrical cardioversion for AF, AFL or AT  
d. AAD Use: Use of a Non-Failed Class I / III AAD or amiodarone 
 
Within the Blanking Period, recurrent arrhythmias can be managed with AADs, cardioversion or one 
re-ablation procedure with the FARAPULSE PFA System without constituting Persistent AF Chronic 
Failure. Titration of Class I/III antiarrhythmic medications are allowed during the Blanking Period. 
Subjects are allowed to remain on Class I/III antiarrhythmic medications at the historic maximum 
ineffective dose (prior to the ablation procedure) after the 90-day Blanking Period, except 
amiodarone.  Subjects that undergo more than one re-ablation procedure within the Blanking Period 
will be classified as a Persistent AF Chronic Failure.  Complete definitions of the endpoint terms 
(including Blanking Period, Detectable AF, AFL, or AT, Failed AAD and Non-Failed AAD), can be 
found in Section 23.2. 
  
 
1 Post-blanking CTI-dependent AFL or re-ablation or cardioversion for CTI-dependent AFL does not constitute 
Treatment Failure if the subject did not have a CTI ablation with the FARAPOINT PFA Catheter but will be a 
Treatment Failure if the subject did receive ablation with the FARAPOINT PFA Catheter. 
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3.5 
Additional Endpoints and Assessments 
The following additional endpoints and assessments will be analyzed and reported for Phase 2 of the 
ADVANTAGE AF Study. 
3.5.1 
Additional Safety Endpoints 
The following endpoints will be descriptively analyzed: 
• 
Primary Safety Endpoint Through Day 360 Assessment: 
Defined as the proportion of subjects with one or more device or procedure-related CSAEs 
assessed through Day 360 (Treatment) or Day 30 (Attempt) 
• 
Composite Non-Serious Adverse Events: 
Defined as the proportion of subjects with one or more composite non-serious AEs otherwise as 
defined in Table 3.3-2: Composite Serious Adverse Event Definitions. 
• 
Related Adverse Events 
Defined as the proportion of subjects with one or more device or procedure-related AEs 
• 
Any Serious Adverse Event 
Defined as the proportion of subjects with one or more SAEs whether or not device or 
procedure-related 
• 
Post-Blanking Arrhythmia Hospitalizations 
Defined as the proportion of Treatment subjects with one or more physician-directed admission 
to an inpatient hospital facility for at least two consecutive calendar days for the primary 
purpose of diagnosing or treating AF, AFL or AT beginning after Day 90 
• 
Post-Blanking Cardioversions 
Defined as the proportion of Treatment subjects with one or more electrical cardioversions for 
AF, AFL or AT after Day 90 
• 
Coronary Spasm Events 
Defined as the proportion of subjects with CTI-mediated AFL ablation using FARAPOINT 
PFA catheter with any of the following events 0-48 hours following procedure: 
o Angiography performed with visualization of severe (≥70%) spasm 
o ST elevation, defined by ST elevation of 2mm in two contiguous leads and adjudicated 
to be a result of coronary spasm 
o Cardiac arrest adjudicated to be a result of coronary spasm.  
• 
Adverse Effects of Intraprocedural Administration of Nitroglycerin  
Defined as the proportion of subjects with CTI-mediated AFL ablation using FARAPOINT 
PFA catheter with any of the following events 0-48 hours following procedure: 
o Persistent hypotension unresponsive to medical intervention 
o Respiratory distress due to acquired methemoglobinemia assessed by an arterial 
blood gas with co-oximetry with MetHb >10%. 
3.5.2 
Additional Effectiveness Endpoints 
The following endpoints will be descriptively analyzed in LUX-Dx monitored Treatment Subjects with 
CTI Ablation using the FARAPOINT PFA Catheter at the indicated time points: 
• 
CTI-Mediated AFL Treatment Success 
Defined as both of the following outcomes:  
CTI-Mediated AFL Acute Procedural Success:  defined as the absence of 
conduction through the cavo-tricuspid isthmus in both directions achieved with the 
FARAPOINT PFA Catheter, confirmed at the end of the Index Procedure/ 
Rescheduled Index Procedure. Use of a catheter modality for treatment of CTI-
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Mediated AFL other than FARAPOINT PFA Catheter will be considered a CTI-
Mediated AFL Acute Procedural Failure. 
 
CTI-Mediated AFL Chronic Success: defined as freedom from documented 
recurrence of CTI-mediated AFL as of the Day 90, Day 180, and Day 360 
Assessment(s), without repeat CTI ablation. If recurrence of AFL is indicated on the 
LUX-Dx recording, recurrence of CTI-mediated AFL must be confirmed with a 12-
lead ECG. 
• 
Re-ablation Rate for CTI-Mediated AFL 
Defined as the proportion of subjects who receive one or more re-ablations during study 
follow-up for CTI-Mediated AFL, at any time during follow-up, and subdivided by Day 90 
and Day 180 Assessment. 
 
The following endpoints will be descriptively analyzed in all LUX-Dx monitored Treatment Subjects 
at the indicated time points: 
• 
Persistent AF Acute Procedural Success 
Defined in Section 3.4.1 at the conclusion of the Index Procedure / Rescheduled Index 
Procedure 
• 
Persistent AF Chronic Success 
Defined in Section 3.4.2 through the Day 360 assessment 
• 
Freedom from Detectable AF, AFL, AT 
Defined as freedom from recurrence of any Detectable AF, AFL, or AT as defined in Section 
23.2 and additionally assessed using different minimum thresholds for the duration of 
asymptomatic episodes which count as recurrence of AF, AFL, or AT based on continuous 
monitoring after the blanking period. Thresholds will include 30 seconds, 4 minutes, 6 minutes, 
1 hour, 6 hours, and 24 hours.   
• 
Freedom from Symptomatic Recurrence and Intervention to Treat AF, AFL, or AT 
Defined as freedom from recurrence of any symptomatic Detectable AF, AFL, or AT as defined 
in Section 23.2 and freedom from intervention to treat AF, AFL, or AT, including re-ablation, 
cardioversion, or use of a Non-Failed Class I/III AAD or amiodarone.  
• 
Single Procedure Treatment Success  
Treatment Success as defined in Section 3.4 but counting subjects with any re-ablation for AF, 
AFL, or AT as Treatment Failures 
• 
Off Drug Treatment Success  
Treatment Success as defined in Section 3.4 but counting subjects treated with any Class I / III 
AAD after Day 90 as Treatment Failures 
• 
Re-Ablation Rate  
Defined as the proportion of subjects who receive one or more re-ablations during study follow-
up for AF, AFL, or AT, at any time during follow-up, and subdivided by re-ablation during 
Days 0 – 90 and by Days 91 and thereafter. CTI only re-ablation is excluded for subjects who 
did not receive CTI ablation with the FARAPOINT catheter.  
• 
AF, AFL, and AT Burden 
Descriptive statistics on AF, AFL, and AT burden, as defined in Section 23.2 and assessed 
during the observation period from Day 91 to Day 360 Assessment. AF, AFL, and AT burden 
will also be calculated for the days from LUX-Dx activation to the Index/ Rescheduled Index 
Procedure (up to 30 days pre-procedure) and compared to the burden calculated from Day 91 to 
Day 360 Assessment. Additionally, AF, AFL, and AT burden statistics from Day 91 to Day 360 
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will be stratified by recurrence based on LUX-Dx detected AF, AFL, or AT using various 
episode duration thresholds.  
• 
Healthcare Utilization by AF, AFL, and AT Burden 
Healthcare utilization, defined by outcomes of all-cause hospitalization, cardioversion for AF, 
AFL, or AT recurrence outside of an ablation procedure, re-ablation for AF, AFL, or AT and 
unscheduled cardiovascular follow-up assessments, will be compared between subjects grouped 
by AF, AFL, and AT burden from Day 91 to Day 360 Assessment. Burden groups will include 
rates of 0%, 0-0.1%, 0.1-1%, 1-5%, 5-10%, and >10% AF, AFL, and AT burden.  
• 
Healthcare Utilization by AF, AFL, or AT Recurrence Duration 
Healthcare utilization, defined by outcomes of all-cause hospitalization, cardioversion for AF, 
AFL, or AT recurrence outside of an ablation procedure, re-ablation for AF, AFL, or AT and 
unscheduled cardiovascular follow-up assessments will be compared between subjects grouped 
by longest duration of AF, AFL, or AT captured by LUX-Dx (based on continuous monitoring) 
between Day 91 and Day 360 Assessment. Groups will include no recurrence and longest 
duration of 0-6 minutes, 6 minutes – 1 hour, 1-6 hours, 6-24 hours, and ≥24 hours.  
 
 
3.5.3 
Procedural Assessments 
The following assessments will be descriptively analyzed at the completion of the Index Procedure / 
Rescheduled Index Procedure: 
Assessments of procedure durations (recorded and rounded to the nearest minute)  
• 
Procedure Time 
Defined as the recorded time of initiation of venous access to the recorded time of venous 
access closure completion 
• 
LA Dwell Time 
Defined as the recorded time between the insertion of the first device into the LA and the 
removal of the last device from the LA 
• 
PVI and PWI Ablation Time 
Defined as the recorded time from the first FARAWAVE PFA Catheter application to the last 
FARAWAVE PFA Catheter application. 
• 
CTI Ablation Time  
Defined as the recorded time from the first application at the isthmus to the last application at 
the isthmus 
• 
Fluoroscopy Time 
Defined as the recorded total duration of exposure to fluoroscopic imaging. 
 
Characterization of lesion sets 
• 
PVI Ablations 
Defined as the number of applications in each attempted vein 
• 
PWI Ablations 
Defined as the number of applications during ablation of the LA posterior wall 
• 
CTI Ablations 
Defined as the number of applications during CTI ablation  
• 
Other Ablations 
For subjects undergoing welfare-required ablations for an accessory pathway, AVNRT, left-
sided AFL or incessant AT a listing and descriptive summary of ablation lesions delivered. 
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3.5.4 
Quality of Life Assessments 
The following assessments will be descriptively analyzed between Baseline and Day 180, and 
between Baseline and Day 360.  
• 
The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L) 
• 
The Atrial Fibrillation Effect on Quality of Life (AFEQT) instrument for the measurement of 
health-related quality of life 
4 ADVANTAGE AF Phase 2 Study Design 
Phase 2 of the ADVANTAGE AF Study is a prospective, single arm, open label, multi-center IDE 
pivotal study enrolling additional subjects and utilizing the FARAPULSE PFA System for treatment 
of drug resistant, symptomatic PersAF, including the adjunctive use of the FARAPOINT ablation 
catheter for the concomitant treatment of CTI-mediated atrial flutter (AFL).  
 
Subjects requiring ablative intervention for PersAF meeting study entry criteria will undergo 
percutaneous ablative pulmonary vein isolation (PVI) and left atrial posterior wall isolation (PWI) 
using the FARAWAVE PFA Catheter. Subjects meeting protocol criteria will undergo ablative 
interruption of the CTI using the FARAPOINT PFA Catheter. 
 
All subjects will receive a commercially available LUX-Dx insertable cardiac monitor (ICM) within 
seven (7) days following the Index Procedure to detect recurrence of cardiac arrhythmias; it is highly 
recommended for LUX-Dx insertion to occur 30 days prior to the Index Procedure. Subjects will be 
followed at Pre-Discharge, Day 7, Day 30, Day 90, Day 180, and Day 360. The Blanking Period will 
include Days 0 through 90. 
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Figure 4-1: ADVANTAGE AF Phase 2 Study Design 
 
