Pulsed Field Ablation (PFA) System for the Treatment of Paroxysmal Atrial Fibrillation (PAF) by Irreversible Electroporation (IRE)
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Biosense Webster, Inc.

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Pulsed Field Ablation (PFA) System for the Treatment of Paroxysmal 
Atrial Fibrillation (PAF) by Irreversible Electroporation (IRE). 
“inspIRE” 
 
 
Protocol Number:  
BWI_2019_08  
 
Sponsor: 
Biosense Webster, Inc., a division of Johnson & Johnson with registered office 
at 31 Technology Drive, Suite 200 Irvine, CA 92618  
 
Operating Company:  
Johnson & Johnson Medical NV/SA with registered office at Leonardo Da 
Vincilaan 15, 1831 Diegem, Belgium, represented by Nathalie Macours. 
 
Funded by: 
Biosense Webster, Inc., part of the Johnson & Johnson family of companies 
 
Version:  
1.0 
Date: 
13 MAR 2020 
 
Eudamed number 
<Available as from submission> 
 
      History of Changes: 
Version— Date 
Description 
 
V 1.0 — 13 MAR 2020 
Original Document 
 
 
 
The Biosense Webster IRE system (Circular IRE Catheter (D-1412-01-SI) and Multi-Channel IRE 
Generator(D-1417-01-I)) is for investigational device use only and is not commercially available 
anywhere in the world. “Circular IRE Catheter and IRE Generator” are internal Biosense Webster project 
names and is not intended for any other external use. The final commercial or trade name of the IRE 
system (Circular IRE Catheter and IRE Generator) may be different. 
 
 

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1. Table of Contents 
1. 
TABLE OF CONTENTS .................................................................................................................................... 2 
2. 
LIST OF FIGURES AND TABLES ....................................................................................................................... 5 
3. 
LIST OF ACRONYMS AND ABBREVIATIONS .................................................................................................... 6 
4. 
KEY ROLES AND RESPONSIBLE PARTIES ......................................................................................................... 9 
5. 
PROTOCOL SUMMARY ............................................................................................................................... 11 
6. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................................................................ 21 
6.1 
BACKGROUND INFORMATION .................................................................................................................................. 21 
6.2 
PREVIOUS EXPERIENCE WITH THE CIRCULAR IRE CATHETER ........................................................................................... 22 
6.2.1 
Circular IRE Catheter In-Vivo Porcine Beating Heart Model ................................................................... 22 
6.3 
RATIONALE FOR DESIGN OF THE CLINICAL INVESTIGATION ............................................................................................. 23 
6.4 
POTENTIAL RISK AND BENEFIT ................................................................................................................................. 24 
6.4.1 
Known Potential Risks ............................................................................................................................ 24 
6.4.2 
Minimization of Risk ............................................................................................................................... 26 
6.4.3 
Known Potential Benefits ....................................................................................................................... 28 
7. 
OBJECTIVES AND PURPOSE ......................................................................................................................... 28 
7.1 
OBJECTIVE ........................................................................................................................................................... 28 
7.2 
PURPOSE ............................................................................................................................................................ 28 
8. 
STUDY DESIGN AND ENDPOINTS................................................................................................................. 29 
8.1 
DESCRIPTION OF THE STUDY DESIGN ........................................................................................................................ 29 
8.1.1 
Wave I Subjects ...................................................................................................................................... 30 
8.1.2 
Wave II: Roll-In Subjects ......................................................................................................................... 30 
8.1.3 
Wave II: Main Study Phase Subjects ....................................................................................................... 31 
8.2 
STUDY ENDPOINTS ................................................................................................................................................ 31 
8.2.1 
Primary Endpoints .................................................................................................................................. 31 
8.2.2 
Secondary Endpoints .............................................................................................................................. 32 
8.2.3 
Additional Endpoints .............................................................................................................................. 32 
9. 
STUDY POPULATION .................................................................................................................................. 33 
9.1 
PARTICIPANT INCLUSION CRITERIA ........................................................................................................................... 33 
9.2 
PARTICIPANT EXCLUSION CRITERIA ........................................................................................................................... 33 
10. 
PARTICIPANT WITHDRAWAL OR TERMINATION .......................................................................................... 35 
10.1 
REASONS FOR WITHDRAWAL OR TERMINATION ..................................................................................................... 35 
10.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION ................................................................................. 35 
10.3 
SUBJECT ENROLLMENT DISPOSITION .................................................................................................................... 35 
11. 
RESPONSIBILITIES ....................................................................................................................................... 36 
11.1 
INVESTIGATOR RESPONSIBILITIES ......................................................................................................................... 36 
11.2 
SPONSOR RESPONSIBILITIES ............................................................................................................................... 37 
12. 
STUDY DEVICE DESCRIPTION ...................................................................................................................... 38 
12.1 
DEVICE ACQUISITION ........................................................................................................................................ 38 
12.2 
DEVICE STORAGE AND STABILITY ......................................................................................................................... 38 
12.3 
DEVICE PREPARATION ....................................................................................................................................... 38 
12.4 
INSTRUCTIONS FOR USE..................................................................................................................................... 38 
12.5 
DEVICE DESCRIPTION AND SPECIFIC CONSIDERATIONS ............................................................................................. 38 
12.5.1 
Multi-Channel IRE Generator (D-1417-01-I) ........................................................................................... 38 
12.5.2 
Circular IRE Catheter (D-1412-01-SI) ...................................................................................................... 39 
12.6 
EQUIPMENT .................................................................................................................................................... 41 
12.6.1 
System Components and Setup .............................................................................................................. 41 

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12.6.2 
Required Study Devices .......................................................................................................................... 43 
12.6.3 
Ablation Parameters .............................................................................................................................. 44 
13. 
STUDY MEDICATION ................................................................................................................................... 44 
14. 
STUDY SCHEDULE ....................................................................................................................................... 45 
14.1 
SCREENING AND INFORMED CONSENT .................................................................................................................. 45 
14.2 
BASELINE EVALUATION AND PROCEDURES ............................................................................................................ 45 
14.2.1 
Pre-Procedure/Baseline Assessments .................................................................................................... 45 
14.2.2 
Study Ablation Procedure Guidelines ..................................................................................................... 47 
14.2.3 
Collection of Ablation Procedure Data for Post-Analysis (non-SOC) ...................................................... 51 
14.2.4 
Pre-Discharge Assessments .................................................................................................................... 51 
14.2.5 
Repeat Ablation Procedures ................................................................................................................... 52 
14.3 
POST-ABLATION FOLLOW-UP SCHEDULE .............................................................................................................. 52 
14.4 
EARLY TERMINATION VISIT ................................................................................................................................ 53 
14.5 
UNSCHEDULED VISIT ......................................................................................................................................... 53 
14.6 
CORE LABORATORY FOR EVALUATION .................................................................................................................. 54 
14.7 
SCHEDULE OF EVENTS TABLE .............................................................................................................................. 55 
15. 
ASSESSMENT OF SAFETY............................................................................................................................. 57 
15.1 
SPECIFIC SAFETY PARAMETERS ............................................................................................................................ 57 
15.1.1 
Definition of Adverse Events (AE) ........................................................................................................... 57 
15.1.2 
Definition of Serious Adverse Event (SAE) .............................................................................................. 58 
15.1.3 
Primary Adverse Event ........................................................................................................................... 58 
15.1.4 
Adverse Device Effect / Serious Adverse Device Effect ........................................................................... 60 
15.1.5 
Unanticipated (Serious) Adverse Device Effect....................................................................................... 60 
15.1.6 
Study Device Deficiency, Failure or Malfunction .................................................................................... 61 
15.2 
CLASSIFICATION OF AN ADVERSE EVENT ............................................................................................................... 61 
15.2.1 
Severity of Event ..................................................................................................................................... 61 
15.2.2 
Relationship to Study Device .................................................................................................................. 61 
15.2.3 
Outcome ................................................................................................................................................. 62 
15.2.4 
Expectedness (Anticipatedness) ............................................................................................................. 62 
15.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................................................................. 65 
15.4 
REPORTING PROCEDURES .................................................................................................................................. 65 
15.4.1 
Adverse Event Documentation and Reporting Requirements ................................................................ 65 
15.4.2 
Serious Adverse Events Reporting .......................................................................................................... 66 
15.4.3 
Unanticipated Device Effect Reporting .................................................................................................. 67 
15.4.4 
Events of Special Interest ....................................................................................................................... 67 
15.5 
SAFETY OVERSIGHT .......................................................................................................................................... 67 
16. 
ADMINISTRATIVE RESPONSIBILITIES ........................................................................................................... 68 
16.1 
ETHICS COMMITTEE AND COMPETENT AUTHORITY APPLICATION ............................................................................... 68 
16.2 
AUDITS AND INSPECTIONS .................................................................................................................................. 68 
17. 
DEVIATIONS FROM THE CLINICAL STUDY PLAN ........................................................................................... 68 
18. 
INVESTIGATIONAL PRODUCT ...................................................................................................................... 69 
18.1 
USE OF THE INVESTIGATIONAL DEVICE AND INVESTIGATOR EXPERIENCE ...................................................................... 69 
18.1.1 
Training .................................................................................................................................................. 69 
18.1.2 
Materials ................................................................................................................................................ 69 
18.2 
DEVICE ACQUISITION AND ACCOUNTABILITY .......................................................................................................... 70 
18.3 
DEVICE RETURNS ............................................................................................................................................. 70 
19. 
CLINICAL MONITORING .............................................................................................................................. 70 
20. 
STATISTICAL METHODOLOGY ..................................................................................................................... 71 
20.1 
LEVELS OF SIGNIFICANCE ................................................................................................................................... 71 
20.2 
SAMPLE SIZE JUSTIFICATION ............................................................................................................................... 71 
20.3 
ANALYSIS SETS ................................................................................................................................................ 72 
20.3.1 
Wave I Analysis Sets ............................................................................................................................... 72 

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20.3.2 
Wave II Analysis Sets .............................................................................................................................. 73 
20.4 
ANALYSES TO BE CONDUCTED ............................................................................................................................. 73 
20.4.1 
General Conventions .............................................................................................................................. 73 
20.4.2 
Disposition and Study Subjects ............................................................................................................... 74 
20.4.3 
Demographic and Baseline Characteristics ............................................................................................ 74 
20.4.4 
Primary Endpoint Analyses and Associated Hypotheses ........................................................................ 74 
20.4.5 
Secondary Endpoint Analysis .................................................................................................................. 78 
20.4.6 
Additional Endpoint Analyses ................................................................................................................. 78 
21. 
ETHICS AND PROTECTION OF HUMAN SUBJECTS ......................................................................................... 78 
21.1 
ETHICAL STANDARD .......................................................................................................................................... 78 
21.2 
INFORMED CONSENT PROCESS ........................................................................................................................... 79 
21.2.1 
Informed Consent Procedure and Documentation ................................................................................. 79 
21.3 
PARTICIPANT AND DATA CONFIDENTIALITY ............................................................................................................ 80 
21.3.1 
Research Use of Stored Data .................................................................................................................. 81 
22. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .......................................................... 81 
23. 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................................... 81 
24. 
DATA HANDLING AND RECORD KEEPING .................................................................................................... 82 
24.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITY .......................................................................................... 82 
24.1.1 
Data Collection ....................................................................................................................................... 82 
24.1.2 
Data Reporting ....................................................................................................................................... 82 
24.1.3 
Data Verification and Review ................................................................................................................. 83 
24.1.4 
Final Data Analysis ................................................................................................................................. 83 
24.2 
STUDY RECORD RETENTION AND ARCHIVING ......................................................................................................... 83 
25. 
STUDY SUSPENSION OR TERMINATION ...................................................................................................... 84 
26. 
DATA AND PUBLICATION POLICY ................................................................................................................ 84 
27. 
DOCUMENT FILING ..................................................................................................................................... 84 
28. 
SCIENTIFIC REFERENCES .............................................................................................................................. 85 
29. 
APPENDIX 1................................................................................................................................................ 89 
 
 
 
 

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2. List of Figures and Tables 
FIGURE 1: PICTURE OF THE IRE CONSOLE ...................................................................................................................... 39 
FIGURE 2: PICTURE OF THE CIRCULAR IRE CATHETER AND CIRCULAR LOOP (UNCONTRACTED AND CONTRACTED) – 
MINIMUM LOOP CONTRACTION RANGE 10 MM .................................................................................................. 40 
FIGURE 3: CONNECTIVITY DIAGRAM FOR SYSTEM SET-UP ............................................................................................ 42 
FIGURE 4: ELECTRODE SELECTION ................................................................................................................................. 47 
FIGURE 5: ALL ELECTRODES TOGGLE ............................................................................................................................. 48 
 
 
TABLE 1: SUBJECT TREATMENT AND FOLLOW-UP SCHEDULE ....................................................................................... 19 
TABLE 2: DESCRIPTION OF CONNECTIVITY ..................................................................................................................... 42 
TABLE 3: REQUIRED STUDY DEVICES .............................................................................................................................. 43 
TABLE 4: INVESTIGATIONAL DEVICE- FUNCTIONAL PARAMETERS AND USER ADJUSTABLE SETTINGS ......................... 48 
TABLE 5: SUMMARY OF SUBJECT VISITS AND ASSESSMENTS ........................................................................................ 55 
TABLE 6: PRIMARY ADVERSE EVENTS ............................................................................................................................ 58 
TABLE 7: INTENSITY OR SEVERITY DEFINITIONS ............................................................................................................. 61 
TABLE 8: ADVERSE EVENT CAUSALITY CLASSIFICATIONS ............................................................................................... 62 
TABLE 9: ADVERSE EVENT OUTCOME CLASSIFICATIONS ............................................................................................... 62 
TABLE 10: COMPREHENSIVE LIST OF ANTICIPATED ADVERSE EVENTS .......................................................................... 63 
TABLE 11: AE REPORTING REQUIREMENTS ................................................................................................................... 66 
TABLE 12: RESPONSIBILITIES FOR PREPARING AND SUBMITTING REPORTS ................................................................. 83 
 
 

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4. Key Roles and Responsible Parties 
SPONSOR:   
Cardiovascular & Specialty Solutions (CSS) 
Biosense Webster Inc., part of the Johnson & Johnson family of companies 
31 Technology Drive,   
Suite 200 Irvine, CA 92618 - USA 
Tel: +1 800-729-9010 
 
The Sponsor will finance the study, and a clinical trial agreement (CTA) will manage the relationship 
between the sponsor, the investigator and the institution. Including but not limited to description and 
aknowledgment of responsibilities, terms of collaboration, indemnification, requirements for 
payment, publication and intellectual property terms and guidelines for dispute resolution. 
 
CONTACTS:   
 
Whereas, the Clinical Study is sponsored by Biosense Webster Inc., Johnson and Johnson Medical 
NV/SA with registered offices at Leonardo Da Vincilaan 15, 1831 Diegem, Belgium, has been duly 
appointed by the Sponsor to conduct the Clinical Study on its behalf. 
 
The sponsor maintains an updated list of Principal Investigators (PIs), the coordinating investigator 
(if appointed), address details of each investigational site, emergency contact details for the PI’s at 
each site, roles and responsibilities and qualifications of each respective investigator, institutions, 

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corelabs (if applicable) and Contract Research Organizations (if applicable). The definitive list shall be 
integrated into the study report. 
 
The current protocol has been developed based on regulations applicable in Europe, for countries 
outside Europe, a country specific version of this study protocol may be developed, further defining 
regional regulations, if applicable. 
 
 

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Premarket or 
Post market 
Premarket 
Study Design 
Prospective, single arm, multi-center, pre-market clinical evaluation of the IRE 
system (Circular IRE Catheter and IRE Generator) to demonstrate safety and 
long-term effectiveness when compared to a performance goal based on a 
historical control.  
 
The study shall include two sequential waves: 
Wave I of the study will enroll up to 40 subjects, who will undergo the index 
procedure and additional neurological, PV and esophageal assessments.  
 
Wave II of the study will enroll roll-ins, and up to 330 subjects in the main 
phase. Wave II subjects will undergo the index procedure and same follow-up 
schedule as Wave I subjects, excluding the additional neurological, and post 
procedural PV (unless symptomatic) and esophageal assessments. 
 
Bayesian adaptive design will be used for sample size selection in Wave II of 
the study. 
 
Sample Size 
As Wave I of the study is a safety characterization phase, a sample size of 40 
subjects is intended to delineate safety and provide preliminary estimates for 
safety and acute effectiveness of the IRE system. 
 
Two sample size selection interim analyses will be performed in Wave II. 
Predictive probabilities of success will be used to determine whether the 
enrollment will be stopped or continued at each sample size selection interim 
analysis. The study may enroll up to a maximum of 330 subjects in the main 
phase. 
 
Study Population 
Patients scheduled to have a clinically-indicated ablation procedure for the 
management of their drug refractory PAF will be screened for enrollment per 
the study’s inclusion and exclusion criteria. 
 
Geographic areas 
to be included 
Up to 30 sites mainly in Europe and possible other regions. 

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Anticipated 
Study Timeline  
Total duration:  
Approximately 17 months of enrollment: 
Wave I: 4 months in a maximum of 7 sites 
Wave II: 13 months in a maximum of 30 sites 
+ 12 months Follow-Up (FU) 
Procedure(s) 
description 
Subjects will arrive to the electrophysiology (EP) laboratory for their ablation 
procedure and will undergo preparation for the procedure per the hospital’s 
standard protocol (discretion of investigator). 
 
The AF Ablation procedure will follow below sequence: 
1. 
Anatomical mapping of the LA 
2. 
PVI using the study catheter 
3. 
Confirmation 
of 
PV 
isolation 
(entrance 
block) 
with 
adenosine/isoproterenol challenge 
4. 
If necessary, treatment of acute reconnections with additional 
applications of PFA energy 
5. 
Confirmation of entrance block of all targeted PVs 
 
In this study protocol, IRE ablation modality is to be used as the primary mode 
for PVI. If PVI cannot be achieved with PFA, the IRE system should be 
disconnected prior to use of a commercial Radiofrequency (RF) system, to 
complete the procedure.  
 
The Circular IRE Catheter should not be used for lesions outside the PV region 
Primary 
Objective 
The primary objective of this clinical investigation is to demonstrate safety and 
long-term effectiveness of the IRE system (Circular IRE Catheter and IRE 
Generator) when used for isolation of the atrial PVs in treatment of subjects 
with PAF.  
 
Primary 
Endpoints  
 
Only Wave II subject data will be used for the purpose of primary hypothesis 
testing. Wave I and roll-in subject data will be separately analyzed (not part of 
the primary hypothesis testing). 
 
Acute Safety 
The primary safety endpoint is the incidence of Primary Adverse Events 
(PAEs) (within seven (7) days of the initial mapping and ablation procedure). 
PAEs include the following Adverse Events (AEs): 
Atrio-Esophageal Fistula* 
Phrenic 
Nerve 
Paralysis 
(permanent) 
Cardiac Tamponade/perforation 
Pulmonary Vein Stenosis* 
Device or procedure related death* 
Stroke/CVA 
Major Vascular Access 
Complication/Bleeding 
Thromboembolism 
Myocardial Infarction 
Transient Ischemic Attack (TIA) 
Pericarditis 
 
* Device or procedure related death, pulmonary vein stenosis and atrio-
esophageal fistula that occur greater than one week (7 days) post-
procedure are considered and analyzed as PAEs. 

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Long term effectiveness 
Freedom from documented (symptomatic and asymptomatic) atrial 
arrhythmia (Atrial Fibrillation (AF), Atrial Tachycardia (AT) or Atrial Flutter 
(AFL)) episodes based on electrocardiographic data (>30 seconds on 
arrhythmia monitoring device) during the effectiveness evaluation period (Day 
91-Day 365). Acute procedural failure (i.e., failure to confirm entrance block, 
with or without touch-up, in all PVs except those that are silent and/or cannot 
be cannulated post-procedure) will be considered a long-term effectiveness 
failure. 
 