 
4.1 
Scale and Duration 
4.1.1 
Phase 1 of ADVANTAGE AF  
All subjects enrolled under Phase 1 of the ADVANTAGE AF protocol will be treated, followed, and 
analyzed as defined within the protocol version in which they were enrolled.   
4.1.2 
Number of ADVANTAGE Phase 2 Subjects 
Approximately 338 treated subjects will be enrolled in Phase 2 of the ADVANTAGE AF study (up to 
80 Roll-In Subjects and approximately 258 Treatment Subjects) after enrollments in Phase 1 of the 
study are complete. Subjects participating in Phase 1 cannot be approached for participation in Phase 
2 for treatment with the FARAPOINT Catheter. 
Roll-In Subjects (up to 80): The first subject enrolled by each ablating Investigator at each site will be 
treated with the investigational devices as part of Investigator preparation, up to a maximum of 80 
subjects across 40 investigational sites. Subjects will be pre-screened prior to enrollment to ensure the 
criteria for CTI ablation will be met and the FARAPOINT PFA Catheter is utilized. Roll-In 
procedures may be adapted based on prior experience, or additional subjects may be required as 
described further in Section 4.2. 
Treatment Subjects (258): A planned 258 Treatment Subjects will be enrolled to support the Primary 
Safety Endpoint. No site may enroll more than 33 Treatment Subjects (13% of those planned). 
Subject enrollment will stop once approximately 258 Treatment Subjects are accrued. It is expected 
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that approximately 30% of the Treatment subjects will be treated with the FARAPOINT PFA 
Catheter for CTI-mediated AFL. Enrollments may be controlled to ensure an estimated 80 subjects 
are treated with the FARAPOINT PFA Catheter. There is no predetermined upper limit for the 
number of Treatment subjects receiving CTI ablation with the FARAPOINT PFA Catheter, therefore 
the FARAPOINT-  treated subjects may exceed 80 when the total number of 258 Treatment subjects 
are accrued.   
4.1.3 
Investigational Sites / Countries 
Up to 40 clinical sites in the United States that participated in Phase 1 will contribute enrollments in 
Phase 2 of the ADVANTAGE AF Study.   
The number of active ablating Investigators at any site is limited to a maximum of three (3). 
4.1.4 
Study Duration 
Enrollment in Phase 2 is expected to be completed in approximately 6 months, and subjects will be 
followed for 12 months. There will be an approximate 2-month period of site close-out visits, for an 
estimated first patient in until last patient last assessment duration of 20 months.  
Subjects who retain the LUX-Dx beyond the Day 360 Assessment for the study may be requested to 
consent to provide long-term follow-up data from the LUX-Dx device, if needed, to potentially fulfill 
post-approval requirements. 
4.1.5 
Participant Duration 
The study duration for each subject will be approximately 13 ± 1 months to allow for screening, pre-
procedural diagnostic procedures, treatment, and 12 ± 1 months of study follow-up. 
4.2 
Treatment Assignment (Roll-In vs Treatment) 
The first subject enrolled by each Investigator at each site will be classified as a Roll-In Subject and 
will be treated with the FARAPULSE PFA System, including the FARAPOINT PFA Catheter as part 
of Investigator preparation. Investigators will pre-screen the first subject(s) prior to enrollment to 
ensure the first subject(s) will meet the protocol criteria for the FARAPOINT PFA Catheter to be 
utilized.   
The number of Roll-In Subjects for each investigator will be determined by BSC depending on prior 
experience. Sites with more than one (1) active investigator may utilize available Roll-In Subjects 
jointly as required since each site will be allocated a maximum of 2 Roll-In Subjects total and will be 
allowed to have a maximum of three (3) ablating investigators. Investigators that enrolled and ablated 
subjects within Phase 1 will be required to utilize a Phase 2 Roll-In subject in order to obtain the 
appropriate experience with the FARAPOINT PFA Catheter.  
After each ablating investigator has completed the Roll-In Subject requirements, BSC will provide 
the investigator with authorization to proceed with the enrollment of Treatment Subjects. 
4.3 
Justification for the Study Design 
The currently ongoing ADVANTAGE AF (Phase 1) clinical trial (NCT05443594) is a prospective, 
single arm, open label IDE trial Study designed to establish the safety and effectiveness of the 
FARAPULSE PFA System, for treatment of drug resistant, symptomatic persistent atrial fibrillation.  
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7 Study Methods 
7.1 
Overview of Study Interactions 
Each Treatment subject will undergo the following formal study interactions: 
• 
Baseline Assessment 
• 
LUX-Dx Insertion (Enrollment to Day 7 post Index Procedure, highly recommended to occur 
30 days prior to Index Procedure) 
• 
Index Procedure / Rescheduled Index Procedure (Day 0) 
• 
Pre-Discharge Assessment (immediately prior to discharge after the Index Procedure) 
• 
Day 7 Safety Assessment (window Day 7 – 11, remote) 
• 
Day 30 Safety Assessment (window Day 30-37, remote) 
• 
Day 90 Assessment (window 90 ± 14 days, in-person) 
• 
Day 180 Assessment (window 180 ± 30 days, remote) 
• 
Day 360 Assessment (window 360 ± 30 days, in-person) 
In addition, the following events may also occur for some study subjects: 
• 
Re-ablation Procedure: Re-ablations for AF, AFL and AT will be captured in the EDC 
database using the Re-Ablation Procedure CRF 
• 
Unscheduled Assessments: Any unscheduled cardiovascular assessments will be captured in 
the EDC database using the Unscheduled Assessment CRF. 
 
The data collection schedule for these various interactions is shown in Table 7.2-1. 
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7.3 
Anticoagulation 
Anticoagulation regimen is consistent with Phase 1 of the ADVANTAGE AF Study. Anticoagulation 
will be guided by the 2017 Heart Rhythm Society Expert Consensus Statement20 and the 2019 
American Heart Association / American College of Cardiology / Heart Rhythm Society Focused 
Update21 relating to this issue.  
With the exception of substantial compliance with 4 weeks of anticoagulation prior to the Index / 
Rescheduled Index Procedure (Section 7.7.3), adjustments in anticoagulation therapy for subject 
welfare may be made by Investigators based on clinical judgment and do not constitute protocol 
deviations. 
Throughout the study: 
• 
Subjects with a CHA2DS2-VASc score ≥ 2 (men) or ≥ 3 (women) should receive oral 
anticoagulants throughout the study.  
• 
DOACs are recommended over warfarin for eligible subjects.  
• 
Subjects on warfarin should have at least monthly INR assessment. 
Peri-procedural: 
• 
Non-anticoagulated subjects will be placed on therapeutic anticoagulation for 4 weeks prior to 
an ablation procedure regardless of baseline CHA2DS2-VASc score. 
• 
Subjects taking warfarin should continue warfarin through the procedure. 
• 
Subjects taking a DOAC should have either uninterrupted treatment (if receiving rivaroxaban) 
or a single dose interruption in DOAC with a restart shortly after the procedure, at Investigator 
discretion. 
• 
A heparin bolus will be delivered prior to or immediately following transseptal puncture 
according to institutional standard of care. Procedural activated clotting times (ACTs) will be 
sampled regularly throughout the procedure according to institutional standard of care and 
maintained at a minimum of 300 seconds at least until all devices are withdrawn from the left 
atrium. 
Post-ablation: 
• 
If the subject is not otherwise indicated for anticoagulation, suitable anticoagulation will be 
maintained for a minimum of 2 months following any ablation procedure. 
• 
Thereafter, decisions regarding anticoagulation should be based on the guidelines referenced in 
this section. 
7.4 
Antiarrhythmic Drugs 
Use of Class I / III AADs during the ADVANTAGE AF Study must be managed carefully. 
The terms “Antiarrhythmic Drugs, Class I and III”, “Blanking Period”, “Failed AAD” and “Non-
Failed AAD” are defined specifically in Section 23.2. 
Failed AADs 
At the Baseline Assessment, Section 7.5, all Class I and III AADs previously used by the subject 
must be defined as Failed AADs or Non-Failed AADs in the CRF, including for any Failed AADs the 
maximum failed dose (see Section 23.2). 
Amiodarone 
• 
May not be used after the Blanking Period or the subject becomes a Treatment Failure. 
• 
If subjects are prescribed Amiodarone, treatment must be stopped by the Day 30 Assessment.  
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Managing AADs During the Blanking Period 
During the Blanking Period the subject should be assessed for AAD continuation. Titration of Class 
I / III AADs is allowed during the Blanking Period.  
To account for the hard cutoff of the Blanking Period at 90 days and given the permitted visit window 
for the Day 90 Assessment (90 ± 14 days), AADs that are taken during the Blanking Period but are 
stopped at the time of a within-window Day 90 visit (up to and including Day 104 ) will not be 
counted as potential Treatment Failures to allow the necessary physician evaluation. 
Managing AADs After the Blanking Period 
If indicated, subjects may remain on Class I / III AADs following the Blanking Period, preferably 
those established as Failed AADs (see Section 23.2) at or below the maximum failed dose so as not to 
create a post-Blanking Period Treatment Failure.  
Use of a Non-Failed AAD after the Day 90 Assessment constitutes a Treatment Failure for the 
primary effectiveness endpoint. 
AAD Monitoring 
At all subsequent follow-up assessments, subject compliance with, and changes in drugs and daily 
doses for any Class I / III AAD, will be elicited and recorded.  
7.5 
Baseline Assessment 
Type of Assessment: In-person at investigational site 
The completion of the Baseline Assessment requires an in-person assessment. Such 
assessments must be deferred if this is not possible. 
The below baseline data will be generated in the window beginning 30 days prior to the Consent Date 
and ending on the date of the Index Procedure, unless otherwise specified.  
This data will include but is not limited to: 
• 
Demographics including gender, height, and weight, race and ethnicity, in accordance with 
local requirements5 
• 
Pertinent medical and cardiovascular history 
• 
AAD history to establish Failed AAD and Non-Failed AAD status 
• 
Anticoagulation medication history 
• 
Cardiac physical examination 
• 
Pregnancy test (all women of child-bearing potential) 
• 
Hematocrit, hemoglobin, electrolytes, blood urea nitrogen (BUN), creatinine 
• 
COVID-19 testing according to investigation site requirements. The following information is 
not required if it is not a site requirement, but if available the data should be recorded: 
o A negative PCR for SARS-CoV-2 virus or equivalent testing, or  
o Confirmation of vaccination with a commercially available vaccine 
 
5 With a goal of achieving an unbiased estimate of treatment effect in the general population, Boston Scientific 
seeks to enroll a diverse population including representative proportions of relevant age, racial, and ethnic 
subgroups, which are consistent with the intended use population of the device. Case Report Forms will collect 
data on age, race and ethnicity in order to achieve this goal, in accordance with local regulations. 
 
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• 
12-lead ECG 
• 
Imaging (within the window beginning 180 days prior to the Consent Date and ending on the 
date of the Index Procedure) 
o TTE or Cardiac CT/ MRI for LA dimensions  
o TTE for LVEF and ventricular wall motion 
o Cardiac CT or MRI establishing cardiac anatomy for mapping and PV dimensions 
• 
NYHA Classification 
• 
National Institutes of Health Stroke Scale (NIHSS) score by NIHSS-certified site personnel 
• 
CHA2DS2-VASc score 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L)  
o The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
• 
Only if available, coronary anatomy characterization based on data obtained from previous heart 
catheterization or CT angiography: left-dominant, right dominant or co-dominant.  
 
7.6 
LUX-Dx Insertion 
A LUX-Dx is required for post ablation rhythm monitoring for all Roll-In and Treatment Subjects. As 
described in the Section 5, subjects with an active LUX-Dx inserted within 6 months of enrollment or 
an estimated one year or greater of battery life may be considered for participation in ADVANTAGE 
AF Phase 2. For those subjects enrolled without a pre-existing LUX-Dx ICM, the LUX-Dx insertion 
must occur after enrollment and within seven (7) days post Index Procedure/Rescheduled Index 
Procedure. It is highly recommended for the LUX-Dx to be inserted 30 days prior to the Index 
Procedure to allow collection of baseline arrhythmia assessment. The LUX-Dx insertion shall be 
performed according to the recommended insertion technique described in the LUX-Dx ICM User’s 
Manual. The study site will collect data associated with the procedure, including printing the 
LATITUDE Clarity programming report. Subjects enrolled with an active LUX-Dx implanted prior to 
enrollment in the study must have LUX-Dx programming settings updated, if necessary, in 
accordance with the initial programming described directly below, and a LATITUDE Clarity 
programming report printed to document the ICM settings. Enrollment in LATITUDE Clarity can be 
performed prior to, during, or immediately after the insertion procedure. Subjects should be shown 
how to use their myLUX patient application to complete manual transmissions when experiencing 
symptoms, and reminded of the importance to remain connected to the LATITUDE Clarity system 
throughout the duration of the trial.  Subjects who become disconnected from the LATITUDE Clarity 
system for greater than 7 days should be contacted and notified to reconnect and remain connected 
through their MyLUX Mobile Patient Device/App. 
Initial programming of the LUX-Dx device aligns with all detection algorithm nominal parameters as 
defined in Table 7.6-1 for Post AF Ablation as the reason for monitoring6, in addition to those 
parameters listed in Table 7.6-1 below.  
 
 
 
6The LATITUDE Clarity Alert Settings are associated with the Post AF Ablation reason for 
management settings with exception of turning on the Alert for AT Events – which is not a nominal 
setting for “Post AF Ablation” reason for monitoring).  
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• 
Procedural anticoagulation data: 
o For subjects on a DOAC whether DOAC therapy was interrupted for procedure 
o For subjects on warfarin, a pre-ablation international normalized ratio (INR) value 
o Procedural heparin administration and timing 
• 
Device deficiencies and malfunctions  
 
7.7.2 
Index Procedure Workflow 
This section contains important information regarding the procedures for cardiac ablation specified in 
Phase 2 of the ADVANTAGE AF Study. Investigators and staff should refer to training materials and 
the IFU documents as applicable per device.   
Ablation under this protocol will generally follow the order below. If performed, CTI ablation should 
be performed after PVI and PWI. However, the Investigator may alter the ablation sequence if necessary 
for subject welfare. 
Unless otherwise directed by Sponsor, at the conclusion of the procedure, all single-use components of 
the FARAPULSE PFA System should be returned to the Sponsor. 
7.7.2.1 
Preparation 
Subjects must be screened for substantial compliance with 4 weeks of systemic anticoagulation prior 
to the Index Procedure and, if in the opinion of the Investigator, this condition has not been met, the 
subject will be rescheduled as defined in Section7.7.3. 
 
TEE or volumetric CT within 48 hours of the procedure or ICE during the procedure will be utilized 
prior to transseptal puncture for exclusion of LA thrombus. If the study reveals atrial thrombus, the 
investigational procedure will not begin or will be terminated before accessing the left atrium, no 
ablation will be performed, and the subject will be rescheduled as defined in Section7.7.3. 
Phrenic nerve function will be assessed prior to ablation per Investigator standard of care, preferably 
by a pre-sedation fluoroscopic sniff test. Subjects will undergo sedation / anesthesia according to 
institutional protocol. They will then be prepared in conventional sterile fashion for a cardiac 
catheterization procedure.  
Femoral vein access will be obtained aseptically under ultrasound guidance.  
Commercially available diagnostic catheters may be placed before or after transseptal access at the 
Investigator’s discretion. Transseptal access to the LA will be obtained using commercially available 
devices, establishing guidewire access to the LA. 
A heparin bolus will be delivered prior to or immediately after transseptal puncture. Procedural ACTs 
will be monitored according to the investigational site’s standard of care and maintained at a 
minimum of 300 seconds at least until all devices are withdrawn from the left atrium. 
Topical anesthetic agents, particularly benzocaine, must not be used for the TEE on the same day as 
the procedure in order to minimize the likelihood of the development of methemoglobinemia due to 
polypharmacy, in those subjects that will undergo the nitro administration protocol (Section 7.7.2.5) 
during CTI ablation with the FARAPOINT PFA Catheter. Methemoglobinemia is a rare but 
potentially serious side effect of nitroglycerin, a blood disorder in which there is an abnormal increase 
in the level of methemoglobin, a form of hemoglobin that cannot carry oxygen effectively.  
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7.7.2.2 
Pulmonary Vein Isolation 
Ablation of the PVs will be performed according to the IFU documents and institutional practice. 
Ablation will be attempted in every clinically relevant PV, including any vein with an electrically 
active muscular sleeve. Small anomalous PVs that are electrically silent need not be attempted. 
 
The use of ICE is recommended but not required for Pulsed Field Ablation procedures. 
 
All catheter exchanges should be carefully performed to avoid introducing air bubbles into the 
FARADRIVE Steerable Sheath. 
 
Esophageal temperature monitoring, esophageal cooling and esophageal deviation are unnecessary 
during PVI and PWI ablation with the FARAWAVE PFA Catheter and should not be utilized. 
7.7.2.3 
Posterior Wall Isolation 
Following PVI ablation, LAPW ablation will be performed according to the IFU documents and 
institutional practice.  
LAPW ablation will be performed in the area below the superior aspect of the superior PVs, above 
the inferior aspect of the inferior veins, and between the insertions of the left sided and right sided 
PVs. In the event the PW is found to be electrically isolated following PVI, LAPW ablation will still 
be performed using the same anatomically guided approach until there is sufficient overlap between 
PFA application sites. No ablation in other locations, including the left atrial appendage, is permitted. 
LAPW ablation should be guided by electroanatomical mapping, ICE and / or fluoroscopy to ensure 
the entire area of LAPW is ablated with the appropriate amount of overlap between PFA application 
sites.  
 
All catheter exchanges should be carefully performed to avoid introducing air bubbles into the 
FARADRIVE Steerable Sheath. 
 
Esophageal temperature monitoring, esophageal cooling and esophageal deviation are unnecessary 
during PVI and LAPW ablation with the FARAWAVE PFA Catheter and should not be utilized. 
7.7.2.4 
Assessment of Isolation and Phrenic Nerve Function 
Assessment of Isolation 
After the completion of the planned PV and LAPW ablations, isolation will be assessed as: 
• 
The isolation of all attempted PVs at least 20 minutes following the last PFA application in 
each respective vein by entrance block performed with or without adenosine testing, AND 
• 
The isolation of the LAPW at the end of the LAPW ablation, performed with or without 
adenosine testing, via interrogation by multipolar diagnostic catheter or 3D electroanatomical 
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mapping. If electroanatomical mapping is used, electrograms demonstrating PWI are required 
per Section 7.18. At the Investigator’s discretion, exit block pacing of the PW may be 
performed to detect any epicardial exit pathways. 
Additional PV and LAPW ablation as described above may be performed as needed at any time to 
achieve complete PVI and PWI. Alternative dosing or fewer applications may be performed as 
needed for subject welfare, technical difficulties, or anatomical challenges and will not constitute a 
Treatment Failure if electrical isolation is still confirmed as required. In the event that touch-ups are 
performed after the initial isolation assessment, further waiting periods are not required.  
Assessment of Phrenic Nerve Function 
Once all PV and LAPW ablation is completed and isolation is confirmed, the functional status of both 
phrenic nerves will be assessed per Investigator standard of care (e.g., radiographically either by 
pacing, fluoroscopy, or a sniff test.7) 
7.7.2.5 
CTI Ablation 
The following subjects will undergo CTI ablation with the FARAPOINT PFA Catheter: 
• 
Required: For subjects with a history of CTI-mediated (typical) AFL and  
o Who have not had a CTI ablation procedure, or 
o Who have had a CTI ablation procedure but have recurrent CTI conduction. 
• 
Required: Subjects who manifest CTI-mediated AFL (spontaneous or induced) during the Index 
Procedure 
• 
At Investigator discretion: Subject welfare indicates that CTI ablation should be performed. 
CTI Ablation with the FARAPOINT PFA Catheter will be performed according to the IFU 
documents and institutional practice. Per the FARAPOINT Catheter IFU, no more than two energy 
applications should be delivered at any given catheter placement. Repeat placement of the 
FARAPOINT Catheter at nearly identical locations should be avoided unless there is a clear clinical 
need for such placements.  
 
The FARAWAVE Catheter is not allowed to complete any CTI lesion. 
 
CTI ablation with the FARAPOINT PFA Catheter must adhere to the following protocol 
requirements in order to mitigate the risk of coronary spasm during ablation application.  
No ablations outside CTI with the FARAPOINT PFA Catheter are allowed. 
 
The following prophylactic workflow is required to be followed when CTI ablation is performed with 
the FARAPOINT PFA Catheter: 
• 
Pre-Treatment (Required): Administer a three milligrams (3mg) nitroglycerin IV bolus via the 
FARADRIVE sheath (or other sheath with central access) approximately one minute prior to the 
first PFA application at the anterior position of the CTI line.  
• 
During Ablation (Required):  
 
7 If anesthesia necessitates, a pre-discharge fluoroscopic sniff test or inspiration / expiration CXR may be 
acceptable. See Section 7.8. 
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o Depending upon procedure duration and patient condition, administer an additional 2mg IV 
bolus via the FARADRIVE sheath (or other sheath with central access) approximately two 
(2) minutes apart until the ablation is complete or a maximum total of 9mg IV of 
nitroglycerin has been administered.  
o If bidirectional block (BDB) is assessed and not present and additional ablation lesions are 
required in the anterior aspect of the cavo-tricuspid isthmus line, Investigator discretion will 
determine whether to administer an additional 2-3 mg of nitroglycerin IV via the 
FARADRIVE sheath (or other sheath with central access) prior to re-ablation. 
Adjustments to the nitroglycerin dosing protocol defined above are allowed per Investigator discretion 
based on patient condition, but the rationale for any changes to the defined workflow will be collected. 
Failure to administer any pre-treatment nitroglycerin will be a protocol deviation.  
Vasopressors may be administered per physician discretion given that comorbidities, drug regimens, 
mode of anesthesia, and baseline blood pressure will vary among subjects.  
200 micrograms (µg) of phenylephrine should be administered prior to the first dose of nitroglycerin. 
If not administered, the rationale will be collected.    
Additional vasopressor doses may be administered at the discretion of the physician depending upon 
the blood pressure response to nitroglycerin.  Investigators may choose to administer a different 
vasopressor depending upon the clinical profile of the subject. All medications administered during the 
procedure, dose, route  and  timing of administration in relation to the PFA applications will be 
recorded.   
For those subjects with a known left dominant coronary artery system, as defined by a left heart 
catheterization or coronary CT angiography, the above prophylactic nitroglycerin workflow is not 
required. The proximity of the catheter to the artery may be directly visualized in real-time via 
intracardiac echocardiography. Routine hemodynamic monitoring for patients undergoing sedation and 
cardiac ablation is recommended. 
A post-procedure 12-lead ECG will be recorded following CTI ablation to assess absence of ischemia. 
If the post-procedure ECG shows any ischemic changes, a transthoracic echocardiographic assessment 
is required the same day as the procedure to assess if intraventricular wall motion abnormalities are 
observed compared to the pre-procedure echocardiographic assessment (Section 7.8).  
After CTI ablation is completed, BDB will be assessed, and if necessary, additional applications may 
be performed until BDB is confirmed. The CTI ablation data will be documented in the CRF. 
7.7.2.6 
Other Ablations for Atrial-Dependent Arrhythmias 
When the Investigator determines that subject welfare requires intervention for either an accessory 
pathway, AVNRT or spontaneously occurring treatment-emergent AFL or AT, ablation for these 
arrhythmias may be performed using any commercially available RF ablation catheter. These ablations 
must not be performed with the FARAPULSE PFA System and should be performed after all ablation 
with the FARAPULSE PFA System is complete.  These permitted ablations and the associated data 
will be documented in the CRF and do not constitute Persistent AF Acute Procedural Failure. 
FARAWAVE usage is not allowed to complete any lesion outside of the PVs and LAPW, as described 
in the IFU.  
Ablation for an arrhythmia that is provoked only by catheter manipulation or is only inducible 
by pacing or pharmacologic stimulation is not permitted. 
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IMPORTANT: FARAWAVE cannot be used to complete any lesion in the Left Atrium except 
for the PVs and LAPW, under any circumstances.  
FARAWAVE cannot be used in any other location, including the right atrium or either 
ventricle! 
 
7.7.3 
Rescheduled Index Procedure 
If, at the Index Procedure, the subject is found to have inadequate pre-procedural anticoagulation, a 
current atrial thrombus, COVID-19, or other temporarily disqualifying condition, the subject may have 
their Index Procedure rescheduled not later than 45 days later. The Rescheduled Index Procedure will 
otherwise follow the data and procedural requirements of Section 7.7.2.  
The Rescheduled Index Procedure must be scheduled within 45 days of the Index Procedure, and only 
one Rescheduled Index Procedure may be allowed; otherwise, the subject will be exited from the study 
as an Intent Subject. 
This rescheduling is permissible and does not create an Acute Procedural Failure. The subject remains 
a potential Treatment Subject.  
References to “Index Procedure” in this protocol should be assumed when appropriate to include 
“Rescheduled Index Procedure” as well if not otherwise specified. 
7.8 
Pre-Discharge Assessment 
Subjects should be prescribed a form of systemic anticoagulation treatment for at least two months 
following the ablation procedure. See Section 7.3 regarding post-ablation anticoagulation 
requirements.  
Type of Assessment: In-person at investigational site 
Prior to hospital discharge, study data will be collected including but not limited to: 
• 
Adverse events 
• 
Hematocrit, hemoglobin, electrolytes, BUN, creatinine  
• 
12-lead ECG to document the subject’s rhythm and if any new conduction disturbances are 
observed.   
o A 12-lead ECG collected at the end of the Index Procedure / Rescheduled Index 
Procedure after all ablation was complete also fulfills this data collection requirement.  
• 
If the post-ablation ECG collected at the end of the Index Procedure/ Rescheduled Index 
Procedure showed any new ischemic changes the following are required:  
o An additional 12-lead ECG at Pre-Discharge  
o A transthoracic echocardiographic assessment (TTE) 
▪ 
The TTE is required the same day as the procedure to assess if ventricular wall 
motion abnormalities are observed compared to the pre-procedure 
echocardiographic assessment. 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs. 
• 
Occurrence, date, indication and outcome of any post-procedure cardioversion(s) 
• 
Phrenic nerve assessment, as only applicable: 
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o If the function of both phrenic nerves could not be confirmed at the end of the Index 
Procedure / Rescheduled Index Procedure, a radiologic examination of the diaphragm 
(fluoroscopic sniff test or inspiration / expiration CXR) 
o If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated 
diminished phrenic nerve response and resolution has not been previously demonstrated, 
complete a radiologic examination of the diaphragm 
 
Pre-Discharge Stroke Evaluation: 
• 
NIHSS score by NIHSS-certified site personnel after the effects of anesthesia have fully 
resolved. 
• 
If either of the following occurs: 
o The post-procedure NIHSS score has increased by 1 or more points over the pre-procedure 
NIHSS score OR 
o There is a clinical suspicion of stroke or TIA 
Then a consulting neurologist will perform a stroke assessment and include the results of a concurrent 
brain DW-MRI scan. This assessment will be sufficient to determine with reasonable certainty 
whether a stroke, TIA or neither have occurred, using the definitions in Table 3.3-2. Please refer to 
Figure 7-1. 
Figure 7-1: Pre-Discharge Stroke Evaluation 
 
 
7.9 
Day 7 Safety Assessment 
Type of Assessment: Remote 
Window: Days 7 – 11 
The Day 7 Assessment is essential to establish the primary safety endpoint and every effort 
must be made to complete this assessment between Day 7 and Day 11.  
If the assessment is delayed, the onset date of an AE must be elicited as carefully as possible to 
establish whether it occurred within the interval between the ablation procedure and Day 7, 
or thereafter. 
Subjects will be assessed remotely between Day 7 and 11 post-Index Procedure / Rescheduled Index 
Procedure. Any subject who continues to be hospitalized at the time of the assessment will have their 
Day 7 assessment performed in-hospital. 
Study data will be collected by interview, including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs. 
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• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since discharge 
• 
Site staff will confirm successful LUX-Dx insertion and LATITUDE Clarity transmissions (if 
available)  
• 
The date and communication method(s) used to collect the data remotely. 
 