Secondary 
Endpoints  
− 
Acute Procedural Success defined as confirmation of entrance block in all 
clinically relevant targeted PVs after adenosine/ isoproterenol challenge. 
Use of a non-study catheter to achieve PVI is considered an acute 
procedural success failure. 
− 
Freedom from documented symptomatic atrial arrhythmia (AF, AT or AFL) 
episodes based on electrocardiographic data (>30 seconds on arrhythmia 
monitoring device) during the effectiveness evaluation period (Day 91-Day 
365). 
− 
Quality of Life (QoL): the change of QoL assessed by comparing the Atrial 
Fibrillation Effect on Quality-of-Life (AFEQT™) scores before and after the 
ablation procedure. 
Additional 
Endpoints  
 
Safety 
− 
Occurrence of individual PAEs from the primary composite 
− 
Occurrence of Serious Adverse Device Effects (SADEs)  
− 
Occurrence of Serious Adverse Events (SAEs) within 7 days (early-
onset), 8-30 days (peri-procedural) and >30 days (late onset) of initial 
ablation procedure 
− 
Occurrence of non-SAEs  
− 
Occurrence of clinically symptomatic severe PV stenosis as 
documented by CT/MRA 
 
Effectiveness 
− 
Ablation by a non-study catheter for PVI (touch-up) among all 
clinically relevant targeted PVs and by subject  
− 
Acute reconnection identified by adenosine/isoproterenol challenge. 
among all clinically relevant targeted PVs and by subject 
− 
% repeat ablation within the 12M FU period 
o Timing (blanking period or after blanking) 
o % PV reconnection 
− 
Freedom from documented symptomatic and asymptomatic atrial 
fibrillation (AF) episodes based on electrocardiographic data (>30 
seconds on arrhythmia monitoring device) during the effectiveness 
evaluation period (Day 91-Day 365). 
− 
Freedom from documented (symptomatic and asymptomatic) atrial 
arrhythmia (AF, AT or AFL) episodes based on electrocardiographic 
data (>30 seconds on arrhythmia monitoring device) during the 
effectiveness evaluation period (Day 91-Day 365) with the following 
criteria also deemed failure:  

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o Taking a new class I/III Antiarrhythmic Drug (AAD) for AF or a 
previously failed class I/III AAD at a greater than the highest 
ineffective historical dose for AF during the effectiveness 
evaluation period 
o Greater than 2 repeat ablations for AF/AT or AFL in the 
blanking period or any repeat ablation for AF/AT or AFL during 
the effectiveness evaluation period 
 
Procedural data, including but not limited to 
− 
Total procedure time 
− 
Mapping time 
− 
PFA application time 
− 
Number of PFA applications by PV and by subject 
− 
Total fluoroscopy time 
− 
Study catheter dwell time 
− 
Ablation settings used  
− 
Use of paralytics and anesthesia 
 
Neurological Assessment (Wave I) 
− 
Occurrence of new post-ablation asymptomatic and symptomatic 
cerebral emboli as determined by Magnetic Resonance Imaging (MRI) 
evaluations 
− 
Occurrence of new or worsening neurological deficits post-ablation 
and at follow-up, compared to baseline 
− 
Occurrence, anatomical location and size of asymptomatic and 
symptomatic cerebral emboli observed pre-and post-ablation as 
determined by MRI evaluations.   
− 
Summary of Mini Mental State Examination (MMSE), National 
Institute of Health Stroke Scale (NIHSS) and Modified Rankin Scale 
(mRS) at baseline, post-ablation and during follow-up (if lesions were 
identified in prior evaluation) 
 
CT/MRA (Wave I) 
− 
Occurrence of severe PV stenosis at 3 months post-ablation as 
determined by Computed Tomography (CT)/ Magnetic Resonance 
Angiogram (MRA) evaluations. 
 
Endoscopy (Wave I) 
− 
Occurrence of post-ablation esophageal lesions as determined by 
post-procedure endoscopy 
Inclusion Criteria 
1. Diagnosed with Symptomatic PAF. 
2. Selected for AF ablation procedure by PVI. 
3. Failed at least one AAD (class I to IV) as evidenced by recurrent 
symptomatic AF, or intolerable or contraindicated to the AAD. 
4. Age 18 -75 years  
5. Willing and capable of providing consent 
6. Able and willing to comply with all pre-, post-, and follow-up testing and 
requirements 
Exclusion Criteria 
1. AF secondary to electrolyte imbalance, thyroid disease, or reversible or 
non-cardiac cause. 
2. Previous LA ablation or surgery 

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3. Patients known to require ablation outside the PV region (e.g. CTI region, 
atrioventricular reentrant tachycardia, atrioventricular nodal reentry 
tachycardia, atrial tachycardia, ventricular tachycardia and Wolff-
Parkinson-White).  
4. Previously diagnosed with persistent AF (> 7 days in duration) 
5. Severe dilatation of the LA (LAD >50mm antero-posterior diameter in 
case of Transthoracic Echocardiography (TTE)) 
6. Presence of LA thrombus  
7. Severely compromised LVEF (LVEF <40%) 
8. Uncontrolled heart failure or New York Heart Association (NYHA) Class III 
or IV  
9. History of blood clotting, bleeding abnormalities or contraindication to 
anticoagulation (heparin, warfarin, or dabigatran) 
10. History of a documented thromboembolic event (including TIA) within 
the past 6 months  
11. Previous PCI/MI within the past 2 months 
12. Coronary Artery Bypass Grafting (CABG) in conjunction with valvular 
surgery, cardiac surgery (e.g. ventriculotomy, atriotomy) or valvular 
cardiac (surgical or percutaneous) procedure. 
13. Unstable angina pectoris within the past 6 months 
14. Anticipated cardiac transplantation, cardiac surgery or other major 
surgery within the next 12 months. 
15. Significant pulmonary disease (e.g., restrictive pulmonary disease, 
constrictive or chronic obstructive pulmonary disease) or any other 
disease or malfunction of the lungs or respiratory system that produces 
severe chronic symptoms 
16. Known significant PV anomaly that in the opinion of the investigator 
would preclude enrollment in this study 
17. Has known pulmonary vein stenosis 
18. Acute illness, active systemic infection or sepsis 
19. Presence of intracardiac thrombus, myxoma, tumor, interatrial baffle or 
patch or other abnormality that precludes catheter introduction or 
manipulation. 
20. Severe mitral regurgitation 
21. Presence of implanted pacemaker or Implantable Cardioverter-
Defibrillator (ICD) or other implanted metal cardiac device that may 
interfere with the IRE energy field. 
22. Presence of a condition that precludes vascular access (such as IVC filter) 
23. Significant congenital anomaly or a medical problem that in the opinion 
of the investigator would preclude enrollment in this study 
24. Categorized as vulnerable population and requires special treatment 
with respect to safeguards of well-being 
25. Current enrollment in an investigational study evaluating another device 
or drug. 
26. Women who are pregnant (as evidenced by pregnancy test if pre-
menopausal), lactating, or who are of child bearing age and plan on 
becoming pregnant during the course of the clinical investigation. 
27. Life expectancy less than 12 months  

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28. Presenting contra-indications for the devices used in the study, as 
indicated in the respective Instructions For Use (IFU) 
 
Additional exclusion criteria for Wave I subjects: 
29. Contraindication for MRI such as use of contrast agents due to advanced 
renal disease, claustrophobia etc. (at PI discretion)  
30. Presence of iron-containing metal fragments in the body  
31. Unresolved pre-existing neurological deficit. 
32. Uncontrolled significant GastroEsophageal Reflux Disease (GERD) 
 
Safety 
Assessments 
The safety endpoint is the incidence of early onset Primary Adverse Events 
(PAEs) (within seven (7) days of the initial ablation procedure).  
Additional safety assessments on neurological lesions, esophageal lesions and 
PV stenosis will be performed for the Wave I subjects. 
Statistical 
Analysis 
The main phase of the study (Wave II) will use a Bayesian adaptive design to 
determine the sample size. The timing of sample size selection interim analyses 
will be described in the Statistical Analysis Plan (SAP). A maximum of 330 
subjects may be enrolled in the main study phase.  An additional interim 
analysis will be performed for claiming early trial success when 30 subjects 
reach full 12-month of follow-up and all subjects in three months of follow-up. 
If the criteria for early success are met, filing for CE Mark will be performed 
while 12-month follow-up is ongoing in the remaining subjects. 
 
Final Primary safety analysis 
 
The final analysis for the primary safety endpoint will use a beta-binomial 
model with a non-informative uniform prior. The endpoint will be considered 
a success if the posterior probability of the safety rate being less than 14% is 
greater than 0.975. 
 
H0: Pr(Ps < 0.14) ≤ 0.975 
Ha: Pr(Ps < 0.14) > 0.975 
 
 
Final Primary effectiveness analysis 
 
The final analysis for the primary effectiveness endpoint will use a beta-
binomial model with a non-informative uniform prior. The endpoint will be 
considered a success if the posterior probability of the primary effectiveness 
success rate being greater than 50% is greater than 0.9775. 
 
H0: Pr(PE > 0.50) ≤ 0.9775 
Ha: Pr(PE > 0.50) > 0.9775 
 
 

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Interim Analysis 
Detailed information on analysis performed within the study will be described 
in the statistical Analysis plan. 
Sample size selection analysis and an interim analysis for claiming early trial 
success will be performed. 
Determination if 
DSMB/DMC/CEC 
required 
DMC and CEC will be established for this study 
− 
DMC will assess subjects’ data for safety on regular intervals for Wave 
I and Wave II and make recommendations on study adaptations. 
− 
CEC will adjudicate primary safety endpoint events for Wave I and 
Wave II.  
Time and Events 
Schedule 
See table 1 below 
 
 
 

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11. AEs must be collected from the time the subject signs the informed consent onward.  
12. To be completed within 6 months prior to ablation procedure, For Wave I subjects: CT-MRA to be repeated at 3M FU. 
For Wave I and Wave II subjects, CT-MRA to be repeated post procedure in case subject presents with PV stenosis 
symptoms. 
13. Endoscopy preferable prior to discharge and no later than 72-hours after procedure. For procedures on Friday a 
window of a maximum of 96 hours is justified. 
14. If observations are noted on the post-procedure MRI, the subject must have follow-up MRI at the next follow-up 
visit(s) until observations are resolved. 
15. A certified/qualified physician expert must perform neurologic exams at pre-and post-ablation and possibly at other 
follow-up visits, pending previous findings of micro-emboli/neurologic deficits. 
16. To be completed within 72-hours pre-procedure. For procedures on Monday a window of a maximum of 96 hours is 
justified. 
17. To be completed within 72-hours post-procedure. For procedures on Friday a window of a maximum of 96 hours is 
justified. 
18. Full neurological follow up to be undertaken if neurologic symptoms and/or cerebral ischemic lesions identified in a 
prior evaluation.  
19. If subject returns for a potential study related cardiovascular or neurological visit outside of the protocol-defined visit 
schedule as deemed required per investigators discretion. 
20. Patient questionnaires will only be used in countries with validated languages. 
 

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6. Background Information and Scientific Rationale 
6.1 Background Information 
 
Atrial Fibrillation (AF) is the most common sustained arrhythmia in humans.  It affects 
anywhere from 0.4% to 1% of the general population, and increases in prevalence with age to 
approximately 8% in patients over 80 years of age.1, 2  The primary clinical benefit of AF 
ablation is improvement in Quality of Life (QoL) resulting from the elimination of arrhythmia-
related symptoms such as palpitations, fatigue, or effort intolerance.3  In recognition of this, 
the elimination of symptomatic atrial arrhythmias was recommended by the 2017 
HRS/EHRA/ECAS Consensus on Catheter and Surgical Ablation of Atrial Fibrillation.3 The 
opinion of the ESC as expressed in their 2019 AF Management Guidelines is that “Catheter 
ablation of symptomatic Paroxysmal Atrial Fibrillation (PAF) is recommended to improve AF 
symptoms in patients who have symptomatic recurrences of AF on Antiarrhythmic Drug (AAD) 
therapy and who prefer further rhythm control therapy, when performed by an 
electrophysiologist who has received appropriate training and is performing the procedure in 
an experienced center.”2, 4, 5 
 
The 2017 HRS/EHRA/ECAS consensus statement states that electrical isolation of the 
Pulmonary Veins (PVs) from the Left Atrium (LA) is the “cornerstone for most AF ablation 
procedures” and that “complete electrical isolation of all PVs should be the goal.”3   Point-by-
point ablation with radiofrequency (RF) catheters has provided positive results for treating 
many types of supraventricular arrhythmias,6, 7 including PAF.6-12 However, the procedure is 
technically complex and has a long learning curve. RF ablation success is highly dependent on 
operator skill and is associated with a high degree of PV reconnection.13-15 Additionally, RF 
ablation carries a major complication rate of roughly 4.5%.16   
 
In order to reduce technical complexity and potentially decrease major complications, circular 
ablation catheters were developed. Use of a Circular IRE Catheter allows for a different energy 
source for ablation and selective tissue destruction utilizing PFA energy17-25 to create lesions 
and isolate PVs. 
 
While RF and cryo-ablation techniques are based on thermal energy transfer to induce local 
tissue necrosis, Irreversible Electroporation (IRE) is a non-thermal cell death following pulsed 
field ablation technology which might be used to treat atrial arrhythmias.23  It is suggested 
that non-thermal IRE is the trigger of apoptotic processes at the cellular level because the 
major damages occur after electroporation, within minutes/hours after the pulse 
application.26-28 Short pulses with high voltages cause unrecoverable permeabilization of cell 
membranes, triggering apoptosis rather than necrosis, and as such might be safer for 
structures adjacent to the myocardium.25 
 
It has been known that unipolar electric pulses cause muscle contractions, using biphasic 
pulses, should prevent muscle contractions during IRE. It is believed that using a biphasic 
waveform will mitigate muscle contractions during IRE and therefore gives the possibility to 
perform procedures without administration of paralytic agents. 
 
High correlation has been observed in animal models between targeted areas and tissue death 
with well distinguishable transition zones between treated and untreated tissue.17 
 

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IRE is considered nonthermal if the optimal balance has been reached to induce nonnecrotic 
selective cellular death. The technique has the capability to spare adjacent heat sensitive 
structures or tissues which would be of benefit in the reduction of possible complications 
know with RF energy. Although using the same electrical parameter, IRE energy delivery may 
be affected by other parameters like active electrode area impacting the tissue-electrode 
impedance. Therefore literature describes the need of balancing Pulsed Field Ablation (PFA) 
application parameters (in example voltage, pulse width and interpulse distance) with physical 
parameters (in example electrode area, reference proximity) to achieve optimal efficacy and 
possible benefits of this approach versus RF energy delivery techniques.24 
 
IRE of the myocardium is studied on animals resulting in clear lesions in the cardiac tissue, 
with no charring or temperature changes. Lesion size correlations are described in literature 
with pulse duration, number of pulses, higher voltage and lower interpulse distance. 
Interestingly the majority of the animal studies report sparing of the extracellular structures. 
29-35 
 
Influence on adjacent structures has been previously studied. Of the well described 
complications in RF ablation techniques, the tissue specificity of IRE has been considered as a 
major advantage.36 Recoverable proof of IRE effect on phrenic nerves has been described, 
suggesting that permanent damage can be avoided with IRE.37-40 As rare but dangerous 
complication of RF ablation, namely development of lethal Atrio-Esophageal Fistula (AEF), 
might be minimized with IRE as it’s suggestive that the risk with IRE would only be limited to 
the muscular layer of the esophagus. 41  
 
Circular catheters are merely referred to and used in animal and clinical trial settings for the 
purpose of Pulmonary Vein Isolation (PVI) by means of IRE ablation. 33, 34, 42 Biosense Webster 
developed the novel proprietary technology system, including Circular IRE Catheter and Multi-
Channel IRE Generator which might confirm that standardization pulse delivery in optimal 
conditions will provide balance between efficacy and safety. 
 
6.2 Previous Experience with the Circular IRE Catheter 
6.2.1 
Circular IRE Catheter In-Vivo Porcine Beating Heart Model 
 
Refer to IB for detailed description of the testing performed.  
 
A single-arm study was used to evaluate overall safety of the Circular IRE Catheter with pulsed 
field ablation, when simulating a clinical electrophysiology (EP) pulmonary vein isolation in a 
canine beating heart model to demonstrate safety and efficacy, Animals were kept alive for 7 
days post ablation procedure before being humanely euthanized, to assess chronic safety and 
effectiveness related to pulmonary vein isolation procedure and for tissue harvest. 
 
The study evaluated the Circular IRE Catheter and its ability to work in conjunction with the 
Multi-Channel IRE Generator and the CARTO®3 V7 and accessories,  
The following equipment was used during testing: 
• 
Circular IRE Catheter 
• 
IRE Generator 
• 
8.5F compatible sheath 
• 
CARTO®3 V7 software compatible with Circular IRE Catheter 
• 
Catheter Interface Cable 

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• 
Standard Pacing and recording system 
• 
nGEN™ irrigation pump 
 
The safety endpoints included: 
• 
Occurrence of thrombus 
• 
Occurrence of steam pop leading to pericardial effusion and or tamponade 
• 
Occurrence of mural thrombus 
• 
Pulmonary vein stenosis 
• 
Occurrence of collateral damage 
• 
Occurrence of intracardiac tissue damage due to mechanical injury 
• 
Occurrence of peripheral thrombo-emboli 
 
The efficacy endpoints included: 
• 
Acute isolation of pulmonary veins 
• 
Acute isolation of right atrial targets 
• 
Durable lesion formation after 7 days 
 
Gross pathology and histopathology examination were performed, and cardiac tissue was 
found to be normal. There was no evidence of thrombus, dissection, perforation, or other 
cardiac injury in LA of all animals where the Circular IRE Catheter was manipulated in the PVs. 
 
Based on the results of safety and performance of Circular IRE Catheter in conjunction with 
Multi-Channel IRE Generator and ancillary equipment, all characteristics passed the 
acceptance criteria. 
 
6.3 Rationale for Design of the Clinical Investigation 
The Sponsor has carefully considered the most appropriate study design for the assessment 
of the IRE Ablation system.  The 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE Expert Consensus3 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation addressed the 
appropriateness and concerns of randomized control (non-inferiority) studies - “…the 
possibility of a downward “creep” in acceptable effectiveness (if each device is numerically 
inferior but statistically equivalent to the prior comparator device).  In the future, we expect 
that devices designed to treat patients with symptomatic PAF might alternatively be evaluated 
in nonrandomized trials, comparing prespecified performance goals or objective performance 
criteria (OPC), if uniformly established and applied.” Similar concerns may be extended to the 
evaluation of safety given the rapid pace of technology development in this arena. This is 
balanced by the establishment of the treatment of PAF by catheter ablation as a safe 
procedure with pulmonary vein isolation (PVI) as the cornerstone of treatment. Data 
published from many recent prospective multi-center clinical trials43-46 for ablation devices 
demonstrate that the safety and effectiveness rates for similar primary endpoints are 
comparable across the varied technologies in a well-defined PAF patient population, further 
supporting acute PVI as a reliable treatment in reducing long-term recurrence of PAF. 
Accordingly, this study is designed to be multicenter and single arm with comparison to 
rigorously determined performance goals for both safety and effectiveness.  
 
The planned performance goal for long term effectiveness is 50%, based on the minimum 
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the 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement3 on Catheter and 
Surgical Ablation of AF. Data from large multicenter pre and post-market clinical trials of AF 
ablation devices which were published between 2014 to 2019 were reviewed as a first step to 
deriving the performance goal for the safety endpoint. A meta-analysis approach was taken 
to estimate the average composite endpoint rate. The following trials were reviewed: Fire & 
Ice43, Heartlight44, TOCCASTAR45, ZERO-AF47, and SMART-AF46. These trials are representative 
of different catheter designs and energy sources. Since the definition of the safety composite 
varies across the studies reviewed, individual complication rates were reviewed and utilized 
to derive composite rates from each trial that are more closely aligned with the proposed 
primary safety composite endpoint definition. The meta-analysis yielded a composite primary 
safety endpoint rate of 7% (95% UCB: 8%).  A margin of indifference of 6 percentage points 
was utilized to set the PG of 14%. 
 
6.4 Potential Risk and Benefit 
The overall risks posed by use of the Circular IRE Catheter, with the Multi-Channel IRE 
Generator are expected to be comparable to those anticipated during routine use of radio 
frequency (RF) catheter ablation systems and use of AAD therapy according to current AF 
management guidelines. Appropriate measures have been outlined in this protocol to 
minimize the risk to subjects, while still providing the possible benefits (including but not 
limited to safety/effectiveness) of the treatment options to be studied. 
 
Pulse-field ablation used to create irreversible electroporation has been used in the treatment 
of oncology for the past decade, although treatment of patients with Atrial Fibrillation with 
this technology began only recently. Nonetheless, when compared to the usual standards of 
practice and published literature few, if any, the occurrence of thermal injuries which can be 
caused by RF ablation, are minimized with pulse field ablation. A summary of risks associated 
with catheter ablation, including analysis of and plans to minimize these risks, is provided 
below. 
 
6.4.1 
Known Potential Risks 
Pericarditis: With any circular-based ablation, pericarditis can occur due to mechanical or 
thermal irritation of the myocardium. This tends to be underreported as it is usually transient 
and resolves without intervention.3 
 
Phrenic Nerve Palsy (PNP): Injury to the Phrenic Nerve (PN) is not expected with the PFA 
energy provided, however, irritation of the phrenic nerve that resolves acutely has been noted 
in the literature.37 Prior to ablation in the region of the RSPV, investigators are encouraged to 
perform precautionary measures such as evaluation of proximity to the phrenic nerve and 
pacing maneuvers.3  
 
Atrio-Esophageal Fistula (AEF): AEF is a rare but catastrophic complication of AF ablation that 
can occur due to the anatomical proximity of the esophagus to the posterior wall of the LA 
and that is associated with a high mortality rate.48 In patients, the application of traditional RF 
energy along the posterior LA can result in thermal injury to the esophagus and the formation 
of an AEF.3 As PFA energy is non-thermal, AEF is not an expected outcome and has not been 
reported in the literature.41, 43 However, it is unknown if extreme overapplication of energy 
could result in AEF.  
 
Many investigators attempt to mitigate esophageal damage by monitoring endoluminal 
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technology itself mitigates the risk for this injury. 
 
Pulmonary vein stenosis: The risk of pulmonary Adverse Events (AEs) (e.g. PV stenosis, 
thrombus and hypertension) associated with a PFA procedure is unknown.  PV stenosis has 
not been reported following pulsed field applications.42, 49 However, in RF procedures, the risk 
of PV stenosis is small (<4%) and can be prevented by delivering energy outside of the 
pulmonary vein ostium.3 
 
Thrombus formation: The Circular IRE Catheter is irrigated. If the catheter was not being 
continuously irrigated, a thrombus could form. Embolization of thrombus could produce to 
produce stroke, Myocardial Infarction (MI), or other ischemic injury. To prevent this injury, 
the irrigation should be maintained throughout the procedure.  
 
Cardiac perforation/ Pericardial effusion/ cardiac tamponade: Cardiac perforation may 
result from catheter manipulation or application of RF current (risk is <1%). Cardiac 
perforation may result in pericardial effusion or cardiac tamponade which requires 
percutaneous pericardial drainage or surgical repair.3  To prevent effusion and tamponade, 
the Circular IRE Catheter should be used as instructed, including ensuring that the catheter is 
not turned counterclockwise while inside of the patient. 
 
Cerebral ischemic lesions:  According to HRS guidelines, 2017, Asymptomatic Cerebral Emboli 
(ACE) incidence is varying from 2%-15% as a complication to AF ablation.3  As pulsed field 
ablation is a new energy modality for treating Atrial Fibrillation, there is limited data on the 
potential for incidence of cerebral ischemic lesions. An ACE is defined as an occlusion of a 
blood vessel in the brain due to an embolus that does not result in any acute clinical symptoms 
and is therefore ‘silent’. Emboli can result from a thrombus, gas, air, tissue or fat. Source of 
micro-emboli include thrombi, which can develop on sheaths, materials, air introduction 
through sheath or during catheter exchange. Additionally, the hazard of microbubble 
formation in pulse field ablation, leads to an unknown level of risk of ACE.51 
 
Heart block: The application of PFA energy close to the AV node or HIS bundle could damage 
or destroy the normal AV conduction system, producing complete heart block and requiring 
implantation of a permanent pacemaker.  
 
Vascular access / bleeding complication: Vascular access complication, femoral 
arteriovenous fistula, hematoma, and pseudoaneurysm are commonly reported in 
procedures requiring femoral access. Arterial or venous injury, including arterial dissection, 
thrombosis, occlusion or hemorrhage at the catheter insertion sites or at other sites along the 
vessels occur in rare circumstances (risk <1%). These types of injuries may cause hemorrhage, 
hematoma or ischemic injury to an extremity or major organ.  Hemorrhage could occur as a 
result of anticoagulation (risk <0.5%), which may require transfusion.3  
 
Radiation exposure: Radiation exposure during the fluoroscopic imaging of the catheters may 
result in an increase in the lifetime risk of developing a fatal malignancy (0.1%) or a genetic 
defect in offspring (0.002%).51-53 
 
 
Infection: The percutaneous procedure carries risk of infection, either at the catheter 
insertion site or systemically, including endocarditis and septic emboli (risk <0.5%).54, 55 This 
risk can be minimized by using standard aseptic technique and, when indicated, by the use of 
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Allergic Reaction: A patient could develop an allergic reaction and/or inflammation due to the 
local anesthetic, sedatives, x-ray dye, heparin, protamine, or other agents administered during 
the procedure (risk <1%).53, 56-60 The If an allergic reaction occurs, typical standard of care 
precautions should be taken.  
 
Ventricular Tachycardia: Ventricular Fibrillation or other arrythmia: The literature suggests 
that in some instances PFA energy could induce ventricular tachycardia, ventricular fibrillation 
(ventricular rate usually >300 bpm), or another arrythmia.61-64 Care should be taken to 
carefully monitor the patient’s ECG recordings throughout the procedure.  
 
Muscular Nerve Injury: Pulse field ablations have been associated with muscular contraction 
in the literature.65, 66 These contractions can cause acute or post procedural patient 
discomfort. Patient comfort should be maintained through local pain management standards 
of care.  
 
Hypervolemia/Fluid Overload: The Circular IRE Catheter is an irrigated catheter. Excessive use 
of irrigation could cause hemodynamic imbalance. To prevent hypervolemia, ensure that the 
catheter is used per its instructions for use.   
 
Risk due to Arcing: The hazard of arcing67 of energy creates a risk for patient injuries including 
Cardiac Arrest, burns, papillary muscle rupture, valve rupture, or cardiac perforation. To 
prevent such harms, the physician should use the catheter and generator per their intended 
directions for use.  
 
 
Pulmonary injury: Pulmonary injuries, such as pneumothorax, may be caused by thermal 
injury during traditional RF injury.68 As pulsed field ablation is a non-thermal modality, this 
injury is not expected to occur. However, to keep the risk of pulmonary injuries low, energy 
should delivery should be halted after ECG signals have been sufficiently attenuated.3  
 
Additional contraindications: Additional contraindications for pulse field ablation include: 
myxoma, prosthetic valves, history of myocardial infarction, implantable device such as a 
pacemaker, defibrillator, or other implanted metal cardiac device, and pregnancy.  
 
6.4.2 
Minimization of Risk 
The criteria for subject selection, methods, personnel, facilities, and training that are specified 
in this study are intended to minimize the risk to subjects undergoing this procedure.  
 
Patient selection:  Subjects will be screened carefully prior to enrollment in the study to 
ensure compliance with the inclusion and exclusion criteria.  The exclusion criteria have been 
developed to exclude subjects with a medical history or condition that increases their risk of 
AEs (refer to section 9.2 for the Exclusion Criteria).22 
 
Pre-procedure 
imaging: 
Subjects 
must 
have 
a 
pre-procedure 
Transesophageal 
Echocardiogram (TEE) or other imaging technique to screen for the presence of LA thrombus, 
which is intended to decrease the potential for thromboembolic complications.   
 
Within procedure safeguards: Investigators highly skilled in intracardiac mapping and AF 
ablation with ablation catheters will be selected for participation in the study.  AF ablation 
procedures will be performed in EP laboratories with the assistance of skilled nurses and 
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section 18.1.1). 
 
The risk of PNP will be minimized by encouraging monitoring the PN with pacing maneuvers 
before the ablation.  No new ablations should be delivered on or near the PN if evidence of 
PN impairment is observed and the catheter should be repositioned.  
 
The risk of PV stenosis will be minimized by not positioning the circular catheter within the 
tubular portion of the target PV.  
 
The risk of ACE will be minimized by implementing an anti-coagulation regimen prior to 
catheter introduction into the LA and during procedure to avoid thrombi/emboli during 
procedure. Investigators will be instructed to remove air bubbles prior to insertion and to 
minimize catheter exchange during procedure to mitigate the of risk air introduction.  
 
The risk of pericarditis will be minimized by encouraging the use of the lowest level of 
appropriate energy. 
 
The risk of cardiac perforation, perfusion, and tamponade events will be minimized by training 
physicians to not rotated the Circular IRE Catheter counterclockwise.  
 
The risks of AEF, pulmonary injury, and other related thermal events will be minimized by the 
technology itself and encouraging the use of the lowest appropriate energy setting.  
  
The risk of thrombi and hypervolemia will be minimized by encouraging the use of irrigation 
settings per the catheter’s Instructions for Use.  
 
The risk of induction of ventricular tachycardia and other arrythmias have been minimized by 
the design of the catheter, which uses biphasic energy with very short duration pulses. 
 
The risk of heart block will be minimized by limited use of the IRE Circular Catheter in the left 
atria during the procedure per the catheter’s instructions for use.  
 
The risk of vascular access complications can be minimized by using clinical standards of care, 
and an IRE Circular catheter compatible sheath. 
 
To mitigate the risk of radiation exposure, Physicians may use standard clinical practices to 
minimize or eliminate X-ray exposure during the procedure.  
 
The risk of infection and allergic reactions can be minimized by using not using product where 
the packaging has been compromised, or already used, or reprocessed. 
 
Pain and discomfort due to muscular contraction, can be mitigated through proper 
administration of pharmaceuticals for patient comfort. 
 
The likelihood for arcing has been mitigated with the design of the generator. To further 
prevent the associated risks from arcing, do not operate the device in patients with metal 
cardiac implants.  
 
Post-procedural management: In accordance with the 2016 ESC AF Management Guidelines3, 
all subjects will be recommended to be maintained on systemic oral anticoagulation therapy 
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months post-procedure, a decision regarding continuation of systemic anti-coagulation 
agents will be based on the patient risk for thromboembolism. Systemic oral anticoagulation 
will be recommended to be continued beyond two-months post-ablation in patients with 
CHA2DS2-VASc score ≥2. 
 
Safety data during enrollment and follow-up will be closely monitored and evaluated per the 
specific safety management plan for the study. Also, refer to safety section (section 15) for 
more information on safety management.   
 
DMC and CEC: Finally, a Data Monitoring Committee (DMC) will assess subjects’ data for safety 
on regular intervals for Wave I and Wave II and make recommendations on study adaptations 
as described in the DMC Charter. A Clinical Events Committee (CEC) will be implemented to 
adjudicate primary safety endpoint events for Wave I and Wave II. The CEC will operate as 
described in the CEC Charter. 
 
6.4.3 
Known Potential Benefits 
In patients with AF, elimination of or a reduction in symptoms is a major driving force for 
therapy. The primary clinical benefit of ablation of AF is an improvement in QoL resulting from 
the elimination of arrhythmia-related symptoms such as palpitations, fatigue, or effort 
intolerance.66 The Circular IRE Catheter is intended to allow for the ablation of larger areas of 
tissue compared to traditional single tip catheters. Thus, the Circular IRE Catheter should 
possess the benefit of reduced procedure time and fewer catheter exchanges.  
 
Influence on adjacent structures has been previously studied. Of the well described 
complications in RF ablation techniques, the tissue specificity of IRE has been considered as a 
major advantage.36 
 
Additionally, other PFA cardiac technologies, have shown in early reports that IRE creates 
durable lesions at effectiveness rates higher than that seen in radiofrequency trials.  
 
Further reference can be made to the Risk-Benefit Analysis (RBA) for more information. 
7. Objectives and Purpose  
7.1 Objective 
The primary objective of this clinical investigation is to demonstrate safety and long-term 
effectiveness of the IRE system (Circular IRE Catheter and IRE Generator) when used for 
isolation of the atrial PVs in treatment of subjects with PAF. Specifically: 
• 
To demonstrate safety based on early-onset Primary Adverse Events (PAEs) (within 7 days 
following the ablation procedure). 
• 
To demonstrate long term effectiveness based on the freedom from documented 
(symptomatic and asymptomatic) atrial arrhythmia (AF, Atrial Tachycardia (AT) or Atrial 
Flutter (AFL)) episodes based on electrocardiographic data (≥30 seconds on arrhythmia 
monitoring device) during the effectiveness evaluation period (Day 91-Day 365). 
7.2 Purpose 
The primary purpose of this study is to prove that the use of the IRE Ablation System, 
incorporating both the Circular IRE Catheter and the IRE Generator, for the isolation of the 
PVs in treatment of subjects with PAF is safe and effective. The results of this provide evidence 
to support CE-mark registration of these devices 
 

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reached 7 days follow up unless the Sponsor deems otherwise per sections 25 (Study 
Suspension or Termination) and 6.4.2 (Minimization of Risk). 
 
An adaptive Bayesian design to will be used to determine the sample size. Two sample size 
selection interim analyses will be performed based on the primary effectiveness endpoint. 
Study success as defined by the main study endpoints will be analyzed for the respective Wave 
II analysis populations further described in the statistical section of this protocol (section 20).  
An additional interim analysis will be performed for claiming early trial success when 30 
subjects reach full 12-month of follow-up and all subjects reach three months of follow-up.  
 
In Wave II, the first 1-3 subjects for each ablating physician will be considered roll-in subjects 
to verify consistent workflow for study device components and to minimize any learning curve 
effects. Operators whom performed procedures in Wave I may be exempted from roll-ins for 
Wave II per training charter. The roll-in phase will include a maximum of 180 subjects. 
 
Subjects will be evaluated prior to the procedure, prior to discharge, and post procedure at 7 
days (Day 7-9), 1 month (Day 23-37), 3 months (Day 76-104), 6 months (Day 166-194), and 12 
months (Day 335-379). 
 
8.1.1 
Wave I Subjects 
 
A prospective evaluation of 40 subjects will be included in Wave I of the study. Wave I subjects 
will, in addition to the general study follow-up schedule, undergo additional neurological, PV 
and esophageal assessments. The subjects of Wave I will meet all inclusion and exclusion 
criteria, including the additional exclusion criteria specific to Wave I. 
 
Additional assessments for Wave I subjects include: 
1. Cerebral MRI, National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale 
(mRS), Mini Mental State Examination (MMSE) and general neurological assessments for 
evaluation of neurological incidences.  Note: Patient questionnaires will only be used in 
countries with validated languages 
2. Cardiac Computed Tomography (CT) or Magnetic Resonance Angiogram (MRA) at 3 
months AND in case of symptoms, for evaluation of PV stenosis. 
3. Endoscopy post-procedure for evaluation of esophageal lesions. 
 
8.1.2 
Wave II: Roll-In Subjects 
 
New devices often require operators to scale a learning curve. The inclusion of a roll-in phase 
in the study will allow learning for the operators, and an evaluation of safety and 
effectiveness of the device that is not diminished by the early learning curve. In addition to 
a requirement for IRE ablation System training for ablating physicians, further experience 
within the context of this clinical investigational plan will serve to generate a clearer 
perspective of the effectiveness of the IRE ablation System in treating PAF subjects. 
Therefore, as of Wave II, up to the first 3 subjects (operator dependent based on criteria 
defined per training charter) treated by an ablating physician with the study catheter will be 
prospectively assigned as roll-in subjects to minimize the learning curve effect. To allow for 
a wide range of physician skill level, up to three physicians per site will be able to participate. 
Because roll-in subjects are at the physician level, some physicians at a site may complete 
their roll-in subjects and move to the main study phase while other physicians at the site are 
still in the roll-in phase. A subject who is excluded or discontinued will not count toward the 

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roll-in subjects. Roll-in subjects will be followed for 12 months post index procedure. The 
results from the roll-in phase will be analyzed and presented separately from the main study 
phase. 
 
8.1.3 
Wave II: Main Study Phase Subjects 
 
Eligible subjects who sign the Informed Consent Form (ICF) and who meet all eligibility will be 
enrolled and treated with the Circular IRE Catheter in conjunction with the IRE Generator. A 
maximum sample size of 330 subjects is planned the main phase. All main phase subjects will 
follow the same follow-up schedule as the other subjects namely be followed-up for 12 
months after study procedure.  
 
Planned statistical analyses of the endpoints and analysis populations are described in the 
Statistical Analysis section (section 20) of this clinical investigational plan and in the Statistical 
Analysis Plan (SAP). 
 
8.2 Study Endpoints 
Only Wave II subject data will be used for the purpose of primary hypothesis testing. Wave I 
and roll-in subject data will be separately analyzed (not part of the primary hypothesis testing), 
further described in the statistical section of this protocol (section 20). 
 
8.2.1 
Primary Endpoints 
 
• 
Acute Safety  
The primary safety endpoint is the incidence of PAEs (within seven (7) days of the initial 
mapping and ablation procedure). PAEs include the following AEs: 
 
Atrio-Esophageal Fistula* 
Phrenic 
Nerve 
Paralysis 
(permanent) 
Cardiac Tamponade/perforation 
Pulmonary Vein Stenosis* 
Device or procedure related death* 
Stroke/CVA 
Major Vascular Access 
Complication/Bleeding 
Thromboembolism 
Myocardial Infarction 
Transient Ischemic Attack (TIA) 
Pericarditis 
 
* 
Device or procedure related death, pulmonary vein stenosis and atrio-esophageal 
fistula that occur greater than one week (7 days) post-procedure are considered and 
analyzed as PAEs. 
 
A 14% performance goal is set for the primary safety endpoint 
 
• 
Long term effectiveness: 
 
Freedom from documented (symptomatic and asymptomatic) atrial arrhythmia (AF, AT or 
AFL) episodes based on electrocardiographic data (>30 seconds on arrhythmia monitoring 
device) during the effectiveness evaluation period (Day 91-Day 365). Acute procedural 
failure (i.e., failure to confirm entrance block, with or without touch-up, in all PVs except 
those that are silent and/or cannot be cannulated post-procedure) will be considered a 
long-term effectiveness failure. 
 

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A 50% performance goal is set for the primary long-term effectiveness endpoint 
 
Further refer to appendix 1 for definitions on long term effectiveness terms. 
 
8.2.2 
Secondary Endpoints 
 
• 
Acute Procedural Success defined as confirmation of entrance block in all clinically 
relevant targeted PVs after adenosine/isoproterenol challenge. Use of a non-study 
catheter to achieve PVI is considered an acute procedural success failure. 
 
• 
Freedom from documented symptomatic atrial arrhythmia (AF, AT or AFL) episodes 
based on electrocardiographic data (>30 seconds on arrhythmia monitoring device) 
during the effectiveness evaluation period (Day 91-Day 365). 
 