7.10 Day 30 Safety Assessment 
Type of Assessment: Remote; In-person allowed 
Window: Days 30 – Day 37 
The Day 30 Assessment is essential to establish the primary safety endpoint and every effort 
must be made to complete this assessment between Day 30 and Day 37.  
If the assessment is delayed, the onset date of an AE must be elicited as carefully as possible to 
establish whether it occurred within the interval between the ablation procedure and Day 30, 
or thereafter. 
AAD Treatment: Between the Day 30 Assessment and the Day 90 Assessment – the subject 
should be assessed for AAD continuation. See Section 7.11. 
Discharged subjects will be assessed remotely between Day 30 and Day 37 post-Index 
Procedure / Rescheduled Index Procedure. Any subject who is hospitalized at the time of the 
assessment will have their Day 30 assessment performed in-hospital.  
Study data will be collected by interview including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since 7-day telephonic 
assessment 
• 
Site staff will confirm ICM programming and successful LATITUDE Clarity transmissions 
since last assessment 
o Assess for any recurrence of AF/AFL/AT  
▪ 
Any reported AFL recurrence will require a 12-lead ECG for ACL 
adjudication 
o Confirm ICM programming parameters 
▪ 
Any programming outside of the defined nominal parameters (Section 7.6) 
prior to a confirmed recurrence of Detectable AF, AT or AFL must be 
entered into the EDC and justification provided. 
▪ 
ICM may be reprogrammed, as needed, to facilitate appropriate arrhythmia 
identification and investigator notification after the subject experiences a 
confirmed recurrence of Detectable AF, AT or AFL. 
• 
The date and communication method(s) used to collect the data remotely 
• 
If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated diminished 
phrenic nerve response and resolution has not been previously demonstrated, the patient must 
return for a radiologic examination of the diaphragm between Day 30 and Day 37. 
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7.11 Day 90 Assessment 
Type of Assessment: In-person at investigational site required; remote only for documented 
COVID-19 related disruption. 
Window: 90 ± 14 Days 
If a COVID-19-related disruption prevents an in-person assessment within window:  
• 
As much data as possible may be collected remotely.  
• 
The absence of a 12-lead ECG during a remote assessment is not a protocol deviation.  
• 
If a radiologic examination is required due to prior diminished phrenic nerve response, an 
inspiration / expiration chest X-ray (CXR) performed in-person or at another healthcare site 
may be substituted. 
AAD Treatment: During the Blanking Period the subject should be assessed for AAD continuation. 
At Investigator discretion, Class I / III AADs may be stopped to allow assessment of the subject’s 
potential for off-drug freedom from recurrent AF, AFL, or AT.  
Subjects who require continued AAD treatment may be continued; preferably with a Failed AAD. 
Using a Non-Failed AAD or amiodarone would create an unnecessary Treatment Failure.  
Subjects will be assessed at Day 90 ± 14 days following the Index Procedure / Rescheduled Index 
Procedure. Study data will be collected at the Day 90 Assessment including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment 
• 
Site staff will confirm ICM programming and successful LATITUDE Clarity transmissions 
since last assessment 
o Assess for any recurrence of AF/AFL/AT  
▪ 
Any reported AFL recurrence will require a 12-lead ECG for ACL 
adjudication 
o Confirm ICM programming parameters 
▪ 
Any programming outside of the defined nominal parameters (Section 7.6) 
prior to a confirmed recurrence of Detectable AF, AT or AFL must be 
entered into the EDC and justification provided. 
▪ 
ICM may be reprogrammed, as needed, to facilitate appropriate arrhythmia 
identification and investigator notification after the subject experiences a 
confirmed recurrence of Detectable AF, AT or AFL. 
• 
Cardiac rhythm as determined by a 12-lead ECG at the time of the assessment (in-person 
assessment only). All 12-lead ECGs for Treatment Subjects will be provided to the Arrhythmia 
Core Laboratory (ACL).   
• 
If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated diminished 
phrenic nerve response and resolution has not been previously demonstrated, complete a 
radiologic examination of the diaphragm 
• 
If there is a clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as the 
baseline scan to assess the dimensions of the PVs. 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the 
data remotely. 
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7.12 Day 180 Assessment 
Type of Assessment: Remote; In-person allowed 
Window: 180 ± 30 Days 
If a COVID-19-related disruption interferes with the performance of this assessment, as much 
data as possible may be collected remotely, in or out of window.  
Subjects will be assessed remotely at Day 180 ± 30 days following the Index Procedure / Rescheduled 
Index Procedure. Any subject who is hospitalized or seen in the office as standard of care at the time 
of the assessment may have their Day 180 assessment performed in-person. 
Study data will be collected at the Day 180 Assessment including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment 
• 
Site staff will confirm ICM programming and successful LATITUDE Clarity transmissions 
since last assessment 
o Assess for any recurrence of AF/AFL/AT  
▪ 
Any reported AFL recurrence will require a 12-lead ECG for ACL 
adjudication 
▪ 
If the investigator determines that the subject has experienced the first 
recurrence after the blanking period of Detectable AF, AFL or AT, upload 
documentation to EDC 
o Confirm ICM programming parameters 
▪ 
Any programming outside of the defined nominal parameters (Section 7.6) 
prior to a confirmed recurrence of Detectable AF, AT or AFL must be 
entered into the EDC and justification provided. 
▪ 
ICM may be reprogrammed, as needed, to facilitate appropriate arrhythmia 
identification and investigator notification after the subject experiences a 
confirmed recurrence of Detectable AF, AT or AFL. 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L) The 
Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
• 
The date, time and communication method(s) used to collect the data remotely. 
7.13 Day 360 Assessment 
Type of Assessment: In-person at investigational site required; remote only for documented 
COVID-19 related disruption. 
Window: 360 ± 30 Days 
If a COVID-19-related disruption interferes with the performance of this assessment:  
• 
As much data as possible may be collected remotely, in or out of window. 
• 
The absence of a 12-lead ECG during a remote assessment is not a protocol deviation.  
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• 
If a radiologic examination is required due to prior diminished phrenic nerve response, an 
inspiration / expiration chest X-ray (CXR) performed in-person or at another healthcare site 
may be substituted. 
Subjects will be assessed at 360 days ± 30 days following the Index Procedure / Rescheduled Index 
Procedure. 
Study data will be collected at the Day 360 Assessment including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment  
• 
Site staff will confirm ICM programming and successful LATITUDE Clarity transmissions since 
last assessment 
o Assess for any recurrence of AF/AFL/AT  
▪ 
Any reported AFL recurrence will require a 12-lead ECG for ACL 
adjudication 
▪ 
If the investigator determines that the subject has experienced the first 
recurrence after the blanking period of Detectable AF, AFL or AT, upload 
documentation to EDC 
o Confirm ICM programming parameters 
▪ 
Any programming outside of the defined nominal parameters (Section 7.6) 
prior to a confirmed recurrence of Detectable AF, AT or AFL must be 
entered into the EDC and justification provided. 
▪ 
ICM may be reprogrammed, as needed, to facilitate appropriate arrhythmia 
identification and investigator notification after the subject experiences a 
confirmed recurrence of Detectable AF, AT or AFL. 
• 
If the post-Index Procedure / Rescheduled Index Procedure fluoroscopy indicated diminished 
phrenic nerve response and resolution has not been previously demonstrated, complete a 
radiologic examination of the diaphragm 
• 
If there is a new clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as 
the baseline scan to assess the dimensions of the PVs. 
• 
Cardiac rhythm as determined by a 12-lead ECG at the time of the assessment (in-person 
assessment only). All 12-lead ECGs for Treatment subjects will be provided to the ACL. 
• 
Quality of Life Measures: 
o The 3-level EuroQol standardized questionnaire of health states (EQ-5D-3L)  
o The Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire (AFEQT) quality of life 
assessments 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the data 
remotely 
At the completion of all components of the Day 360 Assessment a Study Exit CRF will be completed. 
7.14 Re-Ablation Procedures 
7.14.1 Re-Ablation Procedure within the Blanking Period 
For subjects undergoing a first re-ablation procedure within the Blanking Period for Detectable AF, 
AFL or AT, the procedure will be performed by the investigator under the procedures and data 
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requirements of Section 7.7.1, modified to assess and treat only those locations required, and including 
the pre- and post-procedure NIHSS.  
The FARAPOINT PFA Catheter will not be utilized for any re-ablation procedure. If repeat ablation is 
required for CTI-mediated flutter, any commercially available BSC RF catheter will be used.  Such re-
ablation using the methods and devices described in Section 7.7.1 does not constitute a Treatment 
Failure.  
7.14.2 Other Re-Ablation Procedures 
For a second re-ablation during the Blanking Period and for any re-ablation after the Blanking Period, 
any commercially available ablation catheter will be used for re-ablation.  
The FARAPULSE Pulsed Field Ablation System is not permitted to be used for these 
procedures. 
Such re-ablations constitute Treatment Failures, and therefore during such procedures other sites may 
be ablated at Investigator discretion.  
The following data will be collected for these procedures: 
• 
Adverse events 
• 
During re-ablation procedures, a mapping procedure will be performed to characterize the 
reconnection status for each originally treated PV and the PW (if a left-sided re-ablation), and 
the CTI, to characterize lesion durability. 
• 
Limited ablation data. 
7.15 Unscheduled Assessments 
Type of Assessment: Either remote or in-person at investigational site. 
Any unscheduled follow-up assessments for cardiovascular events that occur throughout study 
follow-up will be documented. Study data will be collected including but not limited to: 
• 
Adverse events 
• 
Data regarding the use, changes in or discontinuation of anticoagulation, rate control and / or 
AADs 
• 
Recurrent arrhythmia, cardioversions, ablations, or hospital admissions since last assessment 
• 
Site staff will confirm ICM programming and successful LATITUDE Clarity transmissions 
since last assessment 
o Assess for any recurrence of AF/AFL/AT  
▪ 
Any reported AFL recurrence will require a 12-lead ECG for ACL 
adjudication 
▪ 
If the investigator determines that the subject has experienced the first 
recurrence after the blanking period of Detectable AF, AFL or AT, upload 
documentation to EDC 
o Confirm ICM programming parameters 
▪ 
Any programming outside of the defined nominal parameters (Section 7.6) 
prior to a confirmed recurrence of Detectable AF, AT or AFL must be 
entered into the EDC and justification provided. 
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▪ 
ICM may be reprogrammed, as needed, to facilitate appropriate arrhythmia 
identification and investigator notification after the subject experiences a 
confirmed recurrence of Detectable AF, AT or AFL. 
• 
Cardiac rhythm documentation: 
o At the investigational site: 12-lead ECGs will be collected and provided to the ACL. 
o At another health care site: a record of any ECG should be obtained if available. 
o Remote, not at a health care site: An LUX-Dx manual transmission should be requested. 
• 
If there is a new clinical suspicion of PV stenosis, a cardiac CT or MRI scan of the same type as 
the baseline scan to assess the dimensions of the PVs. 
• 
If data is collected remotely, the date, time and communication method(s) used to collect the 
data remotely. 
7.16 Unforeseen Circumstances 
There may be unforeseen circumstances that occur during the course of the study, such as a natural 
disaster or a global pandemic (e.g., COVID-19) that prevents a subject from participating in study 
assessments during the required follow-up window. While every attempt should be made to avoid 
disruptions in collecting study data, it is important to collect as much data as possible, by any 
available means and from any available resources. This may include obtaining records from an 
outside clinic, hospital or other healthcare facility that is not IRB / EC / REB approved.  
In the event that study data must be collected remotely, every effort should be made to collect the data 
within the study assessment window. Critical data collected during the study includes any device or 
procedure-related adverse events, recurrence of any AF / AT / AFL, and a Cardiac CT or MRI (if PV 
stenosis is suspected). The LUX-Dx will continue to be used to assess the subjects’ heart rhythm. If a 
Cardiac CT or MRI is required because PV stenosis is suspected, the Cardiac CT or MRI – preferably 
using the baseline modality – may be performed at another healthcare facility and the window to 
conduct this test may be extended by up to one month (30 days) following the normal study 
assessment window. 
When such unforeseen circumstances result in a deviation from the requirements of the protocol, the 
deviations will be distinguished from routine protocol deviations and reported separately. 
7.17 Study Completion 
Each Roll-In Subject and Treatment Subject will be followed until the Day 360 Assessment. 
Participation in the study is considered complete upon completion of the Day 360 Assessment. Each 
Attempt Subject will be followed through the Day 30 Assessment following the Index Procedure / 
Rescheduled Index Procedure and then exited from the study. In case of premature termination of the 
study, please refer to Section 20.1 of the Phase 1 ADVANTAGE AF clinical investigational plan. 
Following termination or completion of the study, subjects will be managed according to local 
institution practice. Sites will need to document and complete the “End of Study” CRF to signify 
study completion. 
7.18 Source Documents 
It is preferable that original source documents are maintained, when available. In lieu of original source 
documents, certified copies are required to be maintained. A certified copy is a copy (irrespective of 
the type of media used) of the original record that has been verified (i.e., by a dated signature or by 
generation through a validated process) to have the same information, including data that describe the 
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8.1.2 
Primary Effectiveness Endpoint 
The Primary Effectiveness Endpoint (PEE) is defined in Section 3.4. The definition of the PEE 
remains consistent with the ADVANTAGE AF Phase 1 PEE, apart from the definition of Detectable 
AF, AFL, or AT (Section 23.2), which has been adjusted for recurrence monitoring using an ICM in 
place of standard recurrence monitoring methods.  
The observed one-year treatment success based on standard non-continuous monitoring methods (12-
lead ECG at each follow-up visit, 24-hour Holter every 6 months, regular or scheduled event monitor 
transmissions, and symptom-driven event monitoring) is expected to be higher than what could be 
observed from an ICM, given its capability of continuously monitoring the heart rhythm during the 
entire period of observation. Based on a comparison with data obtained from the CIRCA-DOSE trial 
which included subjects with paroxysmal AF, it has been estimated that an arrhythmia recurrence 
assessment based on ECG, Holter monitoring and symptomatic episodes captured from event 
monitors would lead only to 40.9% sensitivity and 65.3% negative predictive value when compared 
to an ICM19.  
While the value in implementing continuous arrhythmia monitoring post AF ablation is well 
accepted, to date no standards are defined for determining one-year treatment success when using 
ICMs for arrhythmia monitoring, leading to inconsistency in methodology including but not limited 
to, different episode duration cutoffs, variable ICM programming, and inconsistency in symptom-
driven monitoring. The limited number of studies assessing post ablation outcomes with ICM to date 
report variable one-year arrhythmia recurrence rates ranging from 27% to 64%22-32. These studies use 
different arrhythmia duration criteria (from >30 seconds to 24 hours), different timelines for ICM 
insertion in respect to ablation procedure, and different endpoint definitions (recurrence vs burden). 
Accordingly, results obtained from different ablation studies using ICM are heterogeneous and not 
comparable, so they cannot be analyzed collectively to form a hypothesis for the ADVANTAGE 
Phase 2 PEE based on continuous monitoring.  
Alternatively, non-continuous monitoring will be simulated using ICM data to allow for robust 
hypothesis generation. Time periods representing bi-monthly event monitor transmissions and 24-
hour Holter monitor recordings will be selected and reviewed for LUX-Dx detected AF, AFL, and 
AT. The duration and frequency of the time periods will mimic the use of event monitors and Holter 
monitors in ADVANTAGE Phase 1, which is consistent with recommendations set by the 2017 HRS 
consensus statement on AF ablation for monitoring recurrence in persistent atrial fibrillation patients. 
12-lead ECGs will also be used for recurrence monitoring with no change to their contribution to 
Detectable AF, AFL, or AT compared to Phase 1.  
As such, PEE assumptions remain identical to ADVANTAGE Phase 1 (Table 8.1-3). Derivation of 
the expected rate is described in Phase 1 Section 8.1.2. 
A PEE performance goal of 40% has been chosen as it preserves the standard provided by the 2017 
HRS/EHRA/ECAS Expert Consensus document on the minimum chronic acceptable success rate for 
persistent AF at 12-month follow-up:20  
“If minimum chronic success rate is selected as an objective effectiveness endpoint for a 
clinical trial, we recommend that the minimum chronic acceptable success rate for persistent 
AF at 12-month follow-up is 40%.” 
 