• 
Quality of Life: the change of QoL assessed by comparing the Atrial Fibrillation Effect on 
Quality-of-Life (AFEQT™) scores before and after the ablation procedure. Note: Patient 
questionnaires will only be used in countries with validated languages. 
 
8.2.3 
Additional Endpoints  
• 
Safety  
▪ 
Occurrence of individual PAEs from the primary composite 
▪ 
Occurrence of Serious Adverse Device Effects (SADEs)  
▪ 
Occurrence of Serious Adverse Events (SAEs) within 7 days (early-onset), 8-30 days 
(peri-procedural) and >30 days (late onset) of initial ablation procedure 
▪ 
Occurrence of non-SAEs  
▪ 
Occurrence of clinically symptomatic severe PV stenosis as documented by CT/MRA 
 
• 
Effectiveness 
▪ 
Ablation by a non-study catheter for PVI (touch-up) among all clinically relevant 
targeted PVs and by subject  
▪ 
Acute reconnection identified by adenosine/isoproterenol challenge. 
▪ 
% repeat ablation within the 12M FU period 
• 
Timing (blanking period or after blanking) 
• 
% PV reconnection 
▪ 
Freedom from documented (symptomatic and asymptomatic) atrial fibrillation (AF) 
episodes based on electrocardiographic data (>30 seconds on arrhythmia 
monitoring device) during the effectiveness evaluation period (Day 91-Day 365). 
▪ 
Freedom from documented (symptomatic and asymptomatic) atrial arrhythmia (AF, 
AT or AFL) episodes based on electrocardiographic data (>30 seconds on arrhythmia 
monitoring device) during the effectiveness evaluation period (Day 91-Day 365) with 
the following criteria also deemed failure (Appendix 1):  
• 
Taking a new class I/III AAD for AF or a previously failed class I/III AAD at a 
greater than the highest ineffective historical dose for AF during the 
effectiveness evaluation period 
• 
Greater than 2 repeat ablations for AF/AT/AFL in the blanking period or any 
repeat ablation for AF/AT/AFL during the effectiveness evaluation period 
 
• 
Procedural data, including but not limited to 
▪ 
Total procedure time 
▪ 
Mapping time 

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▪ 
PFA application time 
▪ 
Number of PFA applications by PV and by subject 
▪ 
Total fluoroscopy time 
▪ 
Study catheter dwell time 
▪ 
Ablation settings used  
▪ 
Use of paralytics and anesthesia 
 
• 
Neurological Assessment (Wave I) 
▪ 
Occurrence of new post-ablation asymptomatic and symptomatic cerebral emboli as 
determined by MRI evaluations 
▪ 
Occurrence of new or worsening neurological deficits post-ablation and at follow-
up, compared to baseline 
▪ 
Occurrence, anatomical location and size of asymptomatic and symptomatic 
cerebral emboli observed pre-and post-ablation as determined by MRI evaluations.   
▪ 
Summary of MMSE, NIHSS and mRS at baseline, post-ablation and during follow-up 
(if lesions were identified in prior evaluation).  
 
• 
CT/MRA (Wave I) 
▪ 
Occurrence of severe PV stenosis at 3 months post-ablation as determined by 
CT/MRA evaluations 
 
• 
Endoscopy (Wave I) 
▪ 
Occurrence of post-ablation esophageal lesions as determined by post-procedure 
endoscopy 
9. Study Population 
Patients scheduled to have a clinically-indicated ablation procedure for the management of their 
drug refractory PAF will be screened for enrollment per the study’s inclusion and exclusion criteria. 
The “investigation population” (meeting all inclusion and exclusion criteria) represents the “target 
population” (drug resistant PAF subjects) indicated for catheter ablation per consensus guidelines, 
in addition the criteria listed below ensure mitigation of risks (as per instructions for use and user 
manual) associated with the patients’ health status at the time of screening and contraindications 
for study assessments (as specified further in this protocol). 
9.1 Participant Inclusion Criteria 
Candidates for this study must meet ALL of the following criteria: 
1. Diagnosed with Symptomatic PAF 
2. Selected for AF ablation procedure by PVI 
3. Failed at least one AAD (class I to IV) as evidenced by recurrent symptomatic AF, or 
intolerable or contraindicated to the AAD 
4. Age 18-75 years  
5. Willing and capable of providing consent 
6. Able and willing to comply with all pre-, post- and follow-up testing and requirements. 
 
9.2 Participant Exclusion Criteria 
Candidates will be excluded if ANY of the following criteria apply: 
1. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-cardiac 
cause. 
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3. Patients known to require ablation outside the PV region (e.g. CTI region, 
atrioventricular reentrant tachycardia, atrioventricular nodal reentry tachycardia, 
atrial tachycardia, ventricular tachycardia and Wolff-Parkinson-White).  
4. Previously diagnosed with persistent AF (> 7 days in duration) 
5. Severe dilatation of the LA (LAD >50mm antero-posterior diameter in case of 
Transthoracic Echocardiography (TTE)) 
6. Presence of LA thrombus  
7. Severely compromised LVEF (LVEF <40%) 
8. Uncontrolled heart failure or New York Heart Association (NYHA) Class III or IV  
9. History of blood clotting, bleeding abnormalities or contraindication to 
anticoagulation (heparin, warfarin, or dabigatran) 
10. History of a documented thromboembolic event (including TIA) within the past 6 
months  
11. Previous PCI/MI within the past 2 months 
12. Coronary Artery Bypass Grafting (CABG) in conjunction with valvular surgery, cardiac 
surgery (e.g. ventriculotomy, atriotomy) or valvular cardiac (surgical or percutaneous) 
procedure. 
13. Unstable angina pectoris within the past 6 months 
14. Anticipated cardiac transplantation, cardiac surgery or other major surgery within the 
next 12 months. 
15. Significant pulmonary disease (e.g., restrictive pulmonary disease, constrictive or 
chronic obstructive pulmonary disease) or any other disease or malfunction of the 
lungs or respiratory system that produces severe chronic symptoms 
16. Known significant PV anomaly that in the opinion of the investigator would preclude 
enrollment in this study 
17. Has known pulmonary vein stenosis 
18. Acute illness, active systemic infection or sepsis 
19. Presence of intracardiac thrombus, myxoma, tumor, interatrial baffle or patch or 
other abnormality that precludes catheter introduction or manipulation. 
20. Severe mitral regurgitation 
21. Presence of implanted pacemaker or Implantable Cardioverter-Defibrillator (ICD) or 
other implanted metal cardiac device that may interfere with the IRE energy field. 
22. Presence of a condition that precludes vascular access (such as IVC filter) 
23. Significant congenital anomaly or a medical problem that in the opinion of the 
investigator would preclude enrollment in this study 
24. Categorized as vulnerable population and requires special treatment with respect to 
safeguards of well-being 
25. Current enrollment in an investigational study evaluating another device or drug. 
26. Women who are pregnant (as evidenced by pregnancy test if pre-menopausal), 
lactating, or who are of child bearing age and plan on becoming pregnant during the 
course of the clinical investigation. 
27. Life expectancy less than 12 months  
28. Presenting contra-indications for the devices used in the study, as indicated in the 
respective Instructions For Use (IFU) 
 
Additional exclusion criteria for Wave I subjects: 
29. Contraindication for MRI such as use of contrast agents due to advanced renal 
disease, claustrophobia etc. (at PI discretion)  
30. Presence of iron-containing metal fragments in the body  
31. Unresolved pre-existing neurological deficit. 
32. Uncontrolled significant GastroEsophageal Reflux Disease (GERD) 

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10. Participant Withdrawal or Termination 
 
10.1 
Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request 
without penalty or loss of benefits to which they may otherwise be entitled. Participants will 
be informed prior to study entry that they are free to withdraw from the study at any time 
and for any reason without prejudice to their future medical care by a physician or the 
institution. 
 
An investigator may terminate a subject’s participation in the study if:  
• 
Any clinical AE, laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the 
participant  
• 
Withdrawal is in the subjects’ best interest 
• 
Subject withdraws consent 
• 
Subject is lost to follow-up 
 
Every subject should be encouraged to remain in the study until they have completed the 
protocol required follow-up period. 
 
10.2 
Handling of Participant Withdrawals or Termination 
If a subject is removed or withdraws from the study, the date and reason for withdrawal will 
be recorded on the appropriate electronic Case Report Form (eCRF). If the subject is 
withdrawn due to an AE or SAE, the Investigator should follow the subject until the AE/SAE 
has resolved or is considered stable.   
 
If a subject is unable to return for an office/clinic visit or cannot be contacted by telephone, 3 
separate telephone calls should be made to obtain subject related safety information. All 
attempts should be documented in the source documents. If the subject does not respond to 
the 3 telephone calls, then the investigator must send a certified letter to the subject. If the 
subject does not respond to the letter, then the subject will be considered “lost to follow-up” 
for the study.   
Subjects who have signed the ICF, but are later found not to be eligible PRIOR to insertion of 
the study catheter can be replaced. Replacement subjects will be recruited and enrolled 
following the same procedures as non-replacement subjects. 
10.3 
Subject Enrollment Disposition 
• 
Enrolled Subjects: Patients who sign the ICF. 
• 
Excluded Subjects: Subjects who are enrolled but never undergo insertion of the study 
catheter. Excluded subjects will be subjected to safety event reporting between ICF 
signature and date of exclusion. Subjects who signed the ICF but are found to be ineligible 
prior to insertion of the catheter are also considered as excluded. 
• 
Evaluable Subjects: All enrolled subjects who have the study catheter inserted.  
• 
Discontinued Subjects: Evaluable subjects but do not undergo ablation (i.e., no energy is 
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o Discontinued subjects will remain in follow-up for 3-months post catheter 
insertion.  
o Wave I discontinued subjects are not subjected to the additional Wave I study 
assessments (esophageal, neurological and PV).  
o If an SAE is reported for a discontinued subject, the subject will be followed until 
event resolution (with or without sequelae), stabilization, or until the event is 
adequately explained. 
• 
Lost to Follow-up Subjects:  Evaluable subjects of which contact is lost after most recent 
visit (despite 3 documented attempts to contact the subject). 
• 
Withdrawn / Early Termination Subjects:  Subjects who withdraw consent for study 
participation or are withdrawn by the investigator, are terminated from the study prior to 
completion of all follow-up visits. 
• 
Completed Subjects:  Enrolled subjects who have not been excluded, discontinued, 
withdrawn, terminated early, or lost-to-follow-up from the study prior to the final study 
visit. 
 
11. Responsibilities 
11.1 
Investigator Responsibilities 
Investigators at each participating clinical site will have the following responsibilities: 
• 
Assuring compliance by site personnel with the provisions of the protocol 
• 
Providing the Sponsor with: 
o Signed, dated Investigator Agreement 
o Written Ethics Committee (EC) approval letters and EC-approved consent 
forms 
o Signed, dated Financial Disclosure form for each participating investigator 
o Curriculum vitae for each investigator 
• 
Maintain an accurate and current Delegation of Authority log which identifies 
individuals authorized to perform work for the study and assuring compliance by site 
personnel with the provisions of the protocol 
• 
Completing the appropriate training on the device (ablating investigators only) and 
the study protocol prior to enrolling and treating subjects 
• 
Maintain accurate and current logs for the study such as:  
o Subject log, Device Accountability Log 
• 
Obtain initial and amendment (if applicable) EC approval and annual review/approval 
thereafter for the study protocol and informed consent as applicable 
• 
Obtain ICF and enroll patients 
• 
Perform medical procedures 
• 
Order tests required by the study protocol 
• 
Review pre-procedure imaging pertaining to the PV size prior to treatment 
• 
Follow subjects until the end of the study protocol 
• 
Accurately complete and sign eCRFs in a timely manner 
• 
Maintain relevant source documentation and allow Sponsor direct access to perform 
monitoring or auditing duties  
• 
Maintain records and provide reports according to prevailing regulatory requirements 

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• 
Share relevant study-related information with delegated study staff 
• 
Inform the appropriate entities (e.g., Sponsor, Competent Authority (CA), EC) in a 
timely manner regarding the occurrence of AEs and/or product malfunctions. 
• 
Making sufficient effort to maintain contact with treated subjects who fail to comply 
with the follow-up requirements 
• 
Maintain study records for at least 5 years or as specified per country specific record 
retention requirements after the study is completed and or terminated. The Sponsor 
will notify the Investigator of either of these events. 
• 
Complying with EC and Sponsor annual report requirements, including the final 
report. 
 
11.2 
Sponsor Responsibilities 
The Sponsor (Biosense Webster, Inc.) will be responsible for the following: 
• 
Conduct of pre-study site assessment and approval 
• 
Preparation and modification (if applicable) of study documents including but not 
limited to the protocol, CRFs and informed consent  
• 
Selection of appropriately qualified and trained individuals, including monitors, to 
conduct the study  
• 
Conduct protocol and device training for investigators and research personnel as 
applicable 
• 
Set-up of study-specific committees. 
• 
Obtain signed study contracts from investigators/hospitals, Clinical Research 
Organizations (CROs) and other involved parties 
• 
Ship study devices to each site 
• 
Monitor sites for the duration of the study 
• 
Maintain study database 
• 
Inform investigator of his/her responsibilities  
• 
Submit and obtain approval for study from applicable regulatory agencies 
• 
Preparation of reports summarizing the status of the study no less than annually.  
These reports will be supplied to the PI at each site. 
• 
Update Report of Priors, IFU, IB, and Risk Analyses, as applicable 
• 
Update investigators on safety issues, if needed 
• 
Report (including AE’s and DDs) to study investigators and regulatory agencies, as 
required 
• 
Have relevant safety information reviewed by the study-specific committees, as 
required 
• 
Communications with the CA 
• 
Submission of any amendments to the Clinical Study Protocol/Investigational Plan to 
the CA. 
 
 

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12. Study Device Description 
12.1 
Device Acquisition 
After obtaining a fully executed clinical trial agreement and appropriate approvals, the 
sponsor will initiate shipment(s) of investigational devices to the site. The Sponsor will keep 
records of all investigational devices shipped to the site. Approved investigational devices will 
be shipped directly to the site and will be received by the site. Investigators are responsible 
for appropriate logging of the devices received, verification of packing slip information (i.e., 
lot numbers and quantity shipped), date and identity that each device was used in the study, 
disposition information regarding disposal or return to the Sponsor. 
 
12.2 
Device Storage and Stability 
Devices are to be stored in a secure/locked location and in accordance with the catheter IFU 
and generator User Manual (UM). Do not use the (disposable) devices after the “Use By” date. 
Hardware should not be used past its preventative maintenance date.  
 
12.3 
Device Preparation 
Information related to device preparation can be found in the catheter IFU and generator UM. 
 
12.4 
Instructions for Use 
A comprehensive set of IFU and UM for the study system and all accessory cables/interface 
cables is contained in each product package and is also available upon request.   
 
12.5 
Device Description and Specific Considerations 
12.5.1 Multi-Channel IRE Generator (D-1417-01-I) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1: Picture of the IRE Console 
 
12.5.2 Circular IRE Catheter (D-1412-01-SI) 
 
 
 
  
 
 
 
 
 
 
 

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Figure 2: Picture of the Circular IRE Catheter and Circular Loop 
 
 

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12.6 
Equipment 
12.6.1 System Components and Setup 
 
The Circular IRE Catheter and Multi-Channel IRE Generator system are used in connectivity 
with the following devices to conduct an electrophysiology procedure: 
 
To conduct an electrophysiology procedure, the Circular IRE Catheter and Multi-Channel IRE 
Generator System is used with the following Biosense Webster CE marked devices: 
− 
nGEN™ Irrigation Pump (D-1397-01) 
− 
Irrigation Tubing Sets (SAT001) 
− 
CARTO®3 V7 workstation 
− 
Multi-Electrode Catheter Connection Cable (D-1337-01) 
− 
LASSO® or PentaRay® Catheter 
− 
Carto®3 PIU 
− 
8.5F Compatible Sheath (Vizigo) 
 
The following devices, CE marked by other companies, are also required for the procedure: 
− 
8.5F Compatible Sheath 
− 
Electrophysiology (EP) Recording System 
− 
Stimulator 
− 
Body Surface ECG Patches 
− 
Electrocardiogram (ECG) Leads 
− 
Fluoroscopy/X-Ray System 
− 
Cardiac Defibrillator 
− 
Intracardiac Ultrasound (Investigator preference, not required) 
 
A connectivity diagram for system set up is depicted in Figure 3 and the description of the 
connectivity is explained in table 2. 
 

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12.6.3 Ablation Parameters 
 
When used with the Circular IRE Catheter, the nGEN™ Irrigation Pump will deliver a 
continuous infusion of 4 mL/min of room temperature heparinized saline (1u heparin/1 mL 
saline) when not delivering IRE energy. The recommended operating parameters for the 
Circular IRE Catheter are presented in table 4. 
 
13. Study Medication 
The following medications are applicable for this protocol:  
 
• 
PRIOR to the procedure 
- 
Uninterrupted anticoagulation therapy should be in place at least 3 weeks 
prior to ablation procedure.5  
▪ 
Recommendation: anticoagulation with warfarin (INR 2.0 to 3.0), a 
factor Xa inhibitor, or direct thrombin inhibitor is recommended for 
at least 3 weeks before and at least 4 weeks after ablation regardless 
of the CHA2DS2-VASc score or the method (electrical or 
pharmacological) used to restore sinus rhythm. 
- 
AAD therapy and administration of Proton Pump Inhibitors (PPI) should be 
managed as per the institution’s standard of care 
 
• 
DURING the procedure 
− 
Administer a heparin bolus prior to or immediately after transseptal 
puncture.  
− 
Optimally target an Activated Clotting Time (ACT) of 350-400 seconds prior 
to inserting the study catheter and throughout the procedure.  
▪ 
An ACT below 350 requires additional bolus of heparin until a minimal 
targeted ACT of 350 is reached. 
▪ 
It’s strongly recommended to check ACT levels on regular basis 
during the procedure to ensure an ACT target of 350-400 seconds. 
− 
Flush all tubing and sheath continuously with heparinized saline. 
 
• 
FOLLOWING the procedure 
- 
Anticoagulation therapy is strongly recommended for at least 2 months 
following ablation.  
• 
Decisions regarding continuation of systemic anticoagulation beyond 
2 months post ablation should be based on the subject’s stroke risk 
profile. Per HRS guidance systemic anticoagulation is recommended 
be continued beyond two months post-procedure in subjects with a 
CHA2DS2-VASc score of ≥ 2 (unless deemed contraindicated based on 
clinical considerations). 
- 
PPI administration following the procedure is MANDATORY if an endoscopy is 
performed post procedure. 
- 
AAD management during the study will be at the discretion of the investigator 
- 
Additional medications needed to treat clinical indications are at the 
discretion of the clinical investigation physician. 
 
 

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14. Study Schedule  
14.1 
Screening and Informed Consent 
Candidates presenting to the institution with symptomatic PAF and considered for an ablation 
procedure should be screened by the investigator or designated member of the research team 
for study eligibility per the protocol inclusion and exclusion criteria. Sites will be instructed to 
screen all subjects who require a documented ablation procedure for symptomatic PAF 
without regard to sex or race. 
 
The study investigator or designated member of the research team will obtain written 
informed consent from the subject. The patient informed consent procedure must be done 
within 60 days before the actual study procedure takes place. The background of the proposed 
study and the potential benefits and risks of the study should be explained to the subject. The 
subject or legal representative must sign the consent form prior to any study-specific exams 
or tests are provided to them that fall outside of the standard of care. The consent form used 
must have prior approval from the CAs and study site's EC. Failure to obtain informed consent 
renders the subject ineligible for participation in the study. 
 
The investigator and/or designee must also clearly document the process of obtaining 
informed consent in the subject’s source documents. The voluntary process of informed 
consent confirms the subject’s willingness to participate in the study. It’s the investigator’s 
responsibility to ensure that the informed consent process is performed in accordance with 
International Conference on Harmonization-Good Clinical Practices (ICH-GCP) and with 
applicable local and national regulations. If new information becomes available that can 
significantly affect a subject’s future health and/or medical care, this information shall be 
provided to the subject(s) affected in written form. If relevant, all affected subjects shall be 
asked to confirm their continuing informed consent in writing by dating and signing an 
amended ICF. 
 
Each subject screened for enrollment in the clinical investigation who signs the patient ICF will 
be enrolled into the study. No subject should undergo any clinical investigation specific tests 
or examinations that fall outside the standard of care without first signing the patient ICF for 
this clinical investigation.   
 
14.2 
Baseline Evaluation and Procedures 
 
14.2.1 Pre-Procedure/Baseline Assessments 
Below pre-procedure assessments and data collection must be performed prior to the 
ablation procedure.   
- 
Patient Information and Consent (procedure must be done within 60 days of consent) 
- 
Demographics (age, gender, etc). 
- 
Medical history, including but not limited to arrhythmia, heart disease, thromboembolic 
events, lung/respiratory problems. 
o AF history (first evidence of AF, number of episodes, symptoms, etc). 
o NYHA Functional Class Scale. 
o CHA2DS2 VASc Score. Subjects will be scored against the CHA2DS2 VASc.  

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o Vital signs (length, weight, etc.) 
o Medication history: Medication history (cardiac medication, AAD medication, 
anticoagulation regimen and any other clinically significant medication history) 
shall be gathered by interview or from medical records following enrolment but 
prior to the ablation procedure and should be recorded in the eCRF.  
o Anticoagulation therapy: Uninterrupted anticoagulation management is 
mandatory for each study subject. For subjects on warfarin/coumadin therapy, 
subjects shall be maintained on Warfarin/Coumadin for at least 3 weeks prior to 
treatment with an INR ≥ 2 (to be confirmed maximum 48h hours pre-procedure). 
Any INR <2 within 3 weeks prior to ablation will lead to exclusion of the patient or 
postponement of the study procedure. The results must be available prior to start 
of procedure.  
- 
Pregnancy test must be done on all women of childbearing age and potential within 72-
hours prior to the procedure and documented in the subject’s medical chart. 
- 
Imaging (TTE or other acceptable equivalent cardiac imaging – i.e. CT/MRI) within 6 
months prior to procedure to assess the LA and LVEF. Must be collected within 6 months 
prior to procedure, in case of the imaging assessment is older than 6 months LA/LVEF, 
dimensions shall be re-measured during the index procedure prior to insertion of the 
study catheter. In case of re-measurements before study catheter insertion fail to meet 
the LA and/or LVEF criteria, the subject will be considered as not meeting eligibility and 
will be excluded.  
- 
Imaging for detection of left atrial thrombus or other structural contraindications to an 
ablation procedure is mandatory the day before or the day of the ablation procedure. 
Presence of a thrombus will require postponement of the ablation procedure or may even 
lead to exclusion of the subject from further study involvement. The imaging method to 
be used for atrial thrombus detection is TEE, Intracardiac Echocardiography (ICE), Cardiac 
CT or MRI 
- 
Electrocardiogram (12-Lead ECG). Data from 12-lead ECG recordings will be collected if 
performed standard of care.  
- 
Adverse Events must be collected from the time the subject signs the informed consent 
onwards. 
- 
Quality of life via the Atrial Fibrillation Effect on Quality-of-Life (AFEQT™) questionnaire 
(non-Standard of Care). Note: Patient questionnaires will only be used in countries with 
validated languages 
- 
Cardiac CT/MRA is required to be performed within 6 months prior to the ablation 
procedure to assess the structure and size of the PVs and the left atrial anatomy. 
 
Additional Assessments for Wave I subjects: 
- 
Cerebral MRI, Neurological Exam and Neurological Evaluation using the MMSE, NIHSS 
and mRS (non-SOC) are required to be performed within 72-hours pre-procedure (for 
procedures on Monday a window of a maximum of 96 hours is justified) to evaluate the 
neurological condition and presence of neurological deficits of the subjects before 
undergoing study ablation procedure. A certified/qualified physician expert must perform 
neurologic exams at pre-and post-ablation and possibly at other follow-up visits, pending 
previous findings of micro-emboli/neurologic deficits. Pre-and post-ablation cerebral 
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anatomical location of cerebral micro-emboli, if any. Note: Patient questionnaires will 
only be used in countries with validated languages 
 
14.2.2 Study Ablation Procedure Guidelines 
 
14.2.2.1 
Ablation Selections 
 
There are 10 electrodes in the Circular IRE Catheter. The Multi-Channel IRE Generator creates 
pulsed electrical fields by delivering bipolar and biphasic energy though electrode pairs. 
Ablating with electrode pairs creates a closed electrical circuit between two adjacent 
electrodes and between two alternated electrodes. While the generator activates electrodes 
in groups of adjacent trios, only one electrode pair will deliver energy at a given time. 
 
Ablations can be performed using a minimum of 3 adjacent electrodes or 1 electrode trio, and 
a maximum of 10 electrodes or 8 electrode trios to target desired regions of tissue. Multiple 
electrode trios can be activated during an ablation. When selecting multiple electrodes, the 
system will automatically activate electrode trios (up to two trios) in between the selected 
electrode trios to prevent gaps. For example, if you select electrode trios 1 3 and 4 6, the 
system will automatically activate electrode trios 2 4 and 3 5. See Figure 4 for an example of 
electrodes activated in adjacent trios. To activate all electrodes at once, use the All Electrodes 
toggle, as shown in Figure 5 
 
The system delivers energy in pulses. The quantity of pulses is determined by the PFA levels: 
Min or Max. To adjust the level of energy delivered to the tissue, select the desired PFA level 
prior to starting ablation. 
 
 
Figure 4: Electrode Selection 
 
 
 
 

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▪ 
The type of monitoring method/device and clinical practice associated 
with the observations of this data will be collected in the CRFs. 
- 
Placement of diagnostic catheters: 
▪ 
Coronary sinus catheter in the CS for pacing purposes 
▪ 
Other catheters may be placed at the discretion of the investigator 
- 
At the discretion of the investigator, introduce an Intracardiac Echo (ICE) probe to 
review LA anatomy and PVs 
- 
Administration of heparin bolus prior to or immediately after transseptal 
puncture.  
- 
A single or double transseptal puncture should be performed per standard EP lab 
(at the discretion of the investigator). 
- 
Mapping: 
- 
Following successful transseptal puncture, a left atrial map is required before 
ablating,  
▪ 
Wave I: it’s highly recommended to use the Circular IRE catheter, possible 
substituted by the use of Lasso®, PentaRay® or 3D rotational angio (at 
investigator discretion). 
▪ 
Wave II: utilizing the Circular IRE Catheter, Lasso®, PentaRay®, or 3D 
rotational angio (at investigator discretion). 
- 
Create a voltage map, if SOC 
- 
PVI: 
- 
Confirm targeted ACT 350-400 seconds. Systematic anticoagulation with heparin 
should be administrated with ACT level checked on regular basis during the 
procedure to ensure an ACT target range of 350-400 seconds.  
- 
Introduction of the 8.5 F compatible sheath, if not used for mapping.  
- 
Introduce the Circular IRE Catheter as per IFU, if not used for mapping. 
- 
Advance and position the Circular IRE Catheter at the targeted PV.  
- 
When position is satisfactory, commence energy delivery with the Circular IRE 
Catheter.  
▪ 
Recommended workflow: 
a) Left pulmonary veins and carina position and ablate with 
contracted and wider loop 
b) MANDATORY: prior to ablation in the region of the right sided 
PVs, precautionary measures to evaluate the proximity to the 
phrenic nerve. 
o Evaluate the diaphragm while pacing the phrenic nerve. 
o Assure diaphragmatic capture PRIOR to voltage delivery. 
c) Right pulmonary veins position and ablate with contracted and 
wider loop 
▪ 
Use the maximum PFA level. Consider using the minimum PFA level when 
repeated applications are applied. Use clinical judgment and consider 
patient anatomy and the catheter position to determine if minimum PFA 
level should be used.  
▪ 
Do not allow ablation electrodes to overlap during application of PFA 
energy. Doing so may cause an error message to appear and stop the 
ablation before completion. In case of overlap, change the catheter 
position or turn off overlapping electrodes on the monitor to perform 
ablation. 
- 
All subjects will undergo PV ablation with the Circular IRE Catheter until PVI is 
achieved in all targeted PV’. 
▪ 
IRE ablation is to be used as the primary mode for PVI.  

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▪ 
If isolation is not obtained after circular PFA applications described above, 
review remaining signals and deliver PF energy with corresponding 
electrodes. 
▪ 
ONLY after the investigator deems IRE ablation unable to achieve PVI 
should the lab be switched to commercial RF setup to complete the 
procedure (PVI only). Note, to prevent any risk to the patient, the IRE 
system should be completely disconnected prior to use of an RF system. 
- 
Confirmation of entrance block (and exit block if SOC) (PVI) of all clinically relevant 
targeted PVs. 
▪ 
To verify entrance block, analyze electrograms in coronary sinus and/or 
atrial paced rhythm to confirm that no PV potentials are present.  
- 
Ablation outside the PV region is NOT allowed with IRE ablation modality (further 
details below). 
- 
Post PVI: 
- 
Administer adenosine/isoproterenol for each clinically relevant targeted PV to 
rule out dormant conduction  
▪ 
If any, treat reconnected PV regions by reviewing remaining signals on 
reconnection location and deliver PF energy with corresponding 
electrodes. 
- 
Confirmation and documentation of final entrance block (exit block is optional) 
(PVI) of all clinically relevant targeted PVs 
▪ 
To verify entrance, analyze electrograms in coronary sinus and/or atrial 
paced rhythm to confirm that no PV potentials are present.  
▪ 
Wave I: use Circular IRE Catheter AND Lasso® or PentaRay® for 
confirmation 
▪ 
Wave II: use Circular IRE Catheter, Lasso® or PentaRay® for confirmation 
per investigators choice 
- 
The ablation procedure is considered complete when confirmation of entrance in 
clinically relevant targeted PVs is confirmed. 
- 
Recommendation: after confirmation of final entrance block (exit block is 
optional) block, evaluate diaphragmatic capture while pacing the phrenic nerve. 
 
Ablation outside the PV region 
 
- 
Prophylactic ablation outside the PV region (in example SVC, roofline, CTI) is NOT 
allowed.  
- 
If an arrhythmia requiring ablation outside the PV is identified. 
o prior to insertion of the study catheter (consistent with exclusion criteria) 
investigators will be required to switch to the commercial setup using a 
commercially available Biosense Webster catheter used with a commercially 
available RF generator.  The subject will be considered a screen failure (<ICF 
signature or excluded from the study (> ICF signature). 
o after insertion of the study catheter, the subject will undergo PVI with IRE 
ablation modality followed by commercial RF therapy to complete the 
procedure (treatment of arrhythmia outside PV region). The subject will be 
evaluable for acute success but excluded from the long-term effectiveness 
cohort and followed till 3-months post procedure. Note: Ongoing AE(s) at 
month 3 shall be followed up until resolution (with or without sequelae). 

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14.2.3 Collection of Ablation Procedure Data for Post-Analysis (non-SOC) 
 
At the completion of the study ablation procedure, two back-up copies of the CARTO®3 and 
generator system log files will be made. One copy should be kept at the site within the 
investigator site or patient binders, and one fully anonymized copy will be provided 
to/collected by the Sponsor.  
 
 
14.2.3.1 
Data Collection during Study Ablation Procedure 
 
The following information will be collected during the procedure, including but not limited to: 
Technical parameters are collected via CARTO® datafiles and generator files, including 
but not limited to: 
- 
Number of PFA applications  
- 
Energy delivered  
- 
PFA application time 
- 
Ablation settings 
- 
Ablation lesion information will be collected in the CARTO®3 system and IRE 
Generator  
 
Other procedural parameters are collected via Electronic Data Capture (EDC), including 
but not limited to: 
- 
Use of a non-study catheter for PVI 
- 
Number of PFA applications per target PV 
- 
Number of RF applications required with a non study catheter 
- 
PVI confirmed with Lasso® or PentaRay or Circular IRE Catheter 
- 
PV acute reconnection (early or dormant) 
- 
Procedure time (from first femoral puncture to last catheter out) 
- 
Mapping time (start mapping - end mapping) 
- 
Total fluoroscopy time 
- 
Total study catheter LA dwell time (from first study catheter insertion in LA until study 
catheter removal from LA) 
- 
ECG data 
- 
Total fluid delivered via study catheter 
- 
Total fluid delivered via intravenous line (if captured) 
- 
Fluid output (if captured) 
- 
Device deficiency information (if applicable) 
- 
Procedural medication (paralytics) 
- 
Anesthesia type 
 
14.2.4 Pre-Discharge Assessments 
 
Prior to hospital discharge, the following assessments should be performed: 
- 
Medication regimen (Cardiac, anti-coagulation, PPIs) 
- 
Imaging assessment of pericardial fluid presence 
- 
AEs events 
- 
ECG in case standard of care 

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- 
For Wave I subjects (non-SOC): 
o Cerebral MRI, neurological exam and neurological evaluation using the NIH 
stroke scale within 72-hours post procedure, preferable prior to discharge.  A 
certified/qualified physician expert must perform neurologic exams at pre-
and post-ablation and possibly at other follow-up visits, pending previous 
findings of micro-emboli/neurologic deficits. For procedures on Friday a 
window of a maximum of 96 hours is justified. Note: Patient questionnaires 
will only be used in countries with validated languages 
o Endoscopy to check for any esophageal lesions and/or damage will be 
performed preferable prior to discharge and no later than 72 hours after 
procedure (for procedures on Friday a window of a maximum of 96 hours is 
justified). Endoscopy images will be transmitted to a central reader. 
 
14.2.5 Repeat Ablation Procedures 
Repeat procedures may be performed at the discretion of the investigator. It is highly 
recommended to collect arrhythmia documentation (in example documented recurrences) 
before performing a repeat procedure.  
Repeat procedures during the blanking period (90 days post index procedure) must be 
conducted with the investigational device, with or without focal touch-up, if the arrhythmia is 
due to PV triggers. If the arrhythmia is due to non-PV triggers and the subject is treated with 
a commercially available ablation catheter and generator, the subject will be excluded from 
the long term effectiveness cohort. 
Repeat procedures performed after the blanking period may be managed per investigator 
discretion using a commercially available ablation catheter and generator.  
The follow-up schedule will remain based on the initial ablation procedure. 
 
14.3 
Post-Ablation Follow-up Schedule 
 
The subject will be required to complete follow-up visits through 12 months post initial 
ablation procedure. Follow-up will be done at 7 days (phone call or clinic visit), 1, 3, 6 and 12 
months (clinic visit).   
 
At 7-day follow-up visit, the following assessments will be performed: 
Discharged subjects will receive a telephone call or have a clinic visit at 7 days (7D, day 7-9) 
post ablation procedure to assess any occurrence of Primary Adverse Events and any change 
in medication regimen;  
 
Follow-up visits should be scheduled according to the following timeframes: 1 month (1M 23-
37), 3 months (3M, day 76-104), 6 months (6M, day 166-194) and 12 months (12M, day 335-
379). Follow-up visit schedule should be based on the date of the index study ablation 
procedure and will not reset if subject undergoes a repeat AF ablation procedure. 
 
 
At 1, 3, 6 and, 12-month follow-up visits, the following assessments will be performed: 
- 
Medical evaluation: 
▪ 
AEs 
▪ 
Cardiac and Anti-coagulation medication regimen 
▪ 
Cardiac related hospitalization and cardioversions 
▪ 
12 Lead-ECG (if completed per standard of care) 

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- 
Atrial arrhythmia monitoring as from month 3 (non-SOC) 
- 
Remote Monitoring: 
Subjects will be provided with a remote monitoring device at the 3M FU visit and 
asked to record and transmit a minimum of 1 transmission (≥ 30 seconds) every 
week through the end of the month 5 of FU. Starting at month 6 of FU, subjects 
will be asked to record and transmit a minimum of 1 transmission (≥ 30 seconds) 
every month until the effectiveness evaluation period is completed (12 months 
post index procedure). Subjects will also be asked to transmit any symptom-
triggered episode that occurs from the time they receive the remote monitoring 
device through the 12M FU visit. A core lab might be used to evaluate and assess 
the remote monitoring tracings. 
 
Remote monitoring will be conducted as follows:  
• 
Distribution and start by month 3 
• 
<6M: Weekly transmission of at least 1 scheduled recording  
• 
≥6M: Monthly transmission of at least 1 scheduled recording 
• 
Conduct and transmit recording whenever symptoms are present  
 
- 
24 Hour Holter: 
Holter monitor will be used at each follow-up visit to monitor the subjects’ heart 
rhythm for 24 hours continuously. Following the 24h Holter, subjects will be 
contacted by the site to verify if symptoms are experienced during 24h Holter.  
- 
Quality of life via the Atrial Fibrillation Effect on Quality-of-Life (AFEQT™) 
questionnaire (non-SOC), at Month 3, 6 and 12. Note: Patient questionnaires will only 
be used in countries with validated languages. 
- 
Cardiac CT/MRA 
• 
Wave I subjects: is required to be performed at the 3M FU visit (non-SOC) or 
any other point in time when subject presents with symptoms of PV stenosis. 
• 
Wave II subjects: is only required to be performed if subject presents with 
symptoms of PV stenosis. 
- 
Wave I subjects only: Cerebral MRI, Neurological Exam and Neurological Evaluation 
using the MMSE, NIHSS and mRS (non-SOC) are required to be performed if any 
neurological symptoms and/or cerebral ischemic lesions were identified at a prior 
evaluation. Note: Patient questionnaires will only be used in countries with validated 
languages. 
14.4 
Early Termination Visit 
If early termination of the study is required due to safety concerns, each site will undergo a 
monitoring visit to conclude any outstanding issues, collect all outstanding CRF information, 
verify device accountability, and discuss any other items relevant to the conclusion of the 
study.  Any enrolled subjects will continue to be followed per the study protocol requirements. 
In case of early termination due to safety concerns, reporting to EC and CA may be required 
per local regulations. 
 
14.5 
Unscheduled Visit 
If a subject returns for a potential study related cardiovascular or neurological visit outside of 
the protocol-defined visit schedule provided in table 5, the visit will be considered 
“unscheduled” (UNS).  An investigator may request an unscheduled visit in the presence of a 
new or worsened cardiovascular condition or neurological deficit. If the unscheduled visit is 

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for a repeat ablation procedure, the protocol follow-up schedule is based on the index 
ablation procedure.  For all unscheduled visits, an unscheduled visit eCRF must be completed 
and the subject must also return for their next scheduled study visit per clinical investigational 
plan. 
 
14.6 
Core Laboratory for Evaluation 
Independent central core laboratories or expert physician(s) will conduct objective 
evaluations of remote monitoring tracings, Holter, Cerebral MRI, endoscopy and will evaluate 
PV stenosis of all subjects enrolled in Wave I (independently of symptoms) and symptomatic 
subjects of Wave II. 
 