 
 
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LUX-Dx data will be used to simulate intermittent arrhythmia monitoring methods consistent with the 
methods used in ADVANTAGE AF Phase 1. Bi-monthly (asymptomatic) event monitor 
transmissions will be simulated by randomly selecting LUX-Dx data from two, 2-minute time 
windows every 30 days starting on the date of the Day 90 assessment. Each 30-day interval contains 
2,592,000 seconds from which 2 seconds will be selected via simple random sampling  and used as 
the starting point for a 2-minute (120 second) window. The first 2-minute window will be removed 
prior to sampling the second 2-minute window to avoid overlapping windows. The sampling seed will 
equal the date of the first subject enrollment..  
Only 2-minute windows occurring after the blanking period will be used for analysis. Thirty-day 
intervals will repeat until an interval contains an in-window Day 360 Assessment, Day 390, or 
subjects’ End of Study date, whichever occurs first. In the final 30-day interval, only 2-minute 
windows occurring on or prior to the in-window Day 360 Assessment, Day 390, or subjects’ End of 
Study date, will be used for analysis. If a 2-minute window occurs on the same day as a scheduled   
study visit (Day 180 or Day 360 Assessment) or on the same day as the simulated Holter patch, then a 
new 2-minute window will be randomly selected to avoid overlapping with the 12-lead ECG 
recording and simulated Holter patch recording.   
Twenty-four (24) hour Holter patches will be simulated by selecting LUX-Dx data from the day 
before the Day 180 and Day 360 Assessments. The day before was selected to avoid overlapping with 
the 12-Lead ECG recordings from each visit. For subjects that had a missed visit for the Day 180 or 
Day 360 assessment, the last day of the subject’s visit window will be used for the simulated Holter 
patch. 
Recurrence will be defined as a stored LUX-Dx AT or AF episode that is adjudicated as containing at 
least 30 seconds of atrial arrhythmia and that overlaps a simulated window by any amount. 
Additionally, all LUX-Dx recorded symptomatic episodes and all 12-lead ECGs will be assessed for 
AF, AFL, or AT recurrence as defined in Protocol Section 23.2. 
8.1.3 
Other Endpoints and Assessments 
The following analyses will also be performed as defined in the referenced sections using descriptive 
statistics: 
• 
Additional Safety Endpoints (Section 3.5.1) 
• 
Additional Effectiveness Endpoints (Section 3.5.2) 
• 
Procedural Assessments (Section 3.5.3) 
• 
Quality of Life Assessments (Section 3.5.4) 
 
8.2 
General Statistical Methods 
8.2.1 
Analysis Sets 
All Attempt and Treatment Subjects will be used for the primary safety endpoint and additional safety 
endpoint analyses, unless otherwise specified. All LUX-Dx monitored Treatment Subjects will be 
used for the primary effectiveness endpoint and additional effectiveness endpoint analyses, unless 
otherwise specified. Subjects who do not receive a LUX-Dx device or do not establish a LATITUDE 
Clarity connection by the end of the effectiveness evaluation period will not be included in the main 
effectiveness endpoints. Effectiveness endpoints will be summarized separately for these subjects as 
binary rates or a listing. 
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Endpoint data will be summarized separately for Roll-In Subjects. Roll-In Subjects will not be used in 
the main endpoint analyses. 
8.2.2 
Control of Systematic Error / Bias 
Control and reduction of potential bias associated with a single-arm study design have been addressed 
by a series of measures including but not limited to: 
• 
Patients meeting the eligibility criteria and signing the ICF will be eligible for sequential 
enrollment in the study. 
• 
ECG recurrence data for Non-Roll-In Treatment subjects reported by the site from 12-Lead 
ECGs will be evaluated by a third-party Arrhythmia Core Laboratory according to 
standardized protocols. 
• 
LUX-Dx episodes will be adjudicated to verify recurrence meeting the definition of 
Detectable AF, AFL or AT.   
• 
Cardiac MRI / CT images utilized for assessing potential PV stenosis will be evaluated by a 
third-party Cardiac Imaging Core Laboratory according to standardized protocols. 
• 
The use of a comprehensive set of study procedures as defined in the protocol which ensure 
consistent patient management. 
• 
Comprehensive site and data monitoring to ensure accurate and complete recording of study 
data. 
• 
The use of an independent Clinical Events Committee (Phase 1 Protocol Section 19.2Error! 
Reference source not found.) will review and adjudicate all potential SAEs and primary 
safety outcomes. 
• 
Creation of a complete Clinical Study Report and full dataset to allow scientific and clinical 
reviewers to independently assess potential error and bias. 
• 
To avoid any center effect and bias, no center will be authorized to enroll more than 33 
Treatment Subjects (13% of the total planned enrollment of  258 Treatment Subjects). 
8.2.3 
Study Success and Control of Type I Error 
The Primary Safety Endpoint and Primary Effectiveness Endpoint must pass in order to achieve study 
success. Both primary endpoints will be tested at a significance level of 2.5% while still maintaining 
the overall Type I error level at no greater than 2.5%. This follows the methodology of the 
Intersection-Union Test (IUT).  
8.3 
Data Analyses 
8.3.1 
Roll-In Subject Analyses 
The stipulated analyses for Roll-In Subjects will be summarized with descriptive statistics. Endpoint 
data for Roll-In Subjects will be summarized but no hypothesis testing, subgroups, tipping point, or 
multivariate analyses will be performed. Recurrence data from 12-Lead ECGs for Roll-in subjects 
will not be evaluated by a third-party. Site assessment of the rhythm found on the 12-Lead ECG will 
be captured in the EDC system and used to identify recurrence of AF, AFL, or AT for effectiveness 
endpoint evaluations. 
8.3.2 
Interim Analyses  
No formal interim analyses are planned for the purpose of stopping the study early for declaring 
success or futility. Analysis of each endpoint will be performed for regulatory submission when all 
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applicable data for that endpoint has been collected or based on specific geographic requirementsError! 
Bookmark not defined.. The ADVANTAGE AF Study may be used to satisfy the requirements of multiple 
regulatory bodies. Details on these analyses will be included in the ADVANTAGE AF SAP when 
available. 
8.3.3 
Sensitivity Analyses 
8.3.3.1 
Sensitivity to Missing Data 
Tipping point analyses will be performed for the PSE and PEE to evaluate the impact of missing data 
due to subjects exiting the study prior to the Day 90 Assessment for the PSE or prior to the Day 360 
Assessment for the PEE.  
8.3.3.2 
Sensitivity of Effectivness to Other Ablations in the Left Atrium 
The impact of allowing ablation in the left atrium for concomitant arrhythmias (when deemed 
clinically necessary) without constituting Acute Procedural Failure will be assessed for the PEE. The 
PEE will be calculated counting subjects who received said ablations (excluding ablation of an 
accessory pathway or atypical AVNRT) as Treatment Failures.   
8.3.3.3 
Sensitivity of Effectiveness to Amiodarone Use Post Ablation Procedure 
The impact of allowing Amiodarone use to the end of the blanking period without constituting 
Chronic Treatment Failure will be assessed for the PEE. The PEE will be calculated counting subjects 
with Amiodarone use beyond 30 days after the Index Ablation Procedure as Treatment Failures.   
8.3.3.4 
Sensitivity of Effectiveness to the timing of AAD discontinuation 
The impact of allowing the use of Non-failed Class I/III AADs and Amiodarone through the Day 90 
Assessment (or Day 104 when Day 90 Assessment is completed late or missed) without constituting 
Chronic Treatment Failure will be assessed for the PEE. The PEE will be calculated counting subjects 
with any Non-Failed Class I/III AAD or Amiodarone use after the blanking period as Treatment 
Failures. 
8.3.3.5 
Sensitivity of Effectness to the timing of Day 360 Assessment 
For the PEE, if the Day 360 Assessment is completed late (after Day 390) only events that occurred 
within window count as Treatment Failures, as described in Appendix A of the ADVANTAGE AF 
SAP. In this sensitivity analysis, the PEE will be calculated counting events that occur outside of the 
visit window (after Day 390) as Treatment Failures. 
8.3.3.6 
Sensitivity of Effectiveness to AT/AFL Detectection Method (Tipping Point Analysis) 
A tipping point analysis will be performed for the PEE to assess the impact of using the LUX-Dx AT 
algorithm with a minimum duration setting of 4 hours to detect AT and AFL events. All Treatment 
subjects with PEE Success will be one by one considered to have had an undetected AT/AFL event 
counting as a PEE failure. The number of subjects that would need to have had an undetected AT/AFL 
event to fail the PEE will be considered the tipping point. The probability of the tipping point occurring 
will be calculated based on the rate of PEE Failures observed in ADVANTAGE AF Phase 1 that were 
due to AT or AFL recurrence recorded by Holter or Event Monitor with no other mode of failure. 
Additional details for this analysis will be included in the Statistical Analysis Plan. 
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8.3.3.7 
Sensitivity of Effectiveness to LUX-Dx S-ECG Storage 
The impact of the LUX-Dx S-ECG storage capacity on the determination of Detectable AF, AFL, and 
AT will be assessed for the PEE. LUX-Dx detected AT and AF episodes or patient-triggered 
symptomatic episodes without a stored S-ECG will be considered to have confirmed AF, AFL, or AT 
and included in the determination of Detectable AF, AFL, and AT.  
8.3.4 
Subgroup Analyses 
Analyses will be performed to evaluate whether any significantly different effects exist in the Primary 
Safety Endpoint or Primary Effectiveness Endpoint within subgroups of subjects. The list of covariates 
(with applicable subgroups in parentheses) will include at least the following: 
• 
Subject demographics (e.g., age [e.g. age >=65 vs. <65, Medicare eligible], gender) 
• 
Subject baseline characteristics (e.g., LVEF, cardioversion history, BMI, LA diameter, and 
years since AF diagnosis) 
• 
Index Procedure lesion sets 
o PV + LAPW ablation alone versus PV + LAPW plus additional ablations 
o CTI ablation versus no CTI ablation 
• 
Operator learning curve (e.g. number of prior procedures completed by operator at time of 
procedure, counting at a minimum, the procedures from ADVANTAGE AF Phase 1 and Phase 
2) 
• 
Mapping of the PW during Index Procedure 
Additional covariates for the Primary Effectiveness Endpoint only include: 
• 
Amiodarone use post Index Procedure versus no Amiodarone use post Index Procedure. 
• 
LUX-Dx model (LUX-Dx II+ [M312] vs LUX-Dx [M301] or LUX-Dx II [M302]) 
Each subgroup covariate will be included as a single independent variable in a logistic regression model 
with the endpoint outcome as the dependent variable and a test for significance at the 15% level will be 
performed.  
In addition to subgroup analyses, descriptive statistics of subject demographic and baseline 
characteristics will be presented for each subgroup listed in this section. 
8.3.5 
Center Pooling Analysis 
Center-to-center heterogeneity will be assessed for the primary endpoints. Descriptive statistics for 
each primary endpoint will be presented by site and heterogeneity will be tested with a Chi-square 
test, treating site as a fixed effect. If sites are not deemed poolable in the initial Chi-square analysis, 
poolability analysis will be reperformed by treating site as a random effect. A significance level of 
15% will be used for each test. Sites with less than five Non Roll-in Treatment and Attempt subjects 
will be excluded from statistical tests for heterogeneity on the Primary Safety Endpoint, and sites with 
less than five Non Roll-in, LUX-Dx monitored Treatment subjects will be excluded from tests for 
heterogeneity on the Primary Effectiveness Endpoint. 
8.3.6 
Treatment Success Rate by Arrhythmia Detection Method 
PersAF Treatment Success rates through Day 360 Assessment will be compared between 
ADVANTAGE AF Phase 1 and Phase 2 Treatment Subjects to assess differences in chronic success 
when using the continuous monitoring from an ICM to simulate non-continuous monitoring for 
recurrence compared to standard assessment based on true Holter monitoring and periodic 
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transmissions from event monitors. A propensity score analysis utilizing inverse probability of 
treatment weights (IPTW) will be used to estimate the absolute difference in PersAF Treatment 
Success rates between detection groups (ICM vs. Standard) while minimizing the effects of 
confounding variables. Details of this analysis will be included in the Appendix A of the 
ADVANTAGE AF SAP. 
8.3.7 
Multivariable Analyses 
For the Primary Safety Endpoint and Primary Effectiveness Endpoint, univariable analyses of the 
following covariates will be performed, and any found to be significantly associated with the outcome 
at the 0.15 alpha level will be included as covariates in a multivariable regression model. Backward 
selection with 0.15 alpha level stay criterion will be used to determine the final multivariable model.  
The list of baseline covariates includes, but is not necessarily limited to: 
• 
Subject demographics (e.g., age, gender) 
• 
Subject baseline characteristics (e.g., LVEF, cardioversion history, BMI, LA diameter, and 
years since AF diagnosis) 
• 
Index Procedure lesion sets 
o PVI + LAPW ablation alone versus PVI + LAPW plus additional ablations 
o CTI ablation versus no CTI ablation 
• 
Operator learning curve (e.g., number of prior procedures completed by operator at time of 
procedure, counting at a minimum, the procedures from ADVANTAGE AF Phase 1 and 
Phase 2) 
• 
Mapping of the PW during Index Procedure 
Additional covariates for the Primary Effectiveness Endpoint only include: 
o Amiodarone use post Index Procedure versus no Amiodarone use post Index 
Procedure 
o LUX-Dx model (LUX-Dx II+ [M312] vs LUX-Dx [M301] or LUX-Dx II [M302]) 
8.3.8 
Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended Phase 2 Statistical Analysis Plan approved prior to performing the 
analyses. Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the deviation. 
9 Health Economics Outcomes 
A formal health economics analysis may be completed as part of this trial study, given meaningful 
clinical results are obtained. This will take into consideration complication rates, quality of life, and 
resource utilization. The EQ-5D-3L, a generic quality of life measure, will be used to assess health 
utilities. Costs associated with the health care utilization measures may be estimated at all sites. These 
inputs may be used in health economics analysis performed. 
10 Data Management 
Data management processes and requirements remain the same as Phase 1 of the ADVANTAGE AF 
study and can be referenced in Section 10 of the Phase 1 clinical investigational plan.  
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11 Core Laboratories and Independent Assessment 
11.1   Arrhythmia Core Laboratory 
Specified arrhythmic events will be analyzed by an ACL to determine if the episodes are associated 
with Detectable AF, AFL or AT.  
During the ADVANTAGE AF Study, more than one ACL may be utilized to optimize equipment 
availability, vendor capacity or other factors as determined by BSC. Each vendor utilized will be 
described in the final study report. 
11.1.1 Study ECGs 
To ensure objective assessment of rhythm monitoring data, the following 12-lead ECG tracings for 
Non Roll-in Treatment subjects will be reviewed by the ACL and/or CEC and included as study data: 
• 
ECGs obtained during the following assessments: Day 90 and Day 360 
• 
ECGs submitted during monitoring and adjudication of adverse events 
• 
ECGs submitted during the evaluation of potential arrhythmias during the effectiveness 
evaluation period. 
11.2 LUX-Dx Recordings 
Atrial arrhythmia episodes (asymptomatic and symptomatic) captured by the LUX-Dx ICM will be 
analyzed by BeatLogic Core Lab Adjudicator Tool for atrial arrhythmia rhythm determination, 
including episodes captured by LUX-Dx during the pre-defined time periods for the Primary 
Effectiveness Endpoint. Specified arrhythmic events recorded by LUX-Dx ICM may additionally be 
analyzed by independent experts for rhythm determination. The ADVANTAGE AF Phase 2 
Statistical Analysis Plan will define the formal process for adjudication of recurrence episodes 
collected by LUX-Dx for the study for endpoint analyses. 
11.3 Cardiac Imaging Core Laboratory 
A qualified CICL will be established to receive, review, and assess any cardiac MRIs and CTs 
obtained for the evaluation of potential PV stenosis.  
Baseline cardiac MRIs and CTs will only be read by the CICL if subsequent events result in follow-
up imaging for the assessment of potential PV stenosis. 
Pulmonary Vein Dimensions 
Treated veins to be assessed will have the baseline and post-ablation assessments of standardized 
diameters (See definition of PV Diameter in Section 23.2). 
Cardiac Imaging Data Review and Transmission 
The CICL will analyze PV dimensions, calculate changes in dimensions, make available the primary 
data for review and transmit the PV dimensional analyses of each imaging study to the Sponsor for 
inclusion in the study dataset. 
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will be made regarding whether a new ICF needs to be obtained from subjects who provided consent, 
using a previously approved ICF.  
Annual IRB/EC/REB approval and renewals will be obtained throughout the duration of the study as 
required by applicable local/country laws or regulations or IRB/EC/REB requirements. Copies of the 
study reports and the IRB/EC/REB continuance of approval must be provided to the sponsor. any 
amendment to the protocol which may impact the conduct of the study and patient safety, including 
changes of study objectives, study design, patient population, sample sizes, study procedures, will 
require review and approval by the IRB/EC/REB before the changes are implemented to the study.  
All changes to the ICF will be IRB/EC/REB approved; a determination will be made regarding 
whether a new ICF needs to be obtained from subjects who provided consent, using a previously 
approved ICF.  
 