 

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5. 
Performed the day before procedure or day of ablation procedure to rule out the presence of atrial thrombus using 
one of the following modalities TEE, ICE, CT, MRI. 
6. 
If Standard of care assessment (For pre-procedure, can be performed before ICF signature) 
7. 
Arrhythmia monitoring via remote monitoring once per week as from 3-month follow-up visit to the end of 5-month 
follow-up and monthly as of 6-month follow-up visit and whenever subject feels symptoms. 
8. 
Arrhythmia monitoring via 24H Holter, site to contact subject and verify if any symptoms experienced during the 
Holter monitoring. 
9. 
Information on any repeat ablation after the index procedure will be collected 
10. Concomitant medication: only cardiac (i.e. anti-arrhythmia drugs, anticoagulation regimen) & index procedure related 
(i.e. adenosine, pain medication) 
11. AEs must be collected from the time the subject signs the informed consent onward.  
12. To be completed within 6 months prior to ablation procedure, For Wave I subjects: CT-MRA to be repeated at 3M FU. 
For Wave I and Wave II subjects, CT-MRA to be repeated post procedure in case subject presents with PV stenosis 
symptoms. 
13. Endoscopy preferable prior to discharge and no later than 72-hours after procedure. For procedures on Friday a 
window of a maximum of 96 hours is justified. 
14. If observations are noted on the post-procedure MRI, the subject must have follow-up MRI at the next follow-up 
visit(s) until observations are resolved. 
15. A certified/qualified physician expert must perform neurologic exams at pre-and post-ablation and possibly at other 
follow-up visits, pending previous findings of micro-emboli/neurologic deficits. 
16. To be completed within 72-hours pre-procedure. For procedures on Monday a window of a maximum of 96 hours is 
justified. 
17. To be completed within 72-hours post-procedure. For procedures on Friday a window of a maximum of 96 hours is 
justified. 
18. Full neurological follow up to be undertaken if neurologic symptoms and/or cerebral ischemic lesions identified in a 
prior evaluation.  
19. If subject returns for a potential study related cardiovascular or neurological visit outside of the protocol-defined visit 
schedule as deemed required per investigators discretion. 
20. Patient questionnaires will only be used in countries with validated languages. 
 
 

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15. Assessment of Safety 
 
15.1 
Specific Safety Parameters 
Pursuant MDR 2017/745, in the occasion relevant (local) regulations, guidance(s) and 
processes on safety determinations, definitions and reporting become in full force during the 
course of the study, the Sponsor shall adhere to the applicable definitions and processes. 
 
15.1.1 Definition of Adverse Events (AE) 
 
An AE is any untoward medical occurrence in a subject whether or not related to the 
investigational device. 
 
Specifically, an AE is any undesirable experience (sign, symptom, illness, abnormal laboratory 
value, or other medical event) occurring to a subject during the course of the study, whether 
or not it is related to the investigational device or procedure.  Physical findings (including vital 
signs) observed at follow-up, or pre-existing physical findings that worsen compared to 
baseline are considered AEs. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. Such conditions should be added to 
background medical history, if not previously reported. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  
 
Following arrhythmia’s do not meet the definition of an AE: 
• 
AF recurrence by itself is considered a recurrence of disease (pre-existing condition) 
• 
Recurrence of pre-existing or underlying (treated during index procedure) AFL/AT is 
considered as a recurrence of disease 
• 
Onset of non-previously identified AFL/AT which was treated during the index 
procedure as underlying arrhythmia (pre-existing condition) 
• 
Re-ablation for AF or any pre-existing AFL/AT, however any procedural complication 
is considered an AE and shall be reported within the applicable timelines. 
• 
Re-ablation for any non-pre-existing (underlying) AFL/AT which was treated during 
the index procedure, however any procedural complication is considered an AE and 
shall be reported within the applicable timelines. 
• 
Cardioversion (pharmacological or synchronized electrical) for AF/AFL/AT 
recurrence during the hospitalization for the index ablation procedure, or 
throughout the duration of the study. 
 
Following arrhythmia’s meet the definition of an AE: 
• 
Onset of non pre-existing AFL/AT which was not treated during the index procedure. 
 
 
 
 
 
 
 

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Conduction block 
Respiratory failure 
Coronary Artery Stenosis 
Respiratory infection 
Coronary artery thrombosis 
Retinal Artery Embolism 
Death 
Retroperitoneal bleeding 
Deep venous thrombosis 
Rhabdomyolysis, including produced by body 
position or propofol 
Diaphragmatic paralysis 
Sedation induced CO2 retention with lethargy and 
cholecystitis 
Dislodgement/Malfunction of 
pacemaker/defibrillator leads 
Seizure 
Disseminated Intravascular Coagulation 
Sepsis 
Dizziness, presyncope, vertigo 
Sinus bradycardia 
Dysphagia 
Sinus tachycardia 
Dyspnea 
Skin burn or necrosis 
Endocarditis 
Skin discoloration 
Epigastric Distress 
Skin edema 
Epistaxis 
Skin or soft tissue (radiation) injury/tear 
Esophageal injury / perforation 
Subclavian artery puncture 
Expressive aphasia 
Temperature elevation / Fever 
Fatigue 
Thrombocytopenia 
Gastric hypomotility 
Thromboembolism 
Gastroesophageal reflux 
Thrombosis 
Gastrointestinal disorders 
Thyroid disorders 
Gastrointestinal diverticulosis 
Toxic reaction 
Gastroparesis 
Transient extremity numbness 
Headache 
Transient Ischemic attack (TIA) 
Heart failure (acute or chronic) 
Urinary Retention Postoperative 
Heart injury 
Urinary tract injury or infection related to the 
urinary catheter 
Heart valve insufficiency 
Valvular damage/insufficiency 
Hemoptysis 
Vascular (access) dissection (including coronary 
arteries) 
Hemorrhage 
Vascular occlusion 
Hemothorax 
Vasovagal reactions 
High/increased creatine phosphokinase (CPK) 
Ventricular Fibrillation 
Hypertension 
Vessel damage/trauma 
Hypervolemia 
Vessel perforation 
Hypotension 
Vessel spasm (including coronary arteries) 
Hypovolemia 
Visual disturbance 
Hypoxia 
Worsening of pre-existing pulmonary disease  
Increased phosphokinase level 
Wound healing disturbance 
Infection, localized  
  
*Atrial Fibrillation and exacerbation of an existing arrhythmia are anticipated adverse events.  
However, they will not be captured as such under this protocol, as they are considered recurrence of 
disease. 
 

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15.3 
Time Period and Frequency for Event Assessment and Follow-up 
 
The investigator, or designated individual, will record all reportable events with start dates 
occurring any time after informed consent is obtained. At each study visit, the investigator will 
inquire about the occurrence of AEs/SAEs since the last visit.  
 
All AEs, especially SAE’s, need to be followed until the event is resolved (with or without 
sequelae), stabilization, or until the event is adequately explained. The medical monitor or 
designee of this clinical investigation will decide if more follow-up information is needed in 
case the event is not resolved at study completion. All required treatments and outcomes of 
the SAE must be recorded in the eCRF. 
 
15.4 
Reporting Procedures 
 
15.4.1  Adverse Event Documentation and Reporting Requirements  
 
Subjects should be encouraged to report AEs spontaneously or in response to general, non-
directed questioning (e.g. “How was your health been since last visit?”). Anytime during the 
study, the subject may volunteer information that resembles an AE. 
 
Each AE must be reported to the sponsor regardless of classification, seriousness, intensity, 
outcome or causality. The investigator is responsible for ensuring that all AEs observed by the 
investigator, or reported by the subject, that occur from the time that the subject has signed 
the informed consent through the end of the study are properly assessed, recorded, and 
reported as defined and described in the AEs, Adverse Device Effects and Device Deficiencies 
section of this protocol (section 15). All AEs must be documented by completing subject’s 
medical records (source documents) and appropriate eCRF by the investigator or study 
coordinator throughout the study and provided to the Sponsor.  All AEs will be monitored until 
they are adequately resolved or explained.   
 
Anonymized documentation pertaining to the AE (e.g. laboratory tests, consultation reports, 
post-mortem reports, new information relating to a previously reported AE, correspondence 
with the local EC, etc.) will be provided by the investigator to the sponsor or designee in a 
timely manner, when requested.  Follow-up reports relative to the subject’s subsequent 
course must be submitted to the sponsor or designee until the event has resolved or, in case 
of permanent impairment, until the condition stabilizes.  If the subject is withdrawn from the 
study because of the AE, the information must be included on the appropriate eCRFs. 
 
The Sponsor is responsible for the classification of AEs and ongoing safety evaluation of the 
study and shall review the investigator’s assessment of all AEs. The sponsor will determine 
and document in writing their seriousness and relationship to the investigational device. In 
case of disagreement between the sponsor and the PIs, the sponsor shall communicate both 
opinions to the concerned parties. 
 
Biosense Webster will ensure that investigators are instructed to return devices suspected of 
causing an AE or SAE (i.e., definitely (causal relationship) device-related or possibly device-
related) in accordance with relevant regulations and current company procedures. 

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requirements. Event reporting to relevant CAs for non CE-marked devices will occur by the 
sponsor and if indicated per local country requirements by the investigator.  
 
15.4.3 Unanticipated Device Effect Reporting 
 
All UADE/SADE/USADE must be reported to the Sponsor, via eCRF, immediately upon 
awareness of event but no later than 72 hours by the study site personnel.  An investigator 
shall submit to the reviewing EC a report of any UADE occurring during an investigation 
according to EC requirements. 
 
 
15.4.4 Events of Special Interest 
 
All study device failure/malfunction must be reported to the Sponsor, via eCRF, as soon as 
possible, within 72 hours by the study site personnel.  If a device failure is detected or 
suspected, it should be documented on the eCRF and the device returned according to the 
Sponsor’s instructions.  
 
The investigational device should be sent to appropriate R&D team or designated Quality 
engineer. Complaints related to non-investigational products manufactured and/or 
distributed by Biosense Webster, used during the procedure related to other devices (other 
than the study device under investigation), are to be reported according to current Biosense 
Webster procedures and other policies as necessary (i.e., institutional policies, EC policies, and 
local regulations). Investigators are instructed to return devices in accordance with current 
company procedures and other relevant regulations.  
 
Event reporting to relevant CAs in accordance with the jurisdictional regulations will occur by 
the sponsor and/or by the investigator, depending upon the local requirements and will be 
done in EU per MEDDEV 2.12/1 guidelines for CE-marked devices manufactured by Biosense 
Webster and per MEDDEV 2.7/3 guidelines for non CE-marked devices manufactured by 
Biosense Webster.  
 
A device deficiency related to a medical device not manufactured by Biosense Webster should 
be reported by the investigator to their respective manufacturer as per relevant regulation. 
Complaints related to non-Biosense Webster, Inc. products must be handled according to 
institutional policies, EC policies, and local regulations. 
 
15.5 
Safety Oversight 
 
Safety oversight will be conducted as described in the Safety Management Plan. Aggregate 
safety data will be reviewed during enrollment by the study safety lead in order to promptly 
identify new issues or trends which may have an impact on the conduct of the study and/or 
subject safety. Under the rules of an approved study-specific charter, safety events will be 
reviewed by an established committee which may recommend appropriate action(s) to 
ensure subject safety.  
 
 

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16. Administrative Responsibilities 
16.1 
Ethics Committee and Competent Authority Application 
The study protocol (or amendment[s]), ICF, and other applicable study related documents 
must be approved by the EC and CAs before enrollment of subjects. Any additional 
requirement imposed by the EC or CA shall be discussed, agreed upon, and followed. A signed 
copy of the EC and CA approval letters addressed to the investigator must be submitted to 
Biosense Webster certifying study approval prior to subject enrollment. Biosense Webster and 
the EC must approve, in writing, any changes to the protocol that affect the rights safety 
and/or welfare of the subjects or may adversely affect the validity of the study. 
 
In addition, Biosense Webster, Inc. is responsible for notifying the relevant CA of the intention 
to perform a clinical investigation under this protocol and ensure to get the official response/ 
approval before starting the clinical investigation. 
 
16.2 
Audits and Inspections 
The sponsor and/or designee and/or CAs may contact the participating institution to inform 
the investigator of an upcoming audit/inspection. The investigator should immediately notify 
the sponsor of any CA audits/inspection at the study site. The audit/inspection can include the 
review of documents, facilities, records and any other resources deemed by the authorities to 
be related to study. 
 
17. Deviations from the Clinical Study Plan 
 
The investigator is responsible for ensuring that the clinical investigation is conducted in 
accordance with the procedures and evaluations described in this protocol. The study 
monitors shall verify that the conduct of the study is in compliance with the currently 
approved protocol and applicable regulations and shall identify any issues of non-compliance 
with regulations or guidelines. 
 
Issues of non-compliance include but are not limited to repeated protocol deviations; failure 
to obtain proper informed consent; non-conformance to EC requirements; failure to report 
AEs, product malfunctions and other product issues; and other non-conformance to GCP. 
 
A protocol deviation is defined as an instance of failure to follow, intentionally or 
unintentionally, the requirements of the protocol (e.g. missed test or procedure, visit out of 
window, non-adherence to inclusion/exclusion criteria). Investigators are not allowed to 
deviate from the protocol. Waivers are prohibited for this clinical study. Protocol deviations 
will be monitored closely and will be reported per EC/CA requirement.  
 
Under emergency circumstances, deviations from the protocol to protect the rights, safety 
and well-being of a subject may proceed without prior approval of the sponsor and EC.  Such 
deviations shall be documented and reported to the sponsor and the EC as required. 
 
All instructions described in this study protocol are to be followed. If an amendment is 
required, it must be made in written form and receive approval from all persons and 

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authorities who approved the original protocol. Administrative changes (do not affect 
subject’s benefits/risks ratio) may be inserted with abbreviated approval. All amendments will 
be distributed to all original protocol recipients. 
 
18. Investigational Product  
18.1 
Use of the Investigational Device and Investigator Experience 
18.1.1 Training 
The training of applicable clinical site personnel will be the responsibility of the Sponsor. Prior 
to initiating subject enrollment at a site, appropriate study training will be provided.  
Investigators selected to participate in the study will be experienced in intracardiac mapping 
and AF ablation. Investigators will undergo device and IRE technology training in accordance 
with the physician training charter.  
 
To ensure uniform data collection and protocol compliance, the Sponsor will conduct a 
training session that will include reviewing the protocol, eCRF and data collection process, and 
the AE reporting process. The sponsor will reinforce the training or provide clarification 
throughout the study, as needed. 
 
18.1.2 Materials 
 
IRE Generator 
Biosense Webster, Inc. USA, is the legal manufacturer of the generator to be used in this study 
in a manner similar to standard, commercially approved Biosense Webster products.  
 
Complete manufacturing records of each generator manufactured for human use during this 
study are maintained at the respective manufacturing location. Each generator is released for 
human use under a Confirmation of Conformity from Regulatory Affairs that will certify that 
the investigational generator conforms to the Essential Requirements for product release 
apart from those features, that are being investigated in this clinical investigation.  And that, 
with regard to these aspects, every precaution has been taken to protect the health and safety 
of the patient. 
 
Circular IRE Catheter 
Biosense Webster, Inc. USA, is the legal manufacturer of the catheters to be used in this study. 
The investigational devices were built in a clean room environment, and sterilized using EtO 
gas, in a manner similar to standard, commercially approved Biosense Webster products.  
Further detail of catheter components coming into contact with the human body are 
described in the Investigator Brochure. 
 
Complete manufacturing records of every lot of catheter manufactured for human use during 
this study are maintained at the respective manufacturing location. Each lot of catheters is 
released for human use under a Confirmation of Conformity from Regulatory Affairs that will 
certify that the investigational catheters conforms to the Essential Requirements for product 
release apart from those features, that are being investigated in this clinical investigation.  And 
that, with regard to these aspects, every precaution has been taken to protect the health and 
safety of the patient. 
 
 
 

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18.2 
Device Acquisition and Accountability 
After obtaining a fully executed clinical trial agreement and appropriate CA/EC approvals, the 
study site will receive the necessary amount of study-related materials prior to 
commencement. Study-related devices (investigational and non-investigational) will be 
shipped to the site upon completion of required documentation. Investigational Study Devices 
will be labeled as “Investigational Device” and are only to be used for subjects enrolled in this 
clinical study.  
 
The Sponsor will keep records of all investigational devices shipped to the site.  Investigational 
site personnel are responsible for appropriate logging of devices received, verification of 
packing slip information (i.e. lot numbers and quantity shipped) and date and identifying that 
each device was used in the study and disposition information completed when returned to 
the Sponsor.  
 
The Investigational Device Accountability Log shall record the following information: 
- 
Date of receipt 
- 
Person in receipt of the devices 
- 
Quantity received 
- 
Catalog number  
- 
Serial/lot numbers 
- 
Expiry Date 
- 
Date device was used 
- 
Subject ID on whom device was used 
- 
Date of return 
- 
Reason for return (i.e. used without incident, malfunction, expired, end of study, 
…)  
 
18.3 
Device Returns 
All investigational devices (used and unused) will be returned to the Sponsor’s attention and 
per Sponsor’s Instructions. The Circular IRE catheter shall be returned to the below address. 
Device deficiencies should be properly documented on the eCRF. Any suspected 
malfunctioning device or device associated with an AE (device related or possibly device 
related) will undergo a thorough complaint analysis All returned devices must be properly 
labeled with the study name, the subject identification number, date of issue, identified as a 
defective return, non-defective return, or AE (as applicable). All tracking information must be 
retained in the event the package has been lost and requires tracking. All investigational 
devices should be returned to:  
 
ATTN: Complaints Lab 
Biosense Webster, Inc.  
15715 Arrow Highway 
Irwindale, CA 91706 USA 
 
19. Clinical Monitoring 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved 

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protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). Each site 
will undergo periodic monitoring of the study, which involves a visit from a Sponsor 
representative, qualified to perform such visit.  Monitoring visits may include, but are not 
limited to, the following: 
- 
Protocol adherence 
- 
Source documentation verification and accuracy of the eCRFs  
- 
Verification that informed consent is being obtained for all subjects participating in the 
study in accordance with requirements described in the study protocol 
- 
Verification of completeness of the site file 
- 
Verification of accuracy of all study logs such as the Delegation of Responsibility Log, etc.  
- 
Compliance with applicable regulations 
- 
Identification and action to resolve any issues or problems with the study. 
 
Data are to be submitted promptly via e-CRF after collection. Missing or unclear data will be 
corrected as necessary throughout the trial. Biosense Webster will request further 
documentation such as physician and/or cardiac EP lab procedure notes when complications 
or malfunctions are observed and reported. 
 
Further details on clinical monitoring are provided in the study specific monitoring plan. 
 
 
20. Statistical Methodology 
 
The Sponsor will be responsible for the overall analysis of data from this protocol. A separate 
Statistical Analysis Plan (SAP) will be written and approved prior to database lock. The SAP will 
describe all planned analyses based on the statistical design of this study and the subsequent 
data collected. A brief statistical overview of key statistical analyses is provided below. 
 
Wave I will serve as characterization of safety and provide preliminary estimates for safety 
and acute effectiveness of the system under study, accordingly all analyses of Wave I data are 
planned to be descriptive. Only Wave II subject data will be used for the purpose of primary 
hypothesis testing. 
20.1 
Levels of Significance 
Significance levels and the type-I error control for the interim and final analyses of the primary 
endpoints are specified below in the applicable sections describing the analyses. 
 
20.2 
Sample Size Justification 
 
As Wave I of the study is a safety characterization phase, a sample size of 40 subjects is 
intended to delineate safety and provide preliminary estimates for safety and acute 
effectiveness of the IRE system. The maximum enrollment of 40 subjects will provide greater 
than 90% probability of observing at least one primary AE, assuming the PAE rate is 7% and 
that 35 of the enrolled subjects have the study catheter inserted.   
 
A Bayesian adaptive design will be utilized to select the final sample size for Wave II of the 
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Two interim analyses will be performed for sample size selection and the details will be 
provided in the statistical analysis plan (SAP).  Predictive probabilities of success for the 
primary effectiveness endpoint will be used to determine whether the sample size at the time 
of the interim analysis will be sufficient or if Wave II enrollment will continue to the full sample 
size of 330. 
 
Trial simulations were performed to estimate the power for the success of the trial under a 
range of assumptions for the true safety and effectiveness rates. Based on the simulation 
results for the most likely scenario (assumed safety rate of 7.0% and effectiveness rate of 
65%), the power for showing success for both safety and effectiveness endpoints is above 
80.0% and adequate. 
 
Simulations were also performed to estimate the overall Type-I error for the trial under 
various hypothetical scenarios. The highest Type-I error rates were reached in the following 
two scenarios:  
 
1. The true primary safety rate was on the decision boundary (i.e. equal to 14%) and 
the device was assumed to be effective. The Type-I error for this scenario was 
estimated to be 0.0191 with a 95% confidence interval of (0.0156 , 0.0189).  
2. The true primary effectiveness rate was on the decision boundary (i.e. equal to 
50%) and the devices was assumed to be safe. The Type-I error for this scenario 
was estimated to be 0.0145 with a 95% confidence interval of (0.0152 , 0.0185).  
 
As the primary safety or effectiveness rates moves away from the decision boundary, the 
overall Type-I error decreases. Therefore, considering all scenarios, the overall Type-I error for 
claiming success for both safety and effectiveness endpoints was controlled at 2.5%. 
Additional details on the simulation results will be provided in the SAP and the study 
Simulation Report.  
 
Based on the simulation results, the study is adequately powered to meet the primary safety 
and effectiveness endpoints and overall Type-I error is controlled at 2.5%. 
 
20.3 
Analysis Sets  
 
20.3.1 Wave I Analysis Sets 
 
• 
Modified Intent-To-Treat (mITT-Wave I) Analysis Set: The mITT-Wave I analysis set will 
consist of enrolled Wave I subjects who meet eligibility criteria and have had insertion of 
the study catheter. Subjects in this analysis set who are discontinued due to: 
o study catheter related reasons will be considered acute effectiveness failures 
o non-study catheter related reasons (other equipment, pump, anatomy that 
precludes treatment with the study catheter or commercially available catheter) will 
be excluded from the effectiveness analysis. 
 

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• 
Full Analysis Set (FAS- Wave I): The FAS-Wave I Analysis Set will consist of all enrolled 
Wave I subjects who have had insertion of the study catheter (with or without delivery 
of PFA). 
 
• 
Per Protocol Analysis Set (PP-Wave I): The PP-Wave I analysis set will consist of Wave I 
subjects who satisfy the following criteria: 
o are enrolled and without major protocol deviations that would affect the integrity 
of the data  
o have undergone ablation (PFA) with the study catheter 
o are treated for the study-related arrhythmia 
o did not require the use of a non-study catheter for Pulmonary Vein Isolation (PVI) 
o did not require ablations outside the PV region 
20.3.2 Wave II Analysis Sets 
 
• 
Modified Intent-To-Treat (mITT-Wave II) Analysis Set: The mITT-Wave II analysis set will 
consist of enrolled Wave II main study phase subjects who meet eligibility criteria and 
have had insertion of the study catheter. Subjects in this analysis set who are 
discontinued due to: 
o study catheter related reasons will be considered acute effectiveness failures 
o non-study catheter related reasons (other equipment, pump, anatomy that 
precludes treatment with the study catheter or commercially available catheter) will 
be excluded from the effectiveness analysis. 
 
• 
Full Analysis set (FAS-Wave II): The FAS-Wave II Analysis Set will consist of all enrolled 
Wave II main study phase subjects who have had insertion of the study catheter (with or 
without delivery of PFA). 
 
• 
Per Protocol (PP-Wave II) Analysis Set: The PP-Wave II analysis set will consist of Wave 
II main study phase subjects who satisfy the following criteria: 
o are enrolled and without major protocol deviations that would affect the integrity 
of the data  
o have undergone ablation (PFA) with the study catheter 
o are treated for the study-related arrhythmia 
o did not require the use of a non-study catheter for Pulmonary Vein Isolation (PVI) 
o did not require ablations outside the PV region 
• 
Roll-In Analysis Set: The Roll-In analysis set will include all subjects who are enrolled in 
the roll-in phase. All endpoints will be analyzed for the roll-in analysis set separately. 
 
20.4 
Analyses to be Conducted 
20.4.1 General Conventions 
Standard descriptive summaries for continuous data include the number of observations with 
data, number of observations with missing data, mean, standard deviation, median, 25% 
percentile, 75% percentile, minimum, and maximum values. For categorical data, the count 

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and percent will be provided. Percentages will be based on the number of subjects without 
missing data. 
 
20.4.2 Disposition and Study Subjects 
Disposition and accountability of the study subjects will be summarized descriptively for the 
subject categories defined in section 10.3. 
 
20.4.3 Demographic and Baseline Characteristics 
Subject demographics, medical history, previously failed AADs, active AAD use (still 
administered) and other baseline data will be summarized descriptively for subjects in the 
mITT-Wave I and FAS-Wave I analysis sets. These characteristics will also be summarized 
descriptively for subjects in mITT-Wave II, FAS-Wave II, PP-Wave II, and Roll-in analysis set for 
Wave II subjects. 
 
20.4.4 Primary Endpoint Analyses and Associated Hypotheses 
The primary safety endpoint will be summarized descriptively in the mITT-Wave I analysis set 
after all Wave I subjects complete the 12-month follow-up. Similarly, the primary 
effectiveness endpoint will be summarized descriptively in the PP-Wave I analysis set after all 
Wave I subjects complete the 12-month follow-up. 
For the main study phase, the PAE rate will be formally compared against a performance goal 
of 14%. Additionally, the primary effectiveness success rate will be compared to a 
performance goal of 50% for the main study phase. The primary safety endpoint analysis for 
the main phase will be performed in the mITT-Wave II analysis set and the primary 
effectiveness analysis will be performed in the PP-Wave II analysis set.  
 
20.4.4.1 
Interim Analysis for Sample Size Selection for the Main Study Phase 
The sample size for the main study phase is primarily driven by the primary effectiveness 
endpoint.  The methods described in Broglio et al.71 will be used for adaptive determination 
of the sample size based on the effectiveness endpoint alone. Mutiple sample size selection 
interim analyses will be performed when pre-specified enrollment targets described in the 
SAP are reached in the mITT-Wave II analysis set.  
To estimate the predictive probability of success at each sample size selection interim analysis, 
time-to-failure during the 9-month (39 weeks) post-blanking period will be modeled using a 
piecewise exponential model with three distinct intervals (from (0,2], (2,8], and (8,39] weeks).  
The time intervals were chosen to adequately capture the functional form of the survival 
function by taking into account the timing of the occurrence of documented AF/AT or AFL 
events based on previous studies. The probability of a failure during each interval is assumed 
to be exponentially distributed, with a different hazard rate.  The model is: 
 
𝑓(𝑡) = exp(−𝑡∗ℎ(𝑡)) 
Where  
ℎ(𝑡) = {
𝜆1        0 < 𝑡≤2
𝜆2        2 < 𝑡≤8
𝜆3      8 < 𝑡≤39
 
 

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Vague Gamma prior distributions will be assumed for 𝜆1, 𝜆2 and 𝜆3.  
 
The predictive probabilities of success for the effectiveness endpoint will be estimated using 
Monte Carlo integration (details will be provided in the SAP). Enrollment will be stopped at an 
interim if the predictive probability of success for the effectiveness endpoint with the sample 
size at the time of the interim is greater than 90.0%, or if the predictive probability of success 
for the effectiveness endpoint with the maximum sample size of 330 subjects is less than a 
futility threshold of 2.5%. Otherwise, enrollment will continue to the next sample size 
selection interim or the final sample size of 330 subjects.  
 
Additional details on estimation of the predictive probabilities will be provided in a separate 
simulation report and in the Statistical Analysis Plan.  
 
Analysis of the primary safety endpoint will be performed using the final sample size that is 
selected adaptively based on the primary effectiveness endpoint. All sample sizes from the 
interim sample selections will provide greater than 80% power for the primary safety 
endpoint assuming a PAE composite rate of <7% and a performance goal of 14%. 
 
20.4.4.2 
 Early Success Interim Analysis for the Main Study Phase 
An interim analysis will be performed for claiming early trial success in Wave II when 30 
subjects in the PP-Wave II analysis set reach full 12-month of follow-up and all subjects in the 
mITT-Wave II analysis set reach three months of follow-up.  At this interim, the trial will 
declare early success if both safety and effectiveness objectives are met: 
 
1. The posterior probability of the safety rate being less than 14% is greater than 0.975 
2. The posterior probability of the effectiveness proportion 𝑝𝐸 being greater than 50% is 
greater than 0.9975. 
 
For Primary Safety Endpoint: 
The primary safety endpoint analysis performed at this interim will include 3-month safety 
follow-up for all mITT-Wave II subjects and will be the same as the final safety endpoint 
analysis.  
 
A beta-binomial model with a non-informative uniform prior will be used for the primary 
safety rate. The uniform prior for the safety rate will be updated based on the observed 
number of events to obtain the posterior distribution for the primary safety rate. If the 
posterior probability of the safety rate being less than 14% is greater than 0.975, the early 
success primary safety endpoint will have been met.  
The null and alternative hypotheses for the safety endpoint for the early success interim 
analysis are: 
H0: Pr(Ps < 0.14) ≤ 0.975 
Ha: Pr(Ps < 0.14) > 0.975 
 

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Primary Effectiveness Endpoint 
 
In case early success is achieved, the study will continue to follow up the subjects for the full 
follow-up duration, and the primary effectiveness endpoints based on full 12-month follow-
up data will be descriptively summarized in subjects in the PP-Wave II analysis set. The early 
success effectiveness analysis will be performed in the PP-Wave II analysis set. At the time of 
the early success interim analysis, the posterior distribution for the 12-month effectiveness 
proportion will be estimated by using the piecewise exponential model described in 
20.4.4.1￼. Early success effectiveness will be demonstrated if the 𝑝𝐸￼ being greater than 
50% is greater than 0.9975.  
 
For the early success interim analysis, the total number of primary effectiveness events and 
the total subject exposure time will be used to update the vague Gamma priors for the 
hazard rates and obtain posterior Gamma distributions for three segments of the 
effectiveness model. Next, 10,000 random hazard rates will be sampled from the posterior 
distribution for each segment and each triplet set of hazard rates will be used to estimate a 
single 12-month effectiveness rate. The posterior distribution of the 12-month rate is 
estimated based on the 10,000 simulated rates.  Using this distribution, if the probability of 
the 12-month effectiveness rate being greater than 50% is greater than 0.9975(99.75%), the 
trial will declare early success for the effectiveness endpoint. 
 
The null and alternative hypotheses for the primary effectiveness endpoint for the early 
success interim analysis are: 
H0: Pr(PE > 0.50) ≤ 0.9975 
Ha: Pr(PE > 0.50) > 0.9975 
 
where PE is the 12-month effectiveness rate. 
 
 
20.4.4.3 
Final Analysis for the Main Study Phase 
 
If early success is not achieved, then the final effectiveness analysis will be based on complete 
follow-up data for the primary effectiveness endpoint as described in this section. If trial 
success is achieved at the early success interim analysis, then the final analysis for the 
effectiveness endpoint will involve descriptive statistics on the full follow-up effectiveness 
data in the mITT-Wave II and PP-Wave II analysis sets.  
 
For Primary Safety Endpoint: 
The final primary safety endpoint analysis is the same analysis performed at the early success 
interim as all safety data is available at the time of the early success interim look. A beta-
binomial model will be used for this analysis. A non-informative uniform prior will be assumed 
for the primary safety proportion. The primary safety endpoint will be considered a success if  
Pr(PS < 0.14) > 0.975 
 

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The analysis population for the primary safety endpoint will be the mITT-Wave II analysis set. 
If the posterior probability of the safety rate being less than 14% is greater than 0.975, then 
the study will be considered to have demonstrated safety of the device. 
 
For Primary Effectiveness Endpoint: 
If trial success is not declared at the early success interim, the final analysis for the primary 
effectiveness endpoint will use a beta-binomial model similar to the primary safety endpoint 
analysis. A non-informative uniform prior will be assumed for the primary effectiveness rate.  
 
At the time of the final analysis, the trial will be considered a success if  
 
Pr(PE > 0.50) > 0.9775 
 
The analysis population for the primary effectiveness endpoint will be the PP-II analysis set. If 
the posterior probability of the effectiveness rate being greater than 50% is higher than 
0.9775, the study will be considered to have demonstrated effectiveness of the device. 
 
20.4.4.4 
Handling of Missing Data  
 
If a subject has not completed 12 months of follow-up but has had a PAE, then the subject will 
be considered an event for the final primary safety analysis.  If a subject’s follow-up time is 
less than 12 months and the subject has not had a PAE, then that subject will be excluded 
from the primary safety analysis.  
 
For the early success interim analysis of the primary effectiveness endpoint, the subjects with 
incomplete follow-up data who are event free will be censored at the time of their last follow-
up visit, and only their observed partial follow-up time will contribute to estimating model 
parameters. 
 
For the final primary effectiveness analysis, if a subject has an effectiveness failure at any time 
during the evaluation period, then the subject will be considered an event. Subjects without 
an effectiveness failure who do not have full 12 months of follow-up will be excluded from the 
final primary effectiveness analysis. 
 
20.4.4.5 
Sensitivity Analyses 
To investigate the robustness of the analysis result for the primary endpoints, several 
sensitivity analyses will be performed. Details on these analyses will be provided in SAP. 
 
20.4.4.6 
Subgroup Analyses 
Subgroup analyses by clinically relevant factors will be performed and details will be 
provided in SAP. 
 
 
 

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20.4.5 Secondary Endpoint Analysis  
 
All secondary endpoints will be summarized based on the full 12-month follow-up data of 
subjects in the mITT-Wave II analysis sets.  
 
Acute Procedural Success: The rate of acute procedural success (defined in section 8.2.2) 
will be summarized descriptively. 
 
Freedom from Documented Symptomatic Recurrence:  The rate of freedom from 
documented symptomatic atrial arrhythmia (atrial fibrillation (AF), atrial tachycardia (AT) or 
atrial flutter (AFL)) episodes will be summarized descriptively. 
 
Quality of Life (QOL):  AFEQT scores assessed at baseline and follow-up visits will be 
summarized and compared descriptively. 
 
 
20.4.6 Additional Endpoint Analyses 
No formal statistical hypothesis and inferential statistics will be formulated and performed for 
the additional endpoints. Additional safety endpoints will be analyzed in Roll-in, Safety and 
mITT analysis sets for respectively Wave I and Wave II.  Effectiveness endpoints and procedural 
data will be analyzed in FAS and PP analysis sets for respectively Wave I and Wave II. NAE, 
CT/MRA, and esophageal lesion endpoints will be analyzed in the mITT-Wave I analysis set. All 
endpoints will be analyzed for the roll-in analysis set separately. Details of the analyses will be 
described in the SAP.  
 
21. Ethics and Protection of Human Subjects 
21.1 
Ethical Standard 
As the Sponsor of this study, Biosense Webster has the overall responsibility for the conduct 
of the study, including assurance that the study meets the regulatory requirements of the 
Food and Drug Administration (FDA), applicable European medical device regulation and the 
local government. For study under MDR, MDR2017/745 will be applicable, amending Directive 
2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing 
Council Directives 90/385/EEC and 93/42/EEC. 
The Sponsor will also maintain compliance with GCP (ICH E6 (R2), 9 November 2016), the 
European standard EN ISO 14155 (Clinical Investigation of Medical Devices for Human 
Subjects), the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human 
Subjects, Fortaleza 2013), Sponsor general duties (21 CFR 812.40), selection of investigators 
(21 CFR 812.43), monitoring (21 CFR 812.46), supplemental applications (21 CFR 812.35 [a] 
and [b]), maintaining records (21 CFR 812.140 [b]), and submitting reports (21 CFR 812.150 
[b)]), and to local regulations where required. 
 
• 
General Duties  
Biosense Webster’s general duties consist of submitting the clinical investigation 
application to appropriate regulatory agencies, assuring that sites have received EC 

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approvals prior to shipping the devices, selecting investigators, ensuring proper 
clinical site monitoring and ensuring subject informed consent is obtained. 
 
• 
Data Quality and Reporting 
Biosense Webster is responsible for providing quality data that satisfy federal 
regulations and informing proper authorities of serious unanticipated AEs and 
deviations from the protocol.   
 
• 
Selection of Investigators 
All potential investigational sites will undergo an evaluation to ensure that the site 
has the appropriate facilities and personnel to conduct the study in compliance with 
the clinical investigational plan. Based on outcome of evaluation process, Biosense 
Webster will select qualified investigators, ship devices only to participating 
investigators, obtain a signed Investigator’s Agreement and provide the investigators 
with the information necessary to conduct the study. 
 
• 
Supplemental Applications  
As appropriate, Biosense Webster will submit changes in the Clinical Investigational 
Plan to the investigators to obtain all applicable re-approvals. 
 
• 
Maintaining Records  
Biosense Webster will maintain copies of correspondence, data, adverse device 
effects and other records related to the study. Biosense Webster will maintain records 
related to the signed Investigator Agreements. 
 
• 
Submitting Reports  
Biosense Webster will submit any required regulatory reports identified in this section 
of the regulation.  This may include UADEs, withdrawal of EC approval, current 
investigators list, annual progress reports, recall information, final reports and 
protocol deviations.  
 
21.2 
Informed Consent Process 
 
21.2.1 Informed Consent Procedure and Documentation 
 
Subjects informed consent must be obtained and documented according to the principles of 
informed consent in the latest version of the Declaration of Helsinki (Fortaleza, 2013), ISO 
14155, and approved by the reviewing CA and EC. 
 
Informed consent is mandatory and must be obtained from all subjects prior to their 
participation in the study. 
 
Prior to screening or performing any study related procedures that are solely for the purpose 
of determining eligibility for this study, any potential benefits and risks of the study must be 
explained to the subject. Subjects will be informed about aspects of the study that are relevant 
to the subject's decision to participate. Subjects should be made aware that by signing the ICF, 
they are granting approval for study personnel to review their medical records and to 
collect/analyze personal medical information. Subjects should also be informed that study 
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The ICF will be written in a native, non-technical, language that is understandable to the 
subject and is to be approved by the applicable EC prior to enrolling subjects. The subject or 
designee will be provided with ample time to read and understand the ICF and to consider 
participation in the study. Informed consent will be requested prior to enrollment and must 
be personally signed and dated by the subject, or subject’s legal representative, prior to 
performance of any study related activity or procedure. If a subject is unable to read or write, 
informed consent shall be obtained through the aid of an independent witness who will be 
present throughout the process. The written ICF and any other information shall be read aloud 
and explained to the prospective subject and, whenever possible, subject shall sign and date 
the ICF. The witness must also sign and date the ICF attesting that the information was 
accurately explained, and that informed consent was freely given. The point of enrollment 
corresponds with the time that subjects signs the informed consent. 
 
The investigator and/or designee must also clearly document the process of obtaining 
informed consent in the subject’s source documents. The voluntary process of obtaining 
informed consent confirms the subject’s willingness to participate in the study. It’s the 
investigator’s responsibility to ensure that the informed consent process is performed in 
accordance with ICH-GCP and, where applicable, local and federal regulations. Subjects should 
not be coerced, persuaded, or unduly influenced to participate or continue to participate in 
the trial. Subjects or his/her legal representative must be given ample time and opportunity 
to inquire about details of the trial and all questions about the trial should be answered to the 
satisfaction of the patient or the representative. Failure to provide written informed consent 
renders the subject ineligible for the study. If new information becomes available that can 
significantly affect a subject’s future health and/or medical care, this information shall be 
provided to the subject(s) affected in written form. If relevant, all affected subjects shall be 
asked to confirm their continuing informed consent in writing by dating and signing the 
amended ICF. 
 
21.3 
Participant and Data Confidentiality 
During this clinical investigation, all representatives of the Sponsor will comply with all in-
country privacy laws and regulations regarding contact with subjects, their medical record 
information, copying of information, and protection of the subject identities. 
 