15 Monitoring 
Monitoring requirements remain the same as Phase 1 of the ADVANTAGE AF study and can be 
referenced in Section 15 of the Phase 1 clinical investigational plan. 
16 Potential Risks and Benefits 
16.1 Anticipated Adverse Events  
Based upon the current literature, prior reports on adverse events with an ablation catheter, and available 
data on clinical use of the FARAPULSE PFA System, below is an alphabetical list of the possible 
anticipated adverse events and possible adverse device effects associated with ablation with the 
FARAPULSE PFA System for the treatment of PersAF and adjunctive ablation of the CTI for isthmus-
mediated AFL. The occurrence of any of the listed events could lead to harm, the need for intervention, 
or prolonged hospitalization for the subject.  
These anticipated events may be caused by or associated with the proposed use of the investigational 
devices and other devices, the failure, misuse or malfunction of the investigational devices or other 
devices, or the related procedures stipulated by this protocol or associated with this clinical study. There 
may also be additional risks which are unknown at this time.  
• 
Access site complications (e.g., hematoma, fistula, pseudo-aneurysm, laceration, bleeding) 
potentially requiring surgical intervention 
• 
Allergic reaction or fever resulting from contact with catheters or drugs 
• 
Anemia 
• 
Arrhythmia, potentially requiring cardioversion, defibrillation, or rhythm management device 
• 
Arteriovenous fistulah 
• 
Back pain 
• 
Bed sores 
• 
Bleeding, hematoma, hemorrhage, or aneurysm at vascular access sites 
• 
Blood pressure changes including hypotension or hypertension 
• 
Cardiac tamponade or perforation 
• 
Cardiac arrest or cardiac failure  
• 
Cardiogenic shock 
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• 
Catheter entrapment/impingement potentially requiring endovascular or surgical intervention 
• 
Conduction system injury, either transient or permanent, potentially requiring pacemaker 
insertion 
• 
Coronary artery or vein injury 
• 
Damage to cardiac structure 
• 
Death 
• 
Esophageal injury, ulcer, or fistula 
• 
Gastric motility / pyloric spasm disorders 
• 
Harmful large muscular contraction 
• 
Heart failure 
• 
Hemodynamic compromise 
• 
Hemopericardium 
• 
Hemoperitoneum 
• 
Hemothorax 
• 
Local infection, systemic infection and / or sepsis 
• 
Muscle contractions due to electric stimulation 
• 
Myocardial infarction / ischemia 
• 
Nerve damage 
• 
Organ failure 
• 
Pain 
• 
Perforation (e.g., of diaphragm, liver, and lung). 
• 
Pericardial effusion 
• 
Pericarditis 
• 
Peritonitis 
• 
Phrenic nerve injury with potential paralysis of the diaphragm and breathing impairment 
• 
Pneumomediastinum 
• 
Pneumopericardium 
• 
Pneumoperitoneum 
• 
Pneumothorax 
• 
Procedural delay 
• 
PV injury, perforation, or stenosis 
• 
Respiratory Distress 
• 
Risk of cancer or birth defect / harm to fetus from x-ray exposure 
• 
Skin burns / irritation from X-ray exposure  
• 
Stroke / TIA 
• 
Surgical procedure to correct any anticipated AE 
• 
Thrombosis 
• 
Vessel damage, dissection, or occlusion. 
• 
Vessel obstruction due to thrombus, debris, introduction of gas, or vascular spasm 
 
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16.2 Anticipated Adverse Events – LUX-Dx ICM 
As part of study participation, subjects must have a commercially available LUX-Dx inserted for 
arrhythmia monitoring. Potential adverse events related to the insertion of the device are provided in 
the User’s Manual. These risks for subjects pariticpating in the ADVANTAGE AF study do not differ 
from those subjects with a LUX-Dx ICM insertion not participating in the trial.  
16.3 Risks Associated with the Study Device(s)  
Benchtop studies, pre-clinical research, feasibility studies, and CE Mark clinical studies have 
demonstrated that the FARAPULSE PFA System is safe for human use. Potential risks have been 
evaluated and mitigation strategies have been implemented to reduce potential risks to acceptable 
levels. 
16.4 Risks associated with Participation in the Clinical Study 
The investigational aspects related to the use of the FARAPOINT Catheter in the ADVANTAGE AF 
Phase 2 study may increase the risk of coronary artery spasm. There may also be additional risks 
which are unknown at this time.  
16.5 Possible Interactions with Concomitant Medical Treatments 
Anti-arrhythmic and anticoagulant medications included in ADVANTAGE AF procedures are all 
approved for their indicated uses in the relevant geography. Therefore, there is no foreseen increased 
risk to subjects for participating in the ADVANTAGE AF Study. 
16.6 Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, ensuring that an interventional 
cardiologist and cardiac catheterization laboratory are available, adherence to subject selection 
criteria, close monitoring of the subject's physiologic status during research procedures and / or 
follow-ups and by promptly supplying BSC with all pertinent information required by this protocol. 
The use of nitroglycerin as described in Section 7.7.2.5 is intended to minimize the risk of harm from 
vascular spasm related to the investigational use of the FARAPOINT Catheter. Additionally, sites 
should ensure availability of co-oximetry to perform the diagnosis of methemoglobinemia and 
methylene blue to potentially treat the condition for subjects undergoing the nitroglycerin workflow 
when treated with the FARAPOINT PFA Catheter.  
16.7 Anticipated Benefits 
Subjects may or may not receive any benefit from participating in the ADVANTAGE AF Study as 
compared to the current standard of care received for treatment of PersAF. Potential benefits of the 
FARAPULSE PFA System for the subject may include the following: 
• 
Complete or partial reduction in symptoms related to PersAF 
• 
Complete or partial reduction in the number of cardioversions, medications a subject is taking, 
and in the number of hospitalizations related to PersAF 
• 
Treatment using an investigational device which has demonstrated the ability to isolate PVs 
and the PW endocardially, to reduce the subsequent occurrence of symptomatic AF in treated 
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subjects and potentially to reduce the risk for severe ablation complications associated with 
thermal ablation such as phrenic nerve palsy or atrio-esophageal fistula. 
16.8 Risk to Benefit Rationale 
Risk management activities, including Hazard Analyses (HA) and Failure Mode Effects Analyses 
(FMEA), have been performed on the FARAPULSE PFA System and its components to identify and 
analyze known and foreseeable hazards (in both normal and fault conditions) and reasonably 
foreseeable sequences or combinations of events that could result from using this product and the 
risks associated with each hazard. Mitigations have been implemented in the design, processes, and / 
or labeling and directions for use of the product to reduce the residual risk of each hazard as 
necessary and practicable. The HA has been reviewed and approved and the remaining risks are 
acceptable when weighed against the anticipated benefits to the subject. 
17 Safety Reporting 
Safety, device deficiency, and death reporting requirements and definitions remain the same as Phase 
1 of the ADVANTAGE AF study and can be referenced in Section 17 of the Phase 1 clinical 
investigational plan.  
17.1 Reportable Events by Investigator to BSC 
In addition to those events defined in Section 17.1 of the Phase 1 ADVANTAGE AF study, it is the 
responsibility of the Investigator to assess and report to BSC any event which occurs in any of 
following categories: 
• 
The occurrence of ST elevation or clinical signs of ischemia or injury for those subjects 
receiving treatment for CTI-mediated AFL with the FARAPOINT Catheter as a component 
of the FARAPULSE PFA System. 
• 
All study procedure related events, related to the LUX-Dx ICM insertion procedure. 
The start of the FARAPULSE™ Index study procedure is defined as the point in which the 
investigational device is inserted into the subject’s body.  
 