All information and data sent to Biosense Webster concerning subjects or their participation 
in this clinical investigation will be considered confidential. Only authorized Biosense Webster 
personnel or representatives (including contracted service providers, i.e. Core Lab, Clinical 
Research Associate, CRO, etc.), representatives of the FDA or CAs acting in their official 
capacities will have access to these confidential files upon request (including, but not limited 
to, laboratory test result reports, ECG reports, admissions/discharge summaries for hospital 
admission occurring during a patient’s study participation and autopsy reports for deaths 
occurring during the clinical investigation). Some of the countries to which the study subjects 
and investigators personal data may be transferred may not offer as comprehensive a level of 
protection of personal data as within the European Union but Sponsor will take all reasonable 
steps to ensure a sufficient level of data protection. All data used in the analysis and reporting 
of this evaluation will exclude identifiable reference to the subject. 
 
 
 
 

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21.3.1 Research Use of Stored Data 
 
• 
Intended Use: Data collected under this protocol may be used to study AF. 
• 
Storage: Access to stored data will be limited. Data will be stored using codes assigned by 
the sponsor. Data will be kept in password-protected computers. Only investigators and 
the sponsor will have access to the data. 
 
22. Source Documents and Access to Source Data/Documents 
Data entered on to the eCRFs will be taken from source documentation, such as hospital 
procedure reports, admission and discharge summaries, other hospital or investigator 
office/clinic documents, and system data (CARTO, generator system).  If unique study 
parameters are not documented on standard hospital or office reports, a worksheet may be 
developed to record this information.  The worksheet shall be signed by the PI or authorized 
designee and will serve as source document and as basis for monitoring the eCRFs.  Electronic 
subject records will be considered as source documents on the condition that the hospital’s 
database is a validated system.  If this is not the case, electronic records should be printed and 
added to the subject’s paper file.  A print-out of a completed eCRF cannot be used as source 
documentation.  
 
Investigators should maintain information in the subject’s medical records, which corroborate 
data collected on the eCRFs.  In order to comply with these regulatory requirements, at 
minimum, the following is a list of information that should be maintained. 
• 
Medical history/physical condition of the study subject before involvement in the 
study sufficient to verify protocol selection criteria (if not already present). 
• 
Dated and signed notes from the day of entry into the study including the study 
Sponsor (Biosense Webster), protocol number, clinical site, subject number assigned 
and a statement that consent to participate in the study was obtained. 
• 
Dated and signed notes from each study visit with reference to the eCRFs for further 
information, if appropriate (for specific results of procedures and exams). 
• 
Reports on AEs and their resolution, including supporting documents such as 
discharge summaries, EP lab reports, ECGs, lab results. 
• 
Notes regarding protocol-required medication and prescription medications taken 
during the study (including start and stop dates). 
• 
Notes on subject’s condition upon completion of or withdrawal from the study. 
 
Only authorized Biosense Webster personnel or representatives, authorized site personnel, 
local government authorities, or the FDA, acting in their official capacities, will have access to 
these confidential files. 
 
23. Quality Assurance and Quality Control 
 
Quality Control (QC) procedures will be implemented beginning with the data entry system 
and ongoing QC checks will be run on the database. Any missing data or data anomalies will 
be communicated to the site(s) for clarification/resolution.  
 
Following written SOPs, monitors will verify that the clinical trial is conducted and data are 
generated, documented, and reported in compliance with the protocol, GCP, and the 

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applicable regulatory requirements. If noncompliance is identified, Sponsor is required by 
regulation to implement measures to secure compliance.  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and CAs. 
 
24. Data Handling and Record Keeping 
24.1 
Data Collection and Management Responsibility 
 
The Sponsor will be responsible for all data management activities. These activities include 
development of an EDC system and utilizing a validated EDC system into which all study data 
will be entered. The Sponsor will be responsible for reviewing all data to ensure the overall 
integrity of the database. 
 
24.1.1 Data Collection 
eCRFs will be used to collect all subject data during this clinical investigation. eCRFs have been 
developed to capture the information outlined in this clinical investigation Plan. Modification 
to the eCRF will only be made if deemed necessary by the sponsor. Data on these eCRFs will 
be monitored (source verified) and the monitor will ask the site representative to correct if 
necessary, to match the source documents. All changes made to the data will be tracked in 
the electronic audit trail. The investigator will be required to sign designated eCRFs as 
verification that they have been reviewed and the data entered are correct. Data from these 
eCRFs will be used to provide analysis of this clinical investigation.  
 
24.1.2 Data Reporting 
The investigator, or a designated individual, is responsible for ensuring that clinical 
investigation data are timely and properly recorded on each subject’s eCRF and related 
documents. The investigator, or a designated individual, is required to electronically sign the 
eCRF on the appropriate pages to verify that he/she has reviewed and attests to the 
correctness of the recorded data. Completed eCRF will be reviewed and monitored by the 
sponsor personnel, or an appropriately qualified and trained designee, throughout the clinical 
investigation. To this end, the Investigator and institution must permit inspection of the trial 
files and subject eCRFs by such representatives and/or responsible government agencies. 
 
Investigators are required to prepare and submit accurate and timely reports on this study to 
the governing EC and Biosense Webster. 
  
 
 

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25. Study Suspension or Termination 
 
This study may be temporarily suspended or prematurely terminated at the discretion of the 
Sponsor. The Sponsor may also terminate a site prior to study completion if the Sponsor 
believes the site is no longer capable of participating (e.g., cannot fulfill subject enrollment or 
protocol compliance goals, site suspension by EC). If the study is prematurely terminated or 
suspended, the PI will promptly inform the EC and will provide the reason(s) for the 
termination or suspension.  
 
If suspension or premature termination occurs, the terminating party shall justify its decision 
in writing and promptly inform the other parties with whom they are in direct communication. 
The PI and sponsor shall keep each other informed of any communication received from either 
the EC or the CA. 
 
If early termination of the study is required due to safety concerns, each site will undergo a 
monitoring visit to conclude any outstanding issues, collect all outstanding CRF information, 
verify device accountability, and discuss any other items relevant to the conclusion of the 
study. Any enrolled subjects will continue to be followed per the study protocol requirements. 
 
If, for any reason, the sponsor suspends or prematurely terminates the study at an individual 
study site, the sponsor shall inform the responsible CA as appropriate and ensure that the EC 
is notified, either by the PI or by the sponsor. If the suspension or premature termination was 
in the interest of safety, the sponsor shall inform all other PIs. 
  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality is addressed 
and satisfy the sponsor, EC and regulatory agency. 
 
26. Data and Publication Policy 
Publications and/or presentation of clinical investigation results will be coordinated and 
governed between Biosense Webster, Inc., the clinical investigation author(s) and if applicable 
local law. Authorship will be determined prior to development of any manuscript. All 
information concerning the study, investigational medical device, sponsor operations, patent 
application, manufacturing processes, and basic scientific data supplied by the sponsor to the 
investigator and not previously published, are considered confidential and remain the sole 
property of the sponsor.  
 
27. Document Filing 
A copy of all approved versions of the Investigation Protocol will be kept, by the site, in the 
Investigator Site File and in the Sponsor Trial Master File. 
 
 
 

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28. Scientific References 
 
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January, C.T., et al., 2014 AHA/ACC/HRS Guideline for the Management of Patients With 
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3. 
Calkins, H., et al., 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on 
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Kirchhof, P., et al., 2016 ESC Guidelines for the management of atrial fibrillation developed in 
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January, C.T., et al., 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS 
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Jackman, W.M., et al., Catheter ablation of accessory atrioventricular pathways (Wolff-
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Wilber, D.J., et al., Comparison of antiarrhythmic drug therapy and radiofrequency catheter 
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Marrouche, N.F., et al., Circular mapping and ablation of the pulmonary vein for treatment of 
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Oral, H., et al., Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. 
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Pappone, C., et al., Atrial electroanatomic remodeling after circumferential radiofrequency 
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Haissaguerre, M., et al., Electrophysiological breakthroughs from the left atrium to the 
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Nademanee, K. and B.A. Gidney, Pulmonary vein isolation without reconnection: a decade of 
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Sauer, W.H., et al., Clinical predictors and outcomes associated with acute return of 
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Cappato, R., et al., Prospective assessment of late conduction recurrence across 
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Cappato, R., et al., Updated worldwide survey on the methods, efficacy, and safety of 
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Arena, C.B., et al., High-frequency irreversible electroporation (H-FIRE) for non-thermal 
ablation without muscle contraction. Biomed Eng Online, 2011. 10: p. 102. 

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18. 
Gerstenfeld, E.P., Catheter Ablation of Atrial Fibrillation Using Electroporation: Back to the 
Future? JACC Clin Electrophysiol, 2018. 4(8): p. 996-998. 
19. 
Lee, A. and E.P. Gerstenfeld, Electroporation-Application beyond pulmonary vein isolation? J 
Cardiovasc Electrophysiol, 2019. 30(9): p. 1410-1411. 
20. 
Maor, E., et al., Pulsed electric fields for cardiac ablation and beyond: A state-of-the-art 
review. Heart Rhythm, 2019. 16(7): p. 1112-1120. 
21. 
Reddy, V.Y., et al., Pulsed Field Ablation for Pulmonary Vein Isolation in Atrial Fibrillation. J 
Am Coll Cardiol, 2019. 74(3): p. 315-326. 
22. 
Stewart, M.T., et al., Intracardiac pulsed field ablation: Proof of feasibility in a chronic 
porcine model. Heart Rhythm, 2019. 16(5): p. 754-764. 
23. 
Sugrue, A., et al., Irreversible electroporation for catheter-based cardiac ablation: a 
systematic review of the preclinical experience. J Interv Card Electrophysiol, 2019. 55(3): p. 
251-265. 
24. 
Caluori, G., et al., Irreversible electroporation-Let's keep it cool. J Cardiovasc Electrophysiol, 
2018. 29(7): p. E12. 
25. 
Wojtaszczyk, A., et al., Irreversible electroporation ablation for atrial fibrillation. J Cardiovasc 
Electrophysiol, 2018. 29(4): p. 643-651. 
26. 
Frandsen, S.K., et al., Direct therapeutic applications of calcium electroporation to effectively 
induce tumor necrosis. Cancer Res, 2012. 72(6): p. 1336-41. 
27. 
Tracy, C.R., W. Kabbani, and J.A. Cadeddu, Irreversible electroporation (IRE): a novel method 
for renal tissue ablation. BJU Int, 2011. 107(12): p. 1982-7. 
28. 
Schoellnast, H., et al., The delayed effects of irreversible electroporation ablation on nerves. 
Eur Radiol, 2013. 23(2): p. 375-80. 
29. 
Lavee, J., et al., A novel nonthermal energy source for surgical epicardial atrial ablation: 
irreversible electroporation. Heart Surg Forum, 2007. 10(2): p. E162-7. 
30. 
Neven, K., et al., Epicardial ablation: prevention of phrenic nerve damage by pericardial 
injection of saline and the use of a steerable sheath. Indian Pacing Electrophysiol J, 2014. 
14(2): p. 87-93. 
31. 
Neven, K., et al., Myocardial lesion size after epicardial electroporation catheter ablation 
after subxiphoid puncture. Circ Arrhythm Electrophysiol, 2014. 7(4): p. 728-33. 
32. 
Neven, K., et al., Epicardial linear electroporation ablation and lesion size. Heart Rhythm, 
2014. 11(8): p. 1465-70. 
33. 
Neven, K., et al., Safety and feasibility of closed chest epicardial catheter ablation using 
electroporation. Circ Arrhythm Electrophysiol, 2014. 7(5): p. 913-9. 
34. 
Wittkampf, F.H., et al., Myocardial lesion depth with circular electroporation ablation. Circ 
Arrhythm Electrophysiol, 2012. 5(3): p. 581-6. 
35. 
Zager, Y., et al., Optimization of Irreversible Electroporation Protocols for In-vivo Myocardial 
Decellularization. PLoS One, 2016. 11(11): p. e0165475. 
36. 
DeSimone, C.V., S. Kapa, and S.J. Asirvatham, Electroporation: past and future of catheter 
ablation. Circ Arrhythm Electrophysiol, 2014. 7(4): p. 573-5. 
37. 
van Driel, V.J., et al., Low vulnerability of the right phrenic nerve to electroporation ablation. 
Heart Rhythm, 2015. 12(8): p. 1838-44. 
38. 
Schoellnast, H., et al., Acute and subacute effects of irreversible electroporation on nerves: 
experimental study in a pig model. Radiology, 2011. 260(2): p. 421-7. 
39. 
Tam, A.L., et al., Irreversible electroporation of the lumbar vertebrae in a porcine model: is 
there clinical-pathologic evidence of neural toxicity? Radiology, 2014. 272(3): p. 709-19. 
40. 
Li, W., et al., The effects of irreversible electroporation (IRE) on nerves. PLoS One, 2011. 6(4): 
p. e18831. 
41. 
Hong, J., et al., Cardiac ablation via electroporation. Conf Proc IEEE Eng Med Biol Soc, 2009. 
2009: p. 3381-4. 

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42. 
van Driel, V.J., et al., Pulmonary vein stenosis after catheter ablation: electroporation versus 
radiofrequency. Circ Arrhythm Electrophysiol, 2014. 7(4): p. 734-8. 
43. 
Kuck, K., J. Brugada, and J. Albenque, Cryoballoon or Radiofrequency Ablation for Atrial 
Fibrillation. N Engl J Med, 2016. 375(11): p. 1100-1. 
44. 
Dukkipati, S.R., et al., Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: 
Results of the U.S. Feasibility Study. J Cardiovasc Electrophysiol, 2015. 
45. 
Reddy, V.Y., et al., Randomized, Controlled Trial of the Safety and Effectiveness of a Contact 
Force-Sensing Irrigated Catheter for Ablation of Paroxysmal Atrial Fibrillation: Results of the 
TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) Study. 
Circulation, 2015. 132(10): p. 907-15. 
46. 
Natale, A., et al., Paroxysmal AF catheter ablation with a contact force sensing catheter: 
results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol, 2014. 64(7): p. 647-
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47. 
Chavez, P., et al., Atrioesophageal fistula following ablation procedures for atrial fibrillation: 
systematic review of case reports. Open Heart, 2015. 2(1): p. e000257. 
48. 
Neven, K., et al., Acute and Long-Term Effects of Full-Power Electroporation Ablation Directly 
on the Porcine Esophagus. Circ Arrhythm Electrophysiol, 2017. 10(5). 
49. 
Witt, C.M., et al., Intrapulmonary Vein Ablation Without Stenosis: A Novel Balloon-Based 
Direct Current Electroporation Approach. J Am Heart Assoc, 2018. 7(14). 
50. 
Bradley, C.J. and D.E. Haines, Pulsed Field Ablation for Pulmonary Vein Isolation in the 
Treatment of Atrial Fibrillation. J Cardiovasc Electrophysiol, 2020. 
51. 
Kovoor, P., et al., Risk to patients from radiation associated with radiofrequency ablation for 
supraventricular tachycardia. Circulation, 1998. 98(15): p. 1534-40. 
52. 
Nahass, G.T., Fluoroscopy and the skin: implications for radiofrequency catheter ablation. Am 
J Cardiol, 1995. 76(3): p. 174-6. 
53. 
Calkins, H., et al., Radiation exposure during radiofrequency catheter ablation of accessory 
atrioventricular connections. Circulation, 1991. 84(6): p. 2376-82. 
54. 
Lin, A.C. and D. Wilber, Complications associated with radiofrequency catheter ablation, in 
Radiofrequency Catheter Ablation of Cardiac Arrhythmias: Basic Concepts and Clinical 
Applications, S.K.S. Huang and D.J. Wilber, Editors. 2000, Futura Publishing Company, Inc.: 
Grouponk, NY. p. 737-746. 
55. 
Scheinman, M.M. and S. Huang, The 1998 NASPE prospective catheter ablation registry. 
Pacing Clin Electrophysiol, 2000. 23(6): p. 1020-8. 
56. 
Cox, B., M.E. Durieux, and M.A. Marcus, Toxicity of local anaesthetics. Best Pract Res Clin 
Anaesthesiol, 2003. 17(1): p. 111-36. 
57. 
Mertes, P.M. and M.C. Laxenaire, Allergic reactions occurring during anaesthesia. Eur J 
Anaesthesiol, 2002. 19(4): p. 240-62. 
58. 
Morcos, S.K., et al., Prevention of generalized reactions to contrast media: a consensus 
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59. 
Gruchalla, R.S., 10. Drug allergy. J Allergy Clin Immunol, 2003. 111(2 Suppl): p. S548-59. 
60. 
Bick, R.L. and E.P. Frenkel, Clinical aspects of heparin-induced thrombocytopenia and 
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61. 
Thomson, K.R., et al., Investigation of the safety of irreversible electroporation in humans. J 
Vasc Interv Radiol, 2011. 22(5): p. 611-21. 
62. 
Sugrue, A., et al., Feasibility of selective cardiac ventricular electroporation. PLoS One, 2020. 
15(2): p. e0229214. 
63. 
Deodhar, A., et al., Irreversible electroporation near the heart: ventricular arrhythmias can be 
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64. 
Kostrzewa, M., et al., Cardiac impact of R-wave triggered irreversible electroporation 
therapy. Heart Rhythm, 2018. 15(12): p. 1872-1879. 

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65. 
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asymmetrical waveform. Biomed Eng Online, 2019. 18(1): p. 75. 
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Calkins, H., et al., HRS/EHRA/ECAS expert consensus statement on catheter and surgical 
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(EHRA) and the European Cardiac Arrhythmia Society (ECAS); in collaboration with the 
American College of Cardiology (ACC), American Heart Association (AHA), and the Society of 
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29. Appendix 1 
 
Definitions on (long term) effectiveness terms are mentioned below 
 
Term 
Definition 
Recurrent AF/AT/AFL 
Recurrent AF/AFL/AT is defined as AF/AFL/AT of at least 30 seconds’ 
duration that is documented by an ECG or device recording system and 
occurs following catheter ablation. Recurrent AF/AFL/AT may occur 
within or following the post ablation blanking period. Recurrent 
AF/AFL/AT that occurs within the post-ablation blanking period is not 
considered a failure of AF ablation. 
Early recurrence of AF/AFL/AT 
Early recurrence of AF/AFL/AT is defined as a recurrence of atrial 
fibrillation within three months of ablation. Episodes of atrial 
tachycardia or atrial flutter should also be classified as a “recurrence.” 
These are not counted toward the success rate if a blanking period is 
specified. 
Recurrence of AF/AT/AFL 
Recurrence of AF/AFL/AT postablation is defined as a recurrence of 
atrial fibrillation more than 3 months following AF ablation. Episodes 
of atrial tachycardia or atrial flutter should also be classified as a 
“recurrence.” 
 
Electrocardiographical occurrences of new onset non left atrial 
arrhytmia’s, if confirmed by entrainment maneuvers during 
electrophysiology testing, should not be considered an ablation failure 
or primary effectiveness endpoint. Examples are: 
• 
CTI dependant AFL. Cavotricuspid isthmus-dependent atrial 
flutter is easily treated with cavotricuspid isthmus ablation 
and is not an iatrogenic arrhythmia following a left atrial 
ablation procedure for AF. 
• 
Atrioventricular nodal reentry tachycardia (AVNRT) 
Off AAD  
As assessed from the end of the 3-month blanking period (Day 91 or 
Day of the visit whatever comes last) to 12 months following the 
ablation procedure. 
 
Class I and III antiarrhythmic drug therapy, same dose as before 
procedure is not considered as failure 
Class I and III antiarrhythmic drug therapy, higher dose or newly 
prescribed after procedure is considered as failure 
 
Class I and III antiarrhythmic drug therapy prescribed for other 
arrhythmia’s than AF/AT/AFL is not considered as failure