 
17.2 Investigator Reporting Requirements 
In addition to those events defined in Section 17.4 and Table 17.4-1 of Phase 1 of the ADVANTAGE 
AF study, the following must be reported as described in Table 17.2-1 of Phase 2 of the 
ADVANTAGE AF study. 
 
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21 Study Registration and Results 
Study registration and results requirements remain the same as Phase 1 of the ADVANTAGE AF 
study and can be referenced in Section 21 of the Phase 1 clinical investigational plan.  
22 Reimbursement and Compensation for Subjects 
Reimbursement and subject compensation requirements remain the same as Phase 1 of the 
ADVANTAGE AF study and can be referenced in Section 22 of the Phase 1 clinical investigational 
plan.  
23 Abbreviations and Definitions  
23.1 Abbreviations and Acronyms 
 
Table 23.1-1: Abbreviations and Acronyms 
3D 
Three dimensional 
AAD 
Antiarrhythmic drug 
ACL 
Arrhythmia Core Laboratory 
ACT 
Activated clotting time 
ADE 
Adverse Device Effect 
AE 
Adverse event 
AF 
Atrial fibrillation 
AFEQT 
Atrial Fibrillation Effect on QualiTy-of-Life Questionnaire 
AFL 
Atrial flutter 
AT 
Atrial tachycardia 
AVNRT 
Atrioventricular nodal reentrant tachycardia 
BDB 
Bidirectional block 
BMI 
Body Mass Index 
BSC 
Boston Scientific Corporation (Sponsor) 
BUN 
Blood urea nitrogen 
CBA 
Cryoballoon ablation 
CEC 
Clinical Events Committee 
CHA2DS2-VASc  
A clinical prediction rule for stroke 
CHF 
Congestive heart failure 
CICL 
Cardiac Imaging Core Laboratory 
CIP 
Clinical Investigation Plan (synonymous with study protocol) 
COVID-19 
COrona VIrus Disease 2019: an illness caused by SARS-CoV-2 
CPS 
Chronic Procedural Success 
CRF 
Includes CRF (case report form) and eCRF (electronic CRF) 
CT 
Computed tomography 
CTI 
Cavo-tricuspid isthmus 
CXR 
Chest X-ray 
DOAC 
Direct oral anticoagulant 
DW, DWI 
Diffusion weighted, Diffusion weighted image 
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ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EM 
Event monitor (any of several hardware modalities) 
EQ-5D-3L 
The 3-level EuroQol standardized questionnaire of health states 
FDA 
Food and Drug Administration 
HCP 
Health care personnel 
HCT 
Hematocrit 
HGB 
Hemoglobin 
Holter 
Holter monitor 
ICE 
Intracardiac echocardiography 
ICF 
Informed consent form 
INR 
International normalized ratio 
IRB / EC / REB 
Institutional Review Board / Ethics Committee / Research Ethics Board 
IRE 
Irreversible electroporation 
ITT 
Intent(ion)-to-Treat 
IVC 
Inferior vena cava 
LA 
Left atrium or left atrial 
LAPW 
Left atrial posterior wall 
LBBB 
Left bundle branch block 
LTFU 
Lost-to-follow-up 
MITT 
Modified Intent(ion)-to-Treat 
MRI 
Magnetic resonance imaging 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association 
PAF 
Paroxysmal atrial fibrillation 
PersAF 
Persistent atrial fibrillation 
PFA 
Pulsed field ablation 
PP 
Per Protocol 
PV 
Pulmonary vein 
PVI  
Pulmonary vein isolation 
PW 
Posterior wall 
PWI 
Posterior wall isolation 
RFA 
Radiofrequency ablation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious adverse event  
SOC 
Standard of care 
TEE 
Transesophageal echocardiography 
TIA 
Transient ischemic attack 
TSF 
Technical Source Form (see Section 10.3 of ADVANTAGE AF – Phase 1 
protocol) 
TTE 
Transthoracic echocardiography 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
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23.2 Definitions 
Protocol terms not otherwise defined in the protocol are defined in Table 23.2-1:  
Table 23.2-1: Definitions 
Term 
Definition 
AF, AFL, and AT 
Burden 
The proportion of time spent in atrial arrhythmia determined by the ratio 
of the total duration of LUX-Dx detected AF and AT episodes 
adjudicated as true AF, AFL, or AT divided by the total follow-up 
duration less the duration of AF and AT episodes without a stored ECG 
to analyze. Adjudication of episodes will be described in the Statistical 
Analysis Plan.  
Acute Procedural 
Success 
 Defined in Section 3.4.1.  
Antiarrhythmic Drugs, 
Class I and III 
Class I / III AADs are those pharmaceutical agents approved or used in 
the relevant jurisdiction for the treatment of cardiac arrhythmia. For the 
ADVANTAGE AF Study, Class I and III AADs include but are not 
limited to: 
• 
Class I, sodium channel blockers: disopyramide, flecainide, 
procainamide, propafenone, quinidine. 
• 
Class III, potassium channel blockers: amiodarone, dofetilide, 
dronedarone, sotalol. 
Should other Class I or III AADs become approved or used in the 
relevant jurisdiction for the treatment of cardiac arrhythmia during the 
ADVANTAGE AF Study, they will be considered as Class I / III AADs 
for this protocol. 
Attempt Subjects 
Attempt Subjects are defined in Section 6.6.4 of ADVANTAGE Phase 
1 protocol. 
BeatLogic 
The BeatLogic Core Lab Adjudicator Tool (Adjudicator Tool) is a 
software component (ECG Classification system) of the BodyGuardian 
Remote Monitoring System (BGRMS; K192732). The BeatLogic 
software component detects and identifies various rhythms. The 
Adjudicator Tool applies the BeatLogic software algorithm to ECGs 
recorded by the LUX-Dx Insertable Cardiac Monitor (ICM) and 
classifies each episode as atrial arrhythmia or non-atrial arrhythmia. 
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Term 
Definition 
Blanking Period 
An interval in which recurrent AF, AFL or AT, cardioversion or a first 
re-ablation do not constitute Treatment Failure beginning on Day 0 and 
running for 90 days thereafter. 
• 
The Blanking Period has no impact on the assessment of AEs. 
• 
For subjects with only an Index Procedure, the Blanking Period 
will be Day 0 to Day 90 inclusive. 
• 
For subjects who require a Rescheduled Index Procedure, the 
Blanking Period will be the Study Day of the Rescheduled Index 
Procedure (Day 0) plus 90 days inclusive 
• 
For subjects treated with a Non-Failed AAD during the Blanking 
Period, a Treatment Failure due to the use of that drug only occurs 
if there is continued use of that drug following the earlier of either 
the Day 90 visit or Day 104.  
(Persistent AF) Chronic 
Success 
 Defined in Section 3.4.2.  
Composite Serious 
Adverse Events 
Composite Serious Adverse Events are defined in Section 3.3. 
COVID-19 Related 
Disruptions 
A disruption to any study procedure resulting directly or indirectly from 
the COVID 19 pandemic, including but not limited to subject illness, 
study site restrictions and limitations, shipping / manufacturing 
interruptions, significant changes in regulatory guidance and / or 
governmental restrictions on travel, association, and the prioritization of 
healthcare resources. 
Dates 
• 
Consent Date: The date a subject signs the ICF. 
• 
Exit Date: The date on which a subject’s study participation ends. 
• 
Onset Date: The date on which a condition or AE begins. 
• 
Start Date: Day 0, the date of the Index Procedure or Rescheduled 
Index Procedure 
Day (or Study Day) 
A Day is an enumerated day of follow-up that begins on an Enrolled 
Subject’s Start Date (Day 0). 
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Term 
Definition 
Detectable AF, AFL, or 
AT 
Detectable AF, AFL or AT is an episode of AF, AFL or AT which: 
• 
Is recorded for review on a LUX-Dx ICM and meets any of the 
following criteria: 
o Adjudicated symptomatic (patient initiated) recording that 
contains ≥ 30 seconds of continuous atrial arrhythmia.  
o Adjudicated AF or AT episode captured by LUX-Dx that 
contains at least 30 seconds of atrial arrhythmia and 
overlaps a simulated bi-monthly, 2 minute event monitor 
transmission period.  
o Adjudicated AF or AT episode captured by LUX-Dx that  
contains at least 30 seconds of atrial arrhythmia and 
overlaps a simulated 24 hour holter period occurring the day 
before the Day 180 and Day 360 Assessments (or last day of 
respective visit window if visit(s) is missed) 8. 
• 
Continuous AF, AFL or AT for the entirety of a 12 lead ECG if the 
continuous interpretable signal is 10 seconds or longer 
 
• 
Exclusions:  
o CTI isthmus-dependent AFL if the subject did not have a 
CTI ablation with the FARAPOINT PFA Catheter  
o Arrhythmias recorded on other devices, including 
implantable monitors and consumer wearables, not specified 
in the ADVANTAGE AF Study procedures 
Failed AAD 
Failed AADs include any and all Class I / III AAD determined at the 
time of enrollment to have been failed for effectiveness or intolerance.  
Failed AADs do not include Class I / III AADs determined at the time of 
enrollment solely to be contraindicated. 
Failed AADs must be established as part of the Baseline Assessment for 
agent, type of failure (arrhythmia recurrence or AAD intolerance) and 
the maximum failed dose (the total daily dose at which such failure 
occurred).  
Intent Subjects 
Intent Subjects are defined in Section 6.6.3 of the ADVANTAGE Phase 
1 Protocol. 
Non-Failed AAD 
A Non-Failed AAD is: 
• 
Any Class I / III AAD not established at the Baseline Assessment 
as a Failed AAD 
• 
Any Failed AAD used after Day 90 at a daily dose exceeding the 
maximum failed dose established at the Baseline Assessment 
 
8 Day prior to the Day 180 and Day 360 visits was selected to prevent overlap in the rhythm captured by the 
visit-required 12-lead ECG. 
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Term 
Definition 
Persistent atrial 
fibrillation 
PersAF is defined as continuous AF that is sustained beyond 7 days, but 
not greater than 12 months duration. 
Pulmonary vein 
dimensions 
For the purpose of assessing potential PV stenosis: 
• 
PV dimensions will be measured in two roughly orthogonal 
diameters approximating the longest and shortest diameters at the 
plane of measurement.  
• 
The measured PV diameter is defined as the geometric mean of 
these 2 measurements.  
• 
The PV cross-sectional area is computed using the formula for 
area of an ellipse, where the longest and shortest axis 
measurements of the PV diameter serve as the major and minor 
axes of the ellipse, using half of each axis diameter as the radii for 
calculation. 
Roll-In Subjects 
Roll-In Subjects are defined in Section 4.1.1, Section 4.2 and 
ADVANTAGE Phase 1 Protocol Section 6.6.2. 
Severe COVID-19 
Subjects 
Any study subject who contracts COVID-19 infection during study 
participation that: 
• 
Requires supplemental oxygen, positive pressure ventilation, and / 
or intubation OR  
• 
Is associated with any medically serious sequelae of COVID 19, 
including but not limited to new onset cardiac arrhythmia, heart 
failure, myocarditis, neurologic dysfunction or other organ 
dysfunction, or thromboembolic disease. 
Such subjects will be initially defined by the Investigator and confirmed 
by the CEC. The Onset Date will be the date of symptom onset in a 
subsequently clinically confirmed case of COVID-19 infection. 
Source data 
Ref: ISO 14155 
All information in original records, certified copies of original records of 
clinical findings, observations, or other activities in a clinical 
investigation, necessary for the reconstruction and evaluation of the 
clinical investigation This includes source data initially recorded in an 
electronic format. 
Source document 
Ref: ISO 14155 
Original or certified copy of printed, optical, or electronic document 
containing source data, including TSFs. 
Treatment Failure 
Treatment Failure is the absence of Treatment Success due to one or 
more protocol-stipulated reasons. 
Treatment Subjects 
Treatment Subjects are defined in Section 6.6.5 of the ADVANTAGE 
Phase 1 Protocol. 
Treatment Success 
Treatment Success is defined in Section 3.4 
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Term 
Definition 
Vulnerable Subject 
Ref: ISO 14155 
 
Individuals who are unable to fully understand all aspects of the 
investigation that are relevant to the decision to participate, or who 
could be manipulated or unduly influenced as a result of a compromised 
position, expectation of benefits or fear of retaliatory response 
 
 
 
24 
Bibliography – ADVANTAGE AF Phase 2 
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9. Candeias R, Adragcao P, Cavaco D, et al. Atrial fibrillation ablation: importance of 
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12. Kim SH, Oh YS, Choi Y, et al. Long-Term Efficacy of Prophylactic Cavotricuspid Isthmus 
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13. Pontoppidan J, Nielsen JC, Poulsen SH, et al. Prophylactic cavotricuspid isthmus block 
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14. Shah DC, Sunthorn H, Burri H, Gentil-Baron P. Evaluation of an individualized strategy of 
cavotricuspid isthmus ablation as an adjunct to atrial fibrillation ablation. J Cardiovasc 
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15. Yamaji H, Higashiya S, Murakami T, et al. Rates of atrial flutter occurrence and 
cavotricuspid isthmus reconduction after prophylactic isthmus ablation performed during 
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Interv Card Electrophysiol. 2021. 
16. Tohoku S, Fukunaga M, Nagashima M, et al. Clinical impact of eliminating nonpulmonary 
vein triggers of atrial fibrillation and nonpulmonary vein premature atrial contractions at 
initial ablation for persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2021;32(2):224-
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17. BSC. CS1796 Rev A, PersAFOne II Interim Progress Report. 2022. 
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19. Aguilar M.  at al. Influence of Monitoring Strategy on Assessment of Ablation Success and 
Postablation Atrial Fibrillation Burden Assessment: Implications for Practice and Clinical 
Trial Design. Circulation 2022; 145:21-30. 
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expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart 
Rhythm. 2017;14(10):e275-e444. 
21. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 
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Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of 
Thoracic Surgeons. Circulation. 2019;140(2):e125-e151. 
22. Schiavone,M, Gasperetti A, Montemeralo E., et al. Long-term comparisons of atrial 
fibrillation ablation outcomes with a cryoballoon or laser-balloon: A propensity-matched 
analysis based on continuous rhythm monitoring. Hellenic J Cardiol . 2022 May-Jun;65:1-7. 
23. Baimbetov AK; Bizahanov K, Jukenova AM, et al. Comparative Effectiveness and Safety of 
Cryoablation Versus Radiofrequency Ablation Treatments for Persistent Atrial Fibrillation. 
Am J Cardiol. 2022 Dec 1;184:22-30. 
24. Rovaris G, Ciconte G, Schiavone M. et al Second-generation laser balloon ablation for the 
treatment of atrial fibrillation assessed by continuous rhythm monitoring: the LIGHT-AF 
study. Europace. 2021 Sep 8;23(9):1380-1390. 
25. Gessler N, Willems S, Steven D et al. Supervised Obesity Reduction Trial for AF ablation 
patients: results from the SORT-AF trial. Europace. 2021 Oct 9;23(10):1548-1558. 
26. Dulai R, Sulke N, Furniss S, et al. The effect of second-generation cryoablation without 
electrical mapping in persistent AF using continuous monitoring. J Interv Card 
Electrophysiol. 2021 Mar;60(2):175-182. 
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27. Forkmann M, Schwab C, Edler D, et al. Characteristics of early recurrences detected by 
continuous cardiac monitoring influencing the long-term outcome after atrial fibrillation 
ablation. J Cardiovasc Electrophysiol. 2019 Oct;30(10):1886-1893. 
28. Wechselberger S, Kronborg M, Huo Y, . Continuous monitoring after atrial fibrillation 
ablation: the LINQ AF study. Europace. 2018 Nov 1;20(FI_3):f312-f320. 
29. Heeger CH, Tscholl V, Salloum O, et al. What is the real recurrence rate after cryoballoon-
based pulmonary vein isolation? Lessons from rhythm follow-up based on implanted cardiac 
devices with continuous atrial monitoring. Heart Rhythm. 2018 Dec;15(12):1844-1850. 
30. Dekker LR, Pokushalov E, Sanders P, et al . Continuous Cardiac Monitoring around Atrial 
Fibrillation Ablation: Insights on Clinical Classifications and End Points. Pacing Clin 
Electrophysiol. 2016 Aug;39(8):805-13. 
31. Andrade J, Chamnpagne J, Deyell MW, et al. Cryoballoon or Radiofrequency Ablation for 
Atrial Fibrillation Assessed by Continuous Monitoring A Randomized Clinical Trial. 
Circulation. 2019;140:1779–1788. 
32. Andrade J, Wells G , Deyell MW, et al. Cryoablation or Drug Therapy for Initial Treatment 
of Atrial Fibrillation. N Engl J Med. 2021 Jan 28;384(4):305-315. 
33. Andrade J, Deyell MW, et al. Healthcare utilization and quality of life for atrial fibrillation 
burden: the CIRCA-DOSE study. Eur Heart J. 2023 Mar 1;44(9):765-776. 
34. Schiavone, M, Gasperetti A, Montemeralo E., et al. Long-term comparisons of atrial 
fibrillation ablation outcomes with a cryoballoon or laser-balloon: A propensity-matched 
analysis based on continuous rhythm monitoring. Hellenic J Cardiol . 2022 May-Jun;65:1-7. 
35. Rovaris G, Ciconte G, Schiavone M. et al Second-generation laser balloon ablation for the 
treatment of atrial fibrillation assessed by continuous rhythm monitoring: the LIGHT-AF 
study. Europace. 2021 Sep 8;23(9):1380-1390. 
36. Gessler N, Willems S, Steven D et al. Supervised Obesity Reduction Trial for AF ablation 
patients: results from the SORT-AF trial. Europace. 2021 Oct 9;23(10):1548-1558. 
37. Dulai R, Sulke N, Furniss S, et al. The effect of second-generation cryoablation without 
electrical mapping in persistent AF using continuous monitoring. J Interv Card 
Electrophysiol. 2021 Mar;60(2):175-182. 
38. Forkmann M, Schwab C, Edler D, et al. Characteristics of early recurrences detected by 
continuous cardiac monitoring influencing the long-term outcome after atrial fibrillation 
ablation. J Cardiovasc Electrophysiol. 2019 Oct;30(10):1886-1893. 
39. Wechselberger S, Kronborg M, Huo Y, . Continuous monitoring after atrial fibrillation 
ablation: the LINQ AF study. Europace. 2018 Nov 1;20(FI_3):f312-f320. 
40. Heeger CH, Tscholl V, Salloum O, et al. What is the real recurrence rate after cryoballoon-
based pulmonary vein isolation? Lessons from rhythm follow-up based on implanted cardiac 
devices with continuous atrial monitoring. Heart Rhythm. 2018 Dec;15(12):1844-1850. 
41. Poole JE, Bahnson TD, Monahan KH, Johnson G, Rostami H, Silverstein AP, et al. 
Recurrence of atrial fibrillation after catheter ablation or antiarrhythmic drug therapy in the 
CABANA trial. J Am Coll Cardiol 2020;75:3105–3118. 
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42. Worck R, Sorensens SK, Johannessen A et al.  Posterior wall isolation in persistent atrial 
fibrillation. Long-term outcomes of a repeat procedure strategy. J Interv Card Electrophysiol 
2023 Jun;66(4):971-979 
43.  Sirico G,  Sirico D, Montisci A et al.  Contact-Force Guided Posterior Wall Isolation as an 
Adjunctive Ablation Strategy for Persistent Atrial Fibrillation. J Atr Fibrillation. 2021 Aug 
31;14(2):20200475. 
44. O’Neill L, Almorad A, El Haddad M et al.  Impact of Catheter Ablation on Arrhythmia 
Burden in Patients With Shock-Resistant Persistent Atrial Fibrillation. JACC Clin 
Electrophysiol. 2023 9(10):2071-2081. 
45.  Verma A,  Haines DE, Boersma LV et al. Influence of monitoring and atrial arrhythmia 
burden on quality of life and health care utilization in patients undergoing pulsed field 
ablation: A secondary analysis of the PULSED AF trialHeart Rhyhtm 20(9): 1238-1245. 
46. Van Gelder IC, Healey JS, Crijins et al. Duration of device-detected subclinical atrial 
fibrillation and occurrence of stroke in ASSERT. Eur Heart J . 2017, 38(17):1339-1344. 
47. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial 
tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS 
study. Circ Arrhythm Electrophysiol. 2009 Oct;2(5):474-80. 
 
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Appendix B: ADVANTAGE AF Study - LUX-Dx Sub-Study 
ADVANTAGE AF Study LUX-Dx sub-study (Appendix B) may only be implemented by 
sites who are participating in Phase 2 of the ADVANTAGE AF Study. 
 
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APPENDIX B - LUX-Dx Sub-Study 
Note: Data from this sub-study will not be required to be included in the standard FDA reports, 
including s-PMA applications and the ADVANTAGE AF final report.   
The elements defined in this sub-study Appendix are intended to be applied and followed in addition 
to the elements described within APPENDIX A of the ADVANTAGE AF Phase 2 protocol.  
Background 
Post-ablation assessment of arrhythmia recurrence over time is an important aspect to 
determine the chronic success of ablation therapy. An insertable cardiac monitor (ICM) is a 
device able to monitor the heart rhythm over an extended period. The LUX-Dx™ ICM System 
is inserted subcutaneously to provide long term, continuous monitoring over multiple years. 
The ICM has the advantage of automatically capturing and transmitting arrhythmia episodes, 
independent from the patient’s symptoms.  
The ICM also captures the AF burden for each patient, which is the proportion of time an 
individual spends in AF during a period (typically expressed as a percentage per day). 
Additional evidence is needed to determine the relationship of AF burden with AF-related 
outcomes.  
Accordingly, the use of an ICM may identify a novel standard for arrhythmia detection, AF 
burden quantification, and could be considered the gold standard for clinical trials in the future. 
Since this is a novel method of assessment in the context of AF ablation trials (in particular, 
persistent AF), the standards for the determination of a successful treatment in terms of 
arrhythmia rates and distribution (time to first recurrence, minimal duration, and AF burden) 
still need to be established in clinical trials. Continuing to collect long-term data on AF, AT, 
and AFL recurrence with the LUX-Dx device in the ADVANTAGE AF study will provide 
insights into the long-term effectiveness of ablative intervention of persistent AF with the 
FARAPULSE PFA System.   
Sub-Study Objectives 
The objectives of this sub-study are to: 
 
1. Characterize the long-term effectiveness of the FARAPULSE PFA System for 
treatment of persistent atrial fibrillation as assessed by the LUX-Dx ICM device. 
2. Characterize AF burden as determined by the LUX-Dx device.  
 
 
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Subject Selection 
Subjects will be selected for the LUX-Dx sub-study based upon their willingness to agree to 
provide access to their medical record data or medical claims data and LUX-Dx ICM device 
data following completion of the Day 360 assessment visit in Phase 2 of the ADVANTAGE 
AF study.  
 
Inclusion Criteria: 
1. Subjects enrolled in Phase 2 of the ADVANTAGE AF study with an active LUX-Dx 
ICM device. 
 
Exclusion Criteria: 
None 
 
Sub-Study Procedures 
No additional study procedures or follow-up assessments are required for subjects that agree 
to participate in the LUX-Dx sub-study. The LUX-Dx ICM device will continue to be 
programmed as defined within the ADVANTAGE AF Phase 2 protocol or as determined most 
appropriate to assess the subjects’ heart condition per physician assessment.  Subjects will 
continue to use their myLUX patient application to complete manual transmissions when 
experiencing symptoms and remain connected to the LATITUDE ClarityTM system throughout 
the duration of the trial. 
 
Data Collection and Analysis 
Once a LUX-Dx subject completes their Day 360 assessment, they will continue to be remotely 
monitored via LATITUDE Clarity for up to a total of 3 years (36 months) from the 
ADVANTAGE AF index ablation procedure. There is no additional data collection that will 
need to be entered in the study database after the Day 360 assessment.  
Subjects will need to maintain connection between their device and the myLUX patient app to 
ensure continuous arrythmia monitoring. It is recommended that subjects do not stay 
disconnected for more than two (2) weeks to ensure no data is overwritten.  
No additional study procedures or follow-up assessments are required for subjects that agree 
to participate in the LUX-Dx sub-study, however, participating subject’s electronic medical 
records or health care claims may be reviewed to assess for clinical events associated with 
ablation efficacy (e.g., cardioversions, re-ablations, hospitalizations).  
 
Adverse events will not be reported through the clinical study database after the subject 
completes their active participation (i.e., Day 360 assessment visit) in Phase 2 of the 
Released
92836802 H
ADVANTAGE AF Protocol
E.D: 27/Sep/2024
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 2 of 3

Form/Template 90702637_Rev/Ver AU 
Confidential 
ADVANTAGE AF Study – Phase 2, 92836802, Rev/Ver H Appendix B 
LUX-Dx Sub-Study 
Page 3 of 3 
 
  
ADVANTAGE AF Study.  Adverse events will be reported through normal commercial 
channels/complaint processes as applicable by sites. 
 
1.1 
LUX-Dx Recordings 
Recurrence episodes captured by the LUX-Dx ICM may be analyzed by cardiac algorithm 
for rhythm determination. An independent reviewer may also be used to verify recurrences 
captured by the LUX-Dx. 
1.2 
Data Analysis 
There are no pre-specified hypotheses for the sub-study objectives. The purpose of the sub-
study is to characterize the occurrence of atrial arrhythmia events as well as the overall AF 
burden experienced by subjects up to a total of three (3) years post-AF ablation for persistent 
AF using the FARAPULSE PFA System. All subjects enrolled in the sub-study that transmit 
their LUX-Dx data will be included in the analyses.  
 
Risks and Potential Benefits 
1.3 
Risks 
There are no increased risks as it relates to continued participation in the LUX-Dx sub-study 
that haven’t already been defined within the ADVANTAGE AF Phase 2 protocol and 
described within the ADVANTAGE AF Phase 2 informed consent form (ICF).  
1.4 
Potential Benefits 
Subjects that agree to participate in the LUX-Dx sub-study may not directly benefit from 
participating. The information gained from this sub-study may support future improvements 
in the management of post-atrial fibrillation ablation monitoring.  
 
Reporting and Approval Requirements 
Site and subject participation in the LUX-Dx sub-study is optional/not required.  Institutional 
Review Board (IRB) approval of the ADVANTAGE AF Phase 2 LUX-Dx sub-study ICF are 
required prior to subjects participating in the sub-study and providing continued access to 
Boston Scientific to their LUX-Dx ICM data via the LATITUDE Clarity system. 
 
There are no additional reporting requirements related to the sub-study from the Investigator 
or Investigational Site after all subjects complete their Day 360 Assessment per the 
ADVANTAGE AF Phase 2 protocol.   
Released
92836802 H
ADVANTAGE AF Protocol
E.D: 27/Sep/2024
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 3 of 